This Is MS Multiple Sclerosis Knowledge & Support Community

Devil's claw:

1: Phytother Res. 2007 Dec;21(12):1228-33. Links
Effectiveness and safety of Devil's Claw tablets in patients with general rheumatic disorders.Warnock M, McBean D, Suter A, Tan J, Whittaker P.
School of Health Sciences, Queen Margaret University, Edinburgh EH12 8TS, Scotland.

Arthritis and other rheumatic conditions (AORC) are the leading cause of disability, are associated with poor quality of life and incur considerable direct and indirect costs. It is considered that the instance of AORC will continue to increase. To assess the effectiveness, safety and tolerability of Harpagophytum (Bioforce) in the treatment of AORC, a single group open study of 8 weeks duration (259 patients) was performed in the United Kingdom. Effectiveness was assessed by numeric rating scales, the Western Ontario and McMasters Universities Osteoarthritis (WOMAC) Index and the Algofunctional Hand Osteoarthritis Index. Tolerance was measured by a numeric rating scale and safety by self-reporting, blood analysis and liver function tests. Quality of life was measured by SF-12 questionnaire. There were statistically significant (p < 0.0001) improvements in patient assessment of global pain, stiffness and function. There were also statistically significant reductions in mean pain scores for hand, wrist, elbow, shoulder, hip, knee and back pain. Quality of life measurements (SF-12) were significantly increased from baseline and 60% patients either reduced or stopped concomitant pain medication. Harpagophytum is an effective and well-tolerated serious treatment option for mild to moderate degenerative rheumatic disorders providing improved quality of life measure. Copyright (c) 2007 John Wiley & Sons, Ltd.

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More devil's claw:

1: J Ethnopharmacol. 2006 Mar 8;104(1-2):149-55. Epub 2005 Oct 3. Links
Harpagoside suppresses lipopolysaccharide-induced iNOS and COX-2 expression through inhibition of NF-kappa B activation.Huang TH, Tran VH, Duke RK, Tan S, Chrubasik S, Roufogalis BD, Duke CC.
Pharmaceutical Chemistry and Herbal Medicines Research and Education Centre, Faculty of Pharmacy A15, University of Sydney, NSW 2006, Australia.

Preparations of Harpagophytum procumbens, known as devil's claw, are used as an adjunctive therapy for the treatment of pain and osteoarthritis. Pharmacological evaluations have proven the effectiveness of this herbal drug as an anti-inflammatory and analgesic agent. The present study has investigated the mechanism of action of harpagoside, one of the major components of Harpagophytum procumbens, using human HepG2 hepatocarcinoma and RAW 264.7 macrophage cell lines. Harpagoside inhibited lipopolysaccharide-induced mRNA levels and protein expression of cyclooxygenase-2 and inducible nitric oxide in HepG2 cells. These inhibitions appeared to correlate with the suppression of NF-kappaB activation by harpagoside, as pre-treating cells with harpagoside blocked the translocation of NF-kappaB into the nuclear compartments and degradation of the inhibitory subunit IkappaB-alpha. Furthermore, harpagoside dose-dependently inhibited LPS-stimulated NF-kappaB promoter activity in a gene reporter assay in RAW 264.7 cells, indicating that harpagoside interfered with the activation of gene transcription. These results suggest that the inhibition of the expression of cyclooxygenase-2 and inducible nitric oxide by harpagoside involves suppression of NF-kappaB activation, thereby inhibiting downstream inflammation and subsequent pain events.

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6/6/2008
The above give plenty of other options if my trial of curcumin, boswellia, withania, gentiana and rehmannia don't continue to improve my situation over the next few months. A few days ago I started the withania somnifera, taking 8 pills of 125mg a day. Rather like when I started the boswellia I think I have plunged in too excessively. My bad foot became really spongy feeling after I added the withania. This made walking rather more awkward. I also think my bladder control was weaker yesterday so today I have backed off to 4 a day.
The hayfever is back to about 50% of its venom so I may have to add some ganoderma lucidum to the mix but for the time being have turned on the air con and added some more anti-histamine.

7/6/2008
On Saturday the hayfever got worse as the weather improved so late in the day I added 4 grammes of ganoderma lucidum to the 3 pills daily of zirtek. As the evening drew in my hayfever, usually at its worst then, had vanished. I believe the combination of 3 zirtek a day AND 12 grams of ganoderma lucidumhave made my hayfever today (sunday 8/6/2008) virtually unnoticeable which 3 zirtek a day alone did not. Ganoderma lucidum is also effective in inhibiting epstein barr early antigen induction in Raji cells so is plausibly effective in MS. My walking has however been rather stiff today, a hot clear London day. Again I expect this is because I have suddenly added a lot of a new immune modulating drug. However because my hayfever has now vanished this is worth it and my walking will just have to adapt over the next few weeks as the heat and pollen rage on. I went with my partner to the Chelsea physic garden today and the first plant I saw in the herbal medicine section was a withania somnifera! Sadly it looked very dead. I couldn't find any of the other herbs that I'm taking.
Taking suddenly high dose ganoderma lucidum does rather cloud the picture vis-a-vis what dose of withania somnifera to take but I shall just have to muddle through these next few weeks when the pollen season for me is at its worst.
9/6/2008 Zut alors! I had a fairly dreadful hayfever night in spite of zirtek and ganoderma lucidum and wore my surgical mask to keep out the pollen. This morning I woke up with a much stiffer right leg than I've been used to over the last few weeks and during the early hours of the morning I had a number of spasms. Methinks the sudden addition of high dose ganoderma lucidum was a bad idea so today have backed off and my hayfever is doing fine on just zirtek. Ho hum ho hum. Hayfever is soo awful that I may have erroneously latched onto the ganoderma lucidum as the explanation for the absence of sneezing hell but maybe the pollen count just drifted down. Maybe my leg is stiff today because it is hot (28 degrees) or I am feverish from the hayfever or I don't know.... Mind you it was just as hot yesterday although perhaps slightly less humid. Nevertheless I do think adding large doses of known immune modulating drugs are likely to have an initial bad effect. Even when I had the prednisolone infusions at the end of february my leg initially felt worse so I'm glad I've backed off the ganoderma lucidum until my hayfever gets worse again!
10/6/2008
Typical! I am back on 3 zirtek a day and my hayfever is back with a vengeance so maybe the ganoderma lucidum did help! I shall add 2g now to see what happens. I have run out of the guggul plus formulation which I took for my somewhat arthritic right index finger. The pain has now substantially reduced but is still evident in the morning when I bend to check it. Mmm. I think the formulation may have modestly helped but not enough for me to order more of it. I have instead added the gentianae macrophyllae in the form of tea 3 times daily. As per the research above this herb is effective against rheumatoid arthritis and is an anti-inflammatory. I have also added back the fibrinolytic enzymes - serrapeptase and papain which I was taking over christmas to reduce fibrin build up. Papain is also effective against epstein barr so I may try to get more of this. I believe that the large dosages of enzymes I took over the Christmas period helped reduce the night spasms from which I now scarcely suffer so I think a moderate dose of these is sensible. I am reducing the amount of bioperine I take to 30mg daily as I think this has contributed to quite bad constipation over the last week. I'm also adapting the dose of boswellia and withania so that I take 1 of the boswellias 6 times daily and another of the boswellias 3 times daily and I take 1 of the withania 6 times daily. My leg feels a lot less stiff than yesterday but it's definitely not so hot. On the down side I've noticed a slight twitching appear in my right index finger. Not sure if this may be related to use of said finger on computer mouse. Certainly a possibility but more likely the MS has altered in my hand which has previously been mainly affected my stiffness. For a while several months ago my little finger was twitching but that stopped after several weeks. The twitching in my index is much milder than that which affected my little finger...

A tip by DIM has got me interested in DHEA and pregnenolone:

1: Growth Horm IGF Res. 2004 Jun;14 Suppl A:S18-33. Links
Local synthesis and dual actions of progesterone in the nervous system: neuroprotection and myelination.Schumacher M, Guennoun R, Robert F, Carelli C, Gago N, Ghoumari A, Gonzalez Deniselle MC, Gonzalez SL, Ibanez C, Labombarda F, Coirini H, Baulieu EE, De Nicola AF.
Inserm U488, 80 rue du Général Leclerc, 94276 Kremlin-Bicêtre, France. schuma@kb.inserm.fr

Progesterone (PROG) is synthesized in the brain, spinal cord and peripheral nerves. Its direct precursor pregnenolone is either derived from the circulation or from local de novo synthesis as cytochrome P450scc, which converts cholesterol to pregnenolone, is expressed in the nervous system. Pregnenolone is converted to PROG by 3beta-hydroxysteroid dehydrogenase (3beta-HSD). In situ hybridization studies have shown that this enzyme is expressed throughout the rat brain, spinal cord and dorsal root ganglia (DRG) mainly by neurons. Macroglial cells, including astrocytes, oligodendroglial cells and Schwann cells, also have the capacity to synthesize PROG, but expression and activity of 3beta-HSD in these cells are regulated by cellular interactions. Thus, Schwann cells convert pregnenolone to PROG in response to a neuronal signal. There is now strong evidence that P450scc and 3beta-HSD are expressed in the human nervous system, where PROG synthesis also takes place. Although there are only a few studies addressing the biological significance of PROG synthesis in the brain, the autocrine/paracrine actions of locally synthesized PROG are likely to play an important role in the viability of neurons and in the formation of myelin sheaths. The neuroprotective effects of PROG have recently been documented in a murine model of spinal cord motoneuron degeneration, the Wobbler mouse. The treatment of symptomatic Wobbler mice with PROG for 15 days attenuated the neuropathological changes in spinal motoneurons and had beneficial effects on muscle strength and the survival rate of the animals. PROG may exert its neuroprotective effects by regulating expression of specific genes in neurons and glial cells, which may become hormone-sensitive after injury. The promyelinating effects of PROG were first documented in the mouse sciatic nerve and in co-cultures of sensory neurons and Schwann cells. PROG also promotes myelination in the brain, as shown in vitro in explant cultures of cerebellar slices and in vivo in the cerebellar peduncle of aged rats after toxin-induced demyelination. Local synthesis of PROG in the brain and the neuroprotective and promyelinating effects of this neurosteroid offer interesting therapeutic possibilities for the prevention and treatment of neurodegenerative diseases, for accelerating regenerative processes and for preserving cognitive functions during aging.

PMID: 15135772 [PubMed - indexed for MEDLINE]

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1: Microsurgery. 2003;23(1):49-55. Links
Effect of subepineurial dehydroepiandrosterone treatment on healing of transected nerves repaired with the epineurial sleeve technique.Ayhan S, Markal N, Siemionow K, Araneo B, Siemionow M.
Department of Plastic and Reconstructive Surgery, Cleveland Clinic Foundation, Cleveland, Ohio, USA.

The epineurial sleeve technique for nerve repair is designed in part to protect a healing nerve from external humoral influences, but research suggests that the external factor dehydroepiandrosterone (DHEA) may actually improve nerve healing in crush injuries. To test the effect of DHEA, we injected it into the epineurial chambers created to repair transected rat sciatic nerves. In 18 control rats, the nerve was transected and repaired without DHEA treatment. Eighteen animals received subepineurial injections of propylene glycol vehicle, and 18 received subepineurial injections of about 0.2 ml DHEA. Walking-track analysis and toe-contracture measurements showed no significant differences among the three groups. At 12 weeks, the gastrocnemius muscles in the DHEA group were significantly heavier than those of untreated controls. At 6 and 12 weeks, DHEA-treated nerves had significantly more myelinated axons, larger average fiber diameter, and greater axonal cross-sectional areas in the proximal, middle, and distal sections. Myelin thickness did not differ between groups, except at 6 weeks between the DHEA and vehicle-treated groups. We conclude that subepineurial dehydroepiandrosterone treatment reduced the extent of denervation atrophy and induced an earlier onset of axonal regeneration. Copyright 2003 Wiley-Liss, Inc.

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1: J Immunol. 2001 Dec 15;167(12):7094-101. Links
Administration of dehydroepiandrosterone suppresses experimental allergic encephalomyelitis in SJL/J mice.Du C, Khalil MW, Sriram S.
Department of Neurology, Multiple Sclerosis Research Center, Vanderbilt University Medical Center, Nashville, TN 37212, USA. caigan.du@mcmail.vanderbilt.edu

Experimental allergic encephalomyelitis (EAE) is a Th1-mediated inflammatory demyelinating disease in the CNS, an animal model of multiple sclerosis. We have examined the effect of dehydroepiandrosterone (DHEA) on the development of EAE in mice. The addition of DHEA to cultures of myelin basic protein-primed splenocytes resulted in a significant decrease in T cell proliferation and secretion of (pro)inflammatory cytokines (IFN-gamma, IL-12 p40, and TNF-alpha) and NO in response to myelin basic protein. These effects were associated with a decrease in activation and translocation of NF-kappaB. In vivo administration of DHEA significantly reduced the severity and incidence of acute EAE, along with a decrease in demyelination/inflammation and expressions of (pro)inflammatory cytokines in the CNS. These studies suggest that DHEA has potent anti-inflammatory properties, which at least are in part mediated by its inhibition of NF-kappaB activation.

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1: J Soc Biol. 1999;193(3):285-92.Links
[Neurosteroids: trophic effects in the nervous system][Article in French]


Schumacher M, Robert F, Baulieu EE.
U488 INSERM, Le Kremlin-Bicêtre, France. schuma@kb.inserm.fr

Some steroids, named "neurosteroïds", can be synthesized from cholesterol within both the central and peripheral nervous systems. Thus, pregnenolone and progesterone persist in the brain and in peripheral nerves long after removal of the steroidogenic endocrine glands by castration and adrenalectomy. The role of neurosteroids during the development of the nervous system is not well known, although they are synthesized by glial cells and some populations of neurons already during embryonic life. Cell culture experiments suggest that neurosteroids may influence the survival and differentiation of neurons and glial cells. In the adult nervous system, neurosteroids play an important role during regeneration. Progesterone is indeed synthesized by Schwann cells in peripheral nerves, where it plays an important role in the formation of new myelin sheaths after lesion. This is the first demonstration of a vital role for a neurosteroid in the nervous system.

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1: Hum Reprod. 2000 Jun;15 Suppl 1:1-13.Links

Comment in:
Hum Reprod. 2001 Aug;16(8):1542.
Progesterone as a neuroactive neurosteroid, with special reference to the effect of progesterone on myelination.Baulieu EE, Schumacher M.
INSERM U 488, Le Kremlin-Bicetre, France.

Some steroids are synthesized within the central and peripheral nervous system, mostly by glial cells. These are known as neurosteroids. In the brain, certain neurosteroids have been shown to act directly on the function of membrane receptors for neurotransmitters. For example, progesterone inhibits the neuronal nicotinic acetylcholine receptor, whereas its 3alpha,5alpha-reduced metabolite 3alpha,5alpha-tetrahydroprogesterone (allopregnanolone) activates the gamma-aminobutyric acid receptor complex A (GABA-R(A)). Besides these effects, neurosteroids also regulate important glial functions such as the synthesis of myelin proteins. Thus, in cultures of glial cells prepared from neonatal rat brain, progesterone increases the number of oligodendrocytes expressing the myelin basic protein (MBP) and the 2',3'-cyclic nucleotide-3'-phosphodiesterase (CNPase). An important role for neurosteroids in myelin repair has been demonstrated in the rodent sciatic nerve, where progesterone and its direct precursor pregnenolone are synthesized by Schwann cells. After cryolesion of the male mouse sciatic nerve, blocking the local synthesis or action of progesterone impairs remyelination of the regenerating axons, whereas administration of progesterone to the lesion site promotes the formation of new myelin sheaths.

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Praise the lord for PubMed! Or rather praise the humans who put it together!!!!!

Bloody hayfever! It's driving me bananas. At 5:30 am 11/6/08 after a fairly miserable night even with the surgical mask on I take a zirtek. This seems to have no effect on the hayfever and I sneeze a lot until about 8:50 when the sneezing calms down. Whether the 2g of ganoderma lucidum I took at 8:10 and washed down with hot tea had anything to do with this is moot as I suppose the pollen count could have suddenly dropped. I still feel rubbish with my glands in the throat all sore. Judging by the attack of hayfever that started last night in a late night drive through london the ganoderma lucidum doesn't have an effect since I had 2g immediately before a meal about an hour before the drive. However they do say that the herbs need to be taken with hot tea about an hour before a meal....ho hum. I hate the summer!
My right index wasn't painful this am.
My bad right leg was quite stiff but not too bad.
I feel like I have flu. My leg is always seems to be stiffer after I take any ganoderma lucidum and it was this morning after the 8am 2g dose and when I awoke. I think and taking into account an example of how it seems to work below I'm just going to forgo the ganoderma lucidum anti-hayfever strategy.

1: Iran J Immunol. 2007 Dec;4(4):220-6.Links
Effect of Ganoderma lucidum on cytokine release by peritoneal macrophages.Ahmadi K, Riazipour M.
Department of Immunology, Research Center of Molecular Biology, Baqiyatallah University of Medical Sciences, Tehran, Iran. kazahmadi@yahoo.com

BACKGROUND: The water-soluble extract of Ganoderma lucidum (Reishi) has been used as an immunomodulator to stimulate spleen cells proliferation and cytokine expression. OBJECTIVES: To investigate the effect of Ganoderma lucidum (G. lucidum) on cytokine production by mice peritoneal macrophages. METHODS: Mice peritoneal macrophages were prepared by intra-peritoneal injection of 5 ml cold PBS. Peritoneal macrophages were plated out at 1X10(6) cell/well in 1ml RPMI 1640 medium supplemented with 10%FCS, 50 microg streptomycin and 50U penicillin. Cells were incubated in the presence or absence of different concentrations of G. lucidum at 37 degrees C and 5% CO2 for 48 hours. Cell free medium was removed and used for cytokine assay by ELISA method (Bender med system). RESULTS: The results showed no significant differences in cell viability at concentrations ranged from 0-40 microg/ml compared with control group. G. lucidum enhanced IL-1beta, TNF-alpha and NO production in a concentration dependent manner. However, it is not clear if the enhancement of NO release is due to direct effect of G. lucidum on NO synthesis or by indirect endogenous modulation via cytokines. IL-12 release by peritoneal macrophages was also increased in response to different concentrations of G. lucidum, but maximum enhancement was induced in response to 5 microg/ml of G. lucidum (P<0.001). CONCLUSION: Our results indicate that G. lucidum at concentrations used has a positive effect on cytokine release and NO production by peritoneal macrophages. Therefore, it is concluded that G. lucidum at moderate concentrations improves macrophage function through cytokine and NO release.

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Definitely don't want upregulation of NFKappaB below:

1: Int Immunopharmacol. 2007 Jun;7(6):864-70. Epub 2007 Mar 13. Links
Enhancement of IL-2 and IFN-gamma expression and NK cells activity involved in the anti-tumor effect of ganoderic acid Me in vivo.Wang G, Zhao J, Liu J, Huang Y, Zhong JJ, Tang W.
State Key Laboratory of Bioreactor Engineering and School of Pharmacy, East China University of Science and Technology, Shanghai, China.

Ganoderic acid Me (GA-Me) is a lanostane triterpenoid purified from Ganoderma lucidum mycelia, one of the most widely used herbs for cancer treatment and prevention in east Asia. In the present study, it was demonstrated that GA-Me could inhibit both tumor growth and lung metastasis of Lewis lung carcinoma in C57BL/6 mice. Compared with the control group, Natural Killer (NK) cells activity was significantly enhanced by intraperitoneal administration of GA-Me (28 mg/kg). Results of ELISA assay and RT-PCR showed that the expressions of Interleukin-2 (IL-2) and Interferon-gamma (IFN-gamma) were also increased (p<0.05). Additionally, the expression of Nuclear Factor-kappaB (NF-kappaB) was up-regulated after the treatment of GA-Me, which might be involved in the production of IL-2. In conclusion, the findings of this study implied that GA-Me could effectively inhibit tumor growth and lung metastasis through increasing immune function.

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However here it seems to downregulate NF-kappaB

1: Mol Cell Biochem. 2007 Jul;301(1-2):173-9. Epub 2007 Jan 12. Links
Ganoderma lucidum polysaccharide peptide reduced the production of proinflammatory cytokines in activated rheumatoid synovial fibroblast.Ho YW, Yeung JS, Chiu PK, Tang WM, Lin ZB, Man RY, Lau CS.
Department of Pharmacology, University of Hong Kong, Hong Kong SAR, Hong Kong.

The aim of the current study was to elucidate the potential therapeutic effect of Ganoderma lucidum polysaccharide peptide (GL-PP) in rheumatoid arthritis (RA). The effects of GL-PP on cell proliferation and cytokine production were studied in RA synovial fibroblasts (RASF). GL-PP significantly inhibited the proliferation of RASF. Following the incubation with GL-PP, production of interleukin (IL)-6 and monocyte chemoattractant protein (MCP)-1 in RASF were significantly increased as expressed as percentage change from basal values. However, the actual effects were minimal due to the low basal values. When RASF were activated by IL-1beta or lipopolysaccharides, IL-8 and MCP-1 production increased many folds. GL-PP significantly suppressed their productions. The inhibitory effects of GL-PP on cytokine production in RASF were at least in part, by inhibiting the nuclear factor-kappa B (NF-kappaB) transcription pathway. Our results demonstrated that GL-PP had the unique ability to modulate cytokine production in RASF and warrants further investigation into its mechanism of action.

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On balance though there seems to be more articles about upregulation of NF-kappaB than downregulation:

1: J Ethnopharmacol. 2006 Jan 16;103(2):217-22. Epub 2005 Sep 15. Links
Ganoderma lucidum mycelia enhance innate immunity by activating NF-kappaB.Kuo MC, Weng CY, Ha CL, Wu MJ.
Department of Biotechnology, Chia-Nan University of Pharmacy and Science, Tainan 717, Taiwan, ROC.

Ganoderma lucidum is a popular medicinal mushroom in China and Japan for its immunomodulatory and antitumor effects. The goal of this research is to investigate the effect of dried mycelia of Ganoderma lucidum produced by submerged cultivation on the enhancement of innate immune response. We found that Ganoderma lucidum mycelia (0.2-1.6 mg/ml) stimulated TNF-alpha and IL-6 production after 8h treatment in human whole blood. IFN-gamma release from human whole blood was also enhanced after 3 day-culture with Ganoderma lucidum mycelia (0.2-1.0mg/ml). However, Ganoderma lucidum mycelia did not potentiate nitric oxide production in RAW264.7 cells. To better understand the possible immuno-enhancement mechanisms involved, we focused on nuclear factor (NF)-kappaB activation. Electrophoretic mobility shift assay revealed that the Ganoderma lucidum mycelia (1.6 mg/ml) activated kappaB DNA binding activity in RAW264.7 cells. These results provide supporting evidences for the immunomodulatory effect of Ganoderma lucidum mycelia

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Owing to cheerleader's response to Dim's question about DHEA and pregnenlolone wherein she cautions against using DHEA/pregnenolone I have investigated a few more abstracts on pubmed:

1: Eur J Neurol. 2005 Jul;12(7):514-8. Links
Serum uric acid, dehydroepiandrosterone sulphate, and apolipoprotein E genotype in benign vs. progressive multiple sclerosis.Ramsaransing GS, Heersema DJ, De Keyser J.
Department of Neurology, University Hospital Groningen, Groningen, The Netherlands.

The majority of patients with multiple sclerosis (MS) experience gradual progression of disability, either as secondary progressive MS (SPMS) or primary progressive MS (PPMS). A subgroup with relapsing-remitting MS shows a benign course with little or no disease progression and minimal disability decades after the first manifestations, so called benign MS (BMS). In our search to identify factors that are associated with progression of MS, we investigated serum levels of uric acid and dehydroepiandrostenedione sulphate (DHEAS), and apolipoprotein (apo)E genotype in 28 patients with BMS, 33 with SPMS, 21 with PPMS, and 29 healthy individuals. We found no significant changes in uric acid levels and apoE genotype between the four groups. Mean DHEAS levels were lower in MS patients compared with healthy controls (P = 0.049), but there were no significant differences between the clinical subgroups of MS. In patients with SPMS and PPMS there was no correlation between progression rate and serum levels of either uric acid or DHEAS. Our results suggest that serum levels of uric acid and DHEAS, and apoE genotype do not differ between patients with a benign and progressive course of MS.

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I believe people with MS want to upregulate their Th2 response.

1: Exp Biol Med (Maywood). 2001 Dec;226(11):1051-60. Links
Stimulation of Th2 response by high doses of dehydroepiandrosterone in KLH-primed splenocytes.Du C, Guan Q, Khalil MW, Sriram S.
Department of Neurology, Multiple Sclerosis Research Center, Vanderbilt University Medical Center, Nashville, Tennessee 37212, USA. caigan.du@mcmail.vanderbilt.edu

Although dehydroepiandrosterone (DHEA) has long been considered as a precursor for steroid hormones, it has also been shown to have regulatory effects in immune homeostasis. We have examined the effect of high DHEA doses on T cell proliferation, differentiation, and cytokine secretion patterns following stimulation with mitogens and soluble antigens. DHEA profoundly inhibited T cell receptor-mediated T cell proliferation in the upstream of IL-2R signaling. Addition of DHEA to KLH-primed splenocytes stimulated Th2 response, indicated by an increase of IL-4 or a decrease of IFN-gamma production in the cultures. Further studies showed that DHEA enhanced IL-4, but inhibited IL-12-mediated T cell proliferation and IL-12 production in antigen-presenting cells (APCs). Our data demonstrated that supraphysiologic levels of DHEA favored Th2 immune responses in vitro by inhibition of IL-12 production from APCs and/or stimulation of Th2 proliferation during the interactions of T cells with APCs.

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Here's some info on the responses of relapsing and progressive immune response vaguely related to above:

1: J Immunol. 2006 Sep 15;177(6):4196-202. Links
Innate immunity in multiple sclerosis: myeloid dendritic cells in secondary progressive multiple sclerosis are activated and drive a proinflammatory immune response.Karni A, Abraham M, Monsonego A, Cai G, Freeman GJ, Hafler D, Khoury SJ, Weiner HL.
Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Havard Medical School, Boston, MA 02115-5817, USA.

Multiple sclerosis (MS) is postulated to be a T cell-mediated autoimmune disease characterized clinically by a relapsing-remitting (RR) stage followed by a secondary progressive (SP) phase. The progressive phase is felt to be secondary to neuronal degenerative changes triggered by inflammation. The status of the innate immune system and its relationship to the stages of MS is not well understood. Dendritic cells (DCs) are professional APCs that are central cells of the innate immune system and have the unique capacity to induce primary immune responses. We investigated circulating myeloid DCs isolated directly from the blood to determine whether there were abnormalities in myeloid DCs in MS and whether they were related to disease stage. We found that SP-MS subjects had an increased percentage of DCs expressing CD80, a decreased percentage expressing PD-L1, and an increased percentage producing IL-12 and TNF-alpha compared with RR-MS or controls. A higher percentage of DCs from both RR and SP-MS patients expressed CD40 compared with controls. We then investigated the polarization effect of DCs from MS patients on naive T cells taken from cord blood using a MLR assay. Whereas DCs from RR-MS induced higher levels of Th1 (IFN-gamma, TNF-alpha) and Th2 (IL-4, IL-13) cytokines compared with controls, DCs from SP-MS only induced a polarized Th1 response. These results demonstrate abnormalities of DCs in MS and may explain the immunologic basis for the different stages and clinical patterns of MS.

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Should we try to enhance Th2?

1: Immunol Cell Biol. 2006 Dec;84(6):522-9. Epub 2006 Jul 20. Links
Fcgamma receptor-ligating complexes improve the course of experimental autoimmune encephalomyelitis by enhancing basal Th2 responses.La Flamme AC, Harvie M, McNeill A, Goldsack L, Tierney JB, Bäckström BT.
School of Biological Sciences, Victoria University of Wellington, Wellington, New Zealand. anne.laflamme@vuw.ac.nz

IL-12p40 and macrophages are essential for the induction of disease in the mouse model of multiple sclerosis, experimental autoimmune encephalomyelitis. In this paper, we show that treatment of mice with opsonized erythrocytes, which have been shown to ligate Fcgamma receptors on macrophages and alter their cytokine profile, significantly delayed the onset of experimental autoimmune encephalomyelitis. This protection correlated to the induction of Th2 responses by autoreactive T cells, enhanced basal systemic responses and a significant downregulation of IL-12p40 and nitric oxide synthase-2, but not IFN-gamma expression. IL-4 was essential for the protection by opsonized erythrocytes as the effects of treatment were eliminated in IL-4-deficient mice. Together these studies suggest that the ligation of Fcgamma receptors can modify the development of autoimmune disease by altering macrophage activation and enhancing Th2 responses.

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1: J Immunol. 2006 Aug 1;177(3):1679-88. Links
Dendritic cells transduced with SOCS-3 exhibit a tolerogenic/DC2 phenotype that directs type 2 Th cell differentiation in vitro and in vivo.Li Y, Chu N, Rostami A, Zhang GX.
Department of Neurology, Thomas Jefferson University, Philadelphia, PA 19107, USA.

Dendritic cells (DCs) have been suggested to direct a type of Th differentiation through their cytokine profile, e.g., high IL-12/IL-23 for Th1 (named DC1/immunogenic DCs) and IL-10 for Th2 (DC2/tolerogenic DCs). Suppressor of cytokine signaling (SOCS)-3 is a potent inhibitor of Stat3 and Stat4 transduction pathways for IL-23 and IL-12, respectively. We thus hypothesize that an enhanced SOCS-3 expression in DCs may block the autocrine response of IL-12/IL-23 in these cells, causing them to become a DC2-type phenotype that will subsequently promote Th2 polarization of naive T cells. Indeed, in the present study we found that bone marrow-derived DCs transduced with SOCS-3 significantly inhibited IL-12-induced activation of Stat4 and IL-23-induced activation of Stat3. These SOCS-3-transduced DCs expressed a low level of MHC class II and CD86 on their surface, produced a high level of IL-10 but low levels of IL-12 and IFN-gamma, and expressed a low level of IL-23 p19 mRNA. Functionally, SOCS-3-transduced DCs drove naive myelin oligodendrocyte glycoprotein-specific T cells to a strong Th2 differentiation in vitro and in vivo. Injection of SOCS-3-transduced DCs significantly suppressed experimental autoimmune encephalomyelitis, a Th1 cell-mediated autoimmune disorder of the CNS and an animal model of multiple sclerosis. These results indicate that transduction of SOCS-3 in DCs is an effective approach to generating tolerogenic/DC2 cells that then skew immune response toward Th2, thus possessing therapeutic potential in Th1-dominant autoimmune disorders such as multiple sclerosis.

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I think this is my preferred model for MS, given that it is virally induced:

1: J Immunol. 1998 Nov 15;161(10):5586-93. Links
Suppressive effect on Theiler's murine encephalomyelitis virus-induced demyelinating disease by the administration of anti-IL-12 antibody.Inoue A, Koh CS, Yamazaki M, Yahikozawa H, Ichikawa M, Yagita H, Kim BS.
Third Department of Medicine, Shinshu University School of Medicine, Matsumoto, Japan.

We examined the role of IL-12, a cytokine critical to the evolution of cellular responses, in the development of Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD). Treatment with mAbs to IL-12, especially during the effector phase, resulted in significant suppression of the development of this disease both clinically and histologically. In mice treated with these mAbs, the production of inflammatory and Th1-derived cytokines such as TNF-alpha and IFN-gamma in the spleen cells was decreased, and that of Th2-derived cytokines such as IL-4 and IL-10 was increased. The delayed type hypersensitivity and T cell proliferative response specific for TMEV were decreased by this treatment. These data suggest that IL-12 is critically involved in the pathogenesis of TMEV-IDD and that Abs to IL-12 could be a novel therapeutic approach in the clinical treatment of demyelinating diseases such as human multiple sclerosis

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DHEA declines with age:

1: Mech Ageing Dev. 2002 Sep;123(11):1477-86. Links
Changes in peripheral blood lymphocyte subsets in elderly subjects are associated with an impaired function of the hypothalamic-pituitary-adrenal axis.Martínez-Taboada V, Bartolomé MJ, Amado JA, Blanco R, García-Unzueta MT, Rodríguez-Valverde V, López-Hoyos M.
Services of Rheumatology, Immunology, and Endocrinology, Santander, Spain. inmlhm@humv.es

A growing body of evidence indicates that ageing brings a progressive disruption in the immune and endocrine systems. However, very few reports have correlated the changes in the immune system with the endocrine function in the elderly. The aim of the present study was to investigate the changes occurring in the peripheral blood lymphocyte subpopulations with age and correlate them with the hypothalamic-pituitary-adrenal (HPA) function. We determined the peripheral blood lymphocyte phenotype and the T cell receptor usage by flow cytometry analysis. The HPA function was evaluated by the basal serum levels of adrenal steroids and the response to stimulation with a low-dose ACTH. In the elderly, we observed a decrease of major T subsets together with an increase of NK cells and activated T cells. With regard to the HPA function, the most significant decline was found in dehydroepiandrosterone (DHEA) and dehydroepiandrosterone-sulphate (DHEAS). A close correlation between immune changes with ageing and DHEA response to ACTH stimulation was found. The present study showed an inverse correlation of lymphocyte changes with the plasma levels of steroids, especially DHEA and its metabolite, DHEAS. This association was not found for other steroids and points for the possibility of using DHEA to correct the immunological decline associated with ageing.

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Reduced DHEAS leads to increased IL12, an MS bogey:

1: J Endocrinol Invest. 2002;25(10 Suppl):19-23.Links
Hypothalamic-pituitary-adrenal axis impairment in the pathogenesis of rheumatoid arthritis and polymyalgia rheumatica.Cutolo M, Foppiani L, Minuto F.
University of Genova, Genova, Italy. mcutolo@unige.it

Stressful/inflammatory conditions activate the immune system and subsequently the hypothalamic-pituitary-adrenal (HPA) axis through the central and peripheral production of cytokines such as IL-6 and TNF-alpha. A relative adrenal hypofunction, as evidenced by inappropriately normal F levels and reduced DHEAS levels, has been recently claimed to play a causative role in the pathogenesis of autoimmune/inflammatory diseases such as rheumatoid arthritis (RA) and polymyalgia rheumatica (PMR). Thus, we evaluated baseline levels of adrenal androgens, IL-6 and IL-12 together with HPA axis challenge by ovine CRH and low-dose ACTH in premenopausal RA women and aged PMR women. In addition, adrenal steroids, IL-6, and acute-phase reactant levels were measured at baseline and during 12 months of glucocorticoid tapering regimen in a cohort of PMR patients. Reduced DHEAS levels (p<0.05) associated to increased (p<0.05) IL-6 and IL-12 levels were found in RA patients as compared to controls (C). Irrespective of the inflammatory condition, basal and stimulated cortisol levels in RA were similar to C, whereas DHEA secretion after ACTH testing was significantly (p<0.01) reduced. During HPA challenge, F responses in PMR patients proved inadequate in the setting of the inflammatory status, confirmed by increased IL-6 levels. In addition, these patients showed significantly (p<0.05) increased 17-hydroxyprogesterone (17-OHP) responses after ACTH testing as compared to C. The longitudinal study in PMR patients showed that glucocorticoid therapy leads to a stable reduction of IL-6 and of acute-phase reactant levels, which persist even after glucocorticoid tapering. Our data show an inadequate adrenal secretion in RA and PMR, both characterized by increased levels of HPA axis-stimulating cytokines. The reduced basal levels of DHEAS in RA might be ascribed to a reduced biosynthesis as consequence of a cytokine-induced impairment of P450 17.20-lyase activity. In PMR, the ACTH-induced enhanced 17-OHP levels suggest a partial age- and cytokine-induced impairment of the P450 21 beta-hydroxylase, which eventually leads to inadequate glucocorticoid production. The clinical and biochemical improvement observed after glucocorticoid therapy in patient with RA and PMR, might thus be attributed to a direct dampening of pro-inflammatory factors as well as to the restoration of the steroid milieu. Given its multifaceted properties, including the ability to counteract the negative side effects of glucocorticoids, the therapeutical administration of DHEA might be considered in these pathologies, provided its safety is proved.

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On the whole I think I shall order some DHEA and see how things fare before trying any pregnenolone. Thanks for all the comments around the site which led me on this trawl.

Off on a tangent about Theiler's model:

1: Glia. 2008 Jul;56(9):942-53. Links
Replication of Theiler's virus requires NF-kappaB-activation: Higher viral replication and spreading in astrocytes from susceptible mice.Kang MH, So EY, Park H, Kim BS.
Department of Microbiology-Immunology, Northwestern University Medical School, Chicago, Illinois.

To investigate viral replication and cell-cell spreading in astrocytes, recombinant Theiler's murine encephalomyelitis virus (TMEV) expressing green fluorescent protein (GFP) during the replication was generated. GFP and TMEV proteins were processed correctly in infected cells and production of viral proteins could be tracked by fluorescent microscopy. Viral replication of both wild-type TMEV and GFP-TMEV was dependent on the activation of NF-kappaB and partially MAP kinase, based on chemical inhibition studies. Viral replication was significantly reduced in primary astrocytes from NF-kappaB1 (p105)-deficient mice compared with that from wild-type control mice, whereas cytokine production was enhanced. These results suggest an association of canonical NF-kappaB subunits in viral replication, but not cytokine production. Viral replication was also suppressed in both IKKalpha and IKKbeta-deficient mouse embryonic fibroblasts (MEFs), compared with that in wild-type MEF. However, the inhibition was significantly greater in IKKbeta-deficient MEF, suggesting that IKKbeta plays a stronger role in supporting viral replication. Interestingly, viral replication and spreading in primary astrocytes from susceptible SJL/J mice were several-fold higher than those in astrocytes from resistant C57BL/6 mice, suggesting that higher viral replication levels in astrocytes may also contribute to the viral persistence in the central nervous system (CNS) of susceptible SJL/J mice. A relatively higher level of activated NF-kappaB was found in the nuclei of virus-infected SJL astrocytes compared with C57BL/6 astrocytes suggest that the NF-kappaB activation level affects on viral replication. (c) 2008 Wiley-Liss, Inc.

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1: J Virol. 2008 Jun;82(11):5606-17. Epub 2008 Mar 19. Links
Anticapsid immunity level, not viral persistence level, correlates with the progression of Theiler's virus-induced demyelinating disease in viral P1-transgenic mice.Myoung J, Bahk YY, Kang HS, Dal Canto MC, Kim BS.
Department of Microbiology-Immunology, Northwestern University Medical School, 303 East Chicago Ave., Chicago, IL 60611, USA.

Intracranial infection of Theiler's murine encephalomyelitis virus (TMEV) induces demyelination and a neurological disease in susceptible SJL/J (SJL) mice that resembles multiple sclerosis. While the virus is cleared from the central nervous system (CNS) of resistant C57BL/6 (B6) mice, it persists in SJL mice. To investigate the role of viral persistence and its accompanying immune responses in the development of demyelinating disease, transgenic mice expressing the P1 region of the TMEV genome (P1-Tg) were employed. Interestingly, P1-Tg mice with the B6 background showed severe reductions in both CD4(+) and CD8(+) T-cell responses to capsid epitopes, while P1-Tg mice with the SJL background displayed transient reductions following viral infection. Reduced antiviral immune responses in P1-Tg mice led to >100- to 1,000-fold increases in viral persistence at 120 days postinfection in the CNS of mice with both backgrounds. Despite the increased CNS TMEV levels in these P1-Tg mice, B6 P1-Tg mice developed neither neuropathological symptoms nor demyelinating lesions, and SJL P1-Tg mice developed significantly less severe TMEV-induced demyelinating disease. These results strongly suggest that viral persistence alone is not sufficient to induce disease and that the level of T-cell immunity to viral capsid epitopes is critical for the development of demyelinating disease in SJL mice.

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This rather flies in the face of the notion that one should lower ifn gamma as an inflammatory signal. But then the above research suggests that having the virus doesn't so much matter as one's immune response. Thus reducing the CD4(+) and CD8(+) T-cell responses to capsid epitopes might be the solution.

1: J Virol. 2003 Nov;77(22):12252-65. Links
Gamma interferon is critical for neuronal viral clearance and protection in a susceptible mouse strain following early intracranial Theiler's murine encephalomyelitis virus infection.Rodriguez M, Zoecklein LJ, Howe CL, Pavelko KD, Gamez JD, Nakane S, Papke LM.
Department of Immunology, Mayo Clinic, Rochester, Minnesota 55905, USA. rodriguez.moses@mayo.edu

We evaluated the role of gamma interferon (IFN-gamma) in protecting neurons from virus-induced injury following central nervous system infection. IFN-gamma(-/-) and IFN-gamma(+/+) mice of the resistant major histocompatibility complex (MHC) H-2(b) haplotype and intracerebrally infected with Theiler's murine encephalomyelitis virus (TMEV) cleared virus infection from anterior horn cell neurons. IFN-gamma(+/+) H-2(b) mice also cleared virus from the spinal cord white matter, whereas IFN-gamma(-/-) H-2(b) mice developed viral persistence in glial cells of the white matter and exhibited associated spinal cord demyelination. In contrast, infection of IFN-gamma(-/-) mice of the susceptible H-2(q) haplotype resulted in frequent deaths and severe neurologic deficits within 16 days of infection compared to the results obtained for controls. Morphologic analysis demonstrated severe injury to spinal cord neurons in IFN-gamma(-/-) H-2(q) mice during early infection. More virus RNA was detected in the brain and spinal cord of IFN-gamma(-/-) H-2(q) mice than in those of control mice at 14 and 21 days after TMEV infection. Virus antigen was localized predominantly to anterior horn cells in infected IFN-gamma(-/-) H-2(q) mice. IFN-gamma deletion did not affect the humoral response directed against the virus. However, the level of expression of CD4, CD8, class I MHC, or class II MHC in the central nervous system of IFN-gamma(-/-) H-2(q) mice was lower than those in IFN-gamma(+/+) H-2(q) mice. Finally, in vitro analysis of virus-induced death in NSC34 cells and spinal motor neurons showed that IFN-gamma exerted a neuroprotective effect in the absence of other aspects of the immune response. These data support the hypothesis that IFN-gamma plays a critical role in protecting spinal cord neurons from persistent infection and death.

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1: Immunology. 2008 Apr 4. [Epub ahead of print] Links
T helper cell type 1 (Th1), Th2 and Th17 responses to myelin basic protein and disease activity in multiple sclerosis.Hedegaard CJ, Krakauer M, Bendtzen K, Lund H, Sellebjerg F, Nielsen CH.
Institute for Inflammation Research, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

Autoreactive T cells are thought to play an essential role in the pathogenesis of multiple sclerosis (MS). We examined the stimulatory effect of human myelin basic protein (MBP) on mononuclear cell (MNC) cultures from 22 patients with MS and 22 sex-matched and age-matched healthy individuals, and related the patient responses to disease activity, as indicated by magnetic resonance imaging. The MBP induced a dose-dependent release of interferon-gamma (IFN-gamma), tumour necrosis factor-alpha (TNF-alpha) and interleukin-10 (IL-10) by patient-derived MNCs. The patients' cells produced higher amounts of IFN-gamma and TNF-alpha, and lower amounts of IL-10, than cells from healthy controls (P < 0.03 to P < 0.04). Five patients with MS and no controls, displayed MBP-induced CD4(+) T-cell proliferation. These high-responders exhibited enhanced production of IL-17, IFN-gamma, IL-5 and IL-4 upon challenge with MBP, as compared with the remaining patients and the healthy controls (P < 0.002 to P < 0.01). A strong correlation was found between the MBP-induced CD4(+) T-cell proliferation and production of IL-17, IFN-gamma, IL-5 and IL-4 (P < 0.0001 to P < 0.01) within the patient group, and the production of IL-17 and IL-5 correlated with the number of active plaques on magnetic resonance images (P = 0.04 and P = 0.007). These data suggest that autoantigen-driven CD4(+) T-cell proliferation and release of IL-17 and IL-5 may be associated with disease activity. Larger studies are needed to confirm this.

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The Theiler model certainly shares certain features with the EBV model.

1: J Neurovirol. 2004 Oct;10(5):278-83. Links
Cerebrospinal fluid CD4+ T cells from a multiple sclerosis patient cross-recognize Epstein-Barr virus and myelin basic protein.Holmøy T, Kvale EØ, Vartdal F.
Institute of Immunology, Rikshospitalet University Hospital, Oslo, Norway. trygveho@labmed.uio.no

Epstein-Barr virus-specific CD4+ T cells could be involved in the pathogenesis of multiple sclerosis, provided they can gain entry to the intrathecal compartment. The authors have previously demonstrated that cerebrospinal fluid T cells from multiple sclerosis patients recognize autologous Epstein-Barr virus-transformed B cells. They now report that CD4+ T cells specific for the Epstein-Barr virus DNA polymerase peptide EBV 627-641 were present in the cerebrospinal fluid from one of two multiple sclerosis patients, and that a high proportion of these CD4+ T cells cross-recognized an immunodominant myelin basic protein peptide, MBP 85-99. In the observed patient, the proportion of EBV 627-641-specific CD4+ T cells seemed to exceed 1/10,000 in cerebrospinal fluid, compared to approximately 1/100,000 in blood. These findings prove that Epstein-Barr-virus specific CD4+ T cells can gain access to the intrathecal compartment, and suggest that Epstein-Barr virus-specific CD4+ T cells could target myelin basic protein in the central nervous system.

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Herbs to enhance Th2:

1: Immunol Lett. 2007 May 15;110(1):74-81. Epub 2007 Apr 19. Links
Up-regulation of IL-10 expression in dendritic cells is involved in Trichosanthin-induced immunosuppression.Zhou X, Yang N, Lu L, Ding Q, Jiao Z, Zhou Y, Chou KY.
Shanghai Institute of Immunology, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China.

We report here that Trichosanthin (Tk), a primary active component isolated from a Chinese traditional medicinal herb, Trichosanthes kirilowii, potently inhibits lymphocyte proliferative response in vitro. We found that Tk treatment increased production of the interleukins IL-4 and IL-10, while production of IL-2 and interferon-gamma (IFN-gamma) decreased in the allogeneic antigen-induced immune response. Moreover, up-regulation of IL-10 and IL-4 contributed to the inhibitory activities of Tk. Tk induced immunosuppression through an antigen presenting cell dependent way. Dendritic cells (DCs) are the most potent of the antigen presenting cells, which play a critical role in initiation and regulation of immune responses. We found that Tk could stimulate bone marrow-derived dendritic cells (BMDC) to express IL-10. In addition, pre-exposure of BMDC to Tk produced increased levels of IL-10, but decreased levels of IL-12, following subsequent lipopolysaccharide (LPS) stimulation. Using BMDC obtained from IL-10 deficient mice, we provided evidence that it was IL-10 derived from DCs that initiated the Tk-induced immunosuppression. Furthermore, we found that Tk activated c-Jun N-terminal kinase (JNK) of BMDC and that JNK and p38 mitogen-activated protein kinase (MAPK) activations were associated with Tk-induced IL-10 up-regulation. These data suggest that Tk acts on the function of DCs to change the ratio of IL-10 to IL-12 production and, thus, predominantly inhibits Th1 responses.

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1: Inflammation. 2004 Oct;28(5):263-70. Links
Xanthii fructus inhibits inflammatory responses in LPS-stimulated mouse peritoneal macrophages.An HJ, Jeong HJ, Lee EH, Kim YK, Hwang WJ, Yoo SJ, Hong SH, Kim HM.
College of Oriental Medicine, Kyung Hee University, Seoul, Republic of Korea.

Xanthii Fructus (XF) is an herb widely used in medicine for the treatment of a variety of inflammatory pathologies. In this study, using mouse peritoneal macrophages, we have examined whether XF affects nitric oxide (NO), tumor necrosis factor (TNF)-alpha, and interleukin (IL)-12p40 production induced by interferon (IFN)-gamma and lipopolysaccharide (LPS). XF inhibits IFN-gamma and LPS-induced NO production in a dose dependent manner. The decrease in NO synthesis was reflected as a decreased amount of inducible NO synthase protein. Furthermore, we also found that XF inhibits pro-inflammatory cytokine TNF-alpha production. However, treatment of XF in peritoneal macrophages had no effect on IL-12p40 production. These findings suggest that XF may be used in controlling macrophages-mediated inflammatory diseases.

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1: Eur J Pharmacol. 2003 Jan 10;459(1):107-12. Links
Inhibition of macrophage activation and lipopolysaccaride-induced death by seco-steroids purified from Physalis angulata L.Soares MB, Bellintani MC, Ribeiro IM, Tomassini TC, Ribeiro dos Santos R.
Centro de Pesquisas Gonçalo Moniz, Rua Waldemar Falcão, 121-Brotas-FIOCRUZ, 40295-001 BA, Salvador, Brazil. milena@cpqgm@fiocruz.br

Physalis angulata L. is an annual herb widely used in popular medicine for the treatment of a variety of pathologies. Here, we tested immunomodulatory activities of physalins, seco-steroids purified from P. angulata extracts. Addition of physalins B, F or G, but not D, caused a reduction in nitric oxide production by macrophages stimulated with lipopolysaccaride and interferon-gamma. In the presence of physalin B, macrophages stimulated with lipopolysaccaride, alone or in combination with interferon-gamma, produced lower levels of tumour necrosis factor (TNF)-alpha, interleukin-6 and interleukin-12. The inhibitory activity of physalin B, unlike that of dexamethasone, was not reversed by RU486 [(4-dimethylamino) phenyl-17beta-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one], an antiglucocorticoid. Physalin B-treated mice had lower levels of serum TNF-alpha than control mice after lipopolysaccaride challenge. More importantly, mice injected with physalins B, F or G survived after a lethal lipopolysaccaride challenge. These results demonstrate that seco-steroids from P. angulata are potent immunomodulatory substances and act through a mechanism distinct from that of dexamethasone.

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Wo. Gone a bit crazy on pub med but I was very interested about the DHEA/estriol/pregnenolone discussions going on - looks like there is definitely a link between hormones and immunity. Interestingly that bastard bug epstein barr has a real dependence on cholesterol which is the basis for DHEA, which people with MS are low in.

1: Virology. 2007 Apr 10;360(2):461-8. Epub 2006 Dec 5. Links
Cholesterol is critical for Epstein-Barr virus latent membrane protein 2A trafficking and protein stability.Ikeda M, Longnecker R.
Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.

Latent membrane protein 2A (LMP2A) of Epstein-Barr virus (EBV) plays a key role in regulating viral latency and EBV pathogenesis by functionally mimicking signals induced by the B cell receptor (BCR) altering normal B cell development. LMP2A specifically associates with Nedd4 family ubiquitin-protein ligases which downmodulate LMP2A activity by ubiquitinating LMP2A and LMP2A-associated protein tyrosine kinases (PTKs). Since specific ubiquitin tags provide an endocytic sorting signal for plasma membrane proteins which traffic to membrane vesicles, we examined LMP2A localization and trafficking. We found that LMP2A is secreted through exosomes, small endocytic membrane vesicles, as previously demonstrated for LMP1. Interestingly, the treatment of cells with methyl-beta-cyclodextrin (MCD), which depletes cholesterol from plasma membrane, dramatically increased LMP2A abundance and LMP2A exosome secretion. Cholesterol depletion also blocked LMP2A endocytosis resulting in the accumulation of LMP2A on plasma membrane. LMP2A phosphorylation and ubiquitination were blocked by cholesterol depletion. LMP2A in the exosomal fraction was ubiquitinated but not phosphorylated. These results indicate that cholesterol-dependent LMP2A trafficking determines the fate of LMP2A degradation.

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12/6/08
I've been getting a bit confused about my ongoing herbal experiment. I believe that the curcumin and boswellia have been helping keep down the inflammation and have helped me regain some walking ability. I also noted a real change when I added the withania somnifera in that my leg became really spongy that day, the 4th June. It was quite nice walking even on Tuesday 10 evening a hot clear afternoon/evening in London. However I have also had quite a few stiff leg moments recently. For instance on Monday 9th my leg was very stiff in the am which was after a day on 12g of ganoderma lucidum and yesterday and today it has been quite a bit stiffer generally than during May. Now this could be humidity - today it is 82% relative humidity in London and is pretty warm indoors with the windows closed to keep out the damned pollen. My temperature is 37degrees, so normal. Yet I have been feeling quite feverish. Or it could be the change on Monday from guggul plus to gentianae. I have also experienced quite bad nausea after drinking the gentiana tea. Mmm. I see the Chinese doctor today so I think I shall just take the curcumin, boswellia and withania until his tea comes through in a couple of days.

To my slight annoyance I have found some research which shows that withania somnifera increases Th1 response in stressed mice:

1: Int Immunopharmacol. 2006 Sep;6(9):1394-403. Epub 2006 May 8. Links
Augmentation and proliferation of T lymphocytes and Th-1 cytokines by Withania somnifera in stressed mice.Khan B, Ahmad SF, Bani S, Kaul A, Suri KA, Satti NK, Athar M, Qazi GN.
Cell Biology Laboratory, Department of Pharmacology, Regional Research Laboratory, Jammu Tawi 180001, India.

Stress has been associated with reports of both greater severity and prolongation of diseases in patients with the infectious origin as well as other immune-mediated diseases. Withania somnifera, an Indian medicinal plant used widely in the treatment of many clinical conditions in India, was investigated for its anti-stress properties using BALB/c mice subjected to chronic stress. The study aimed to investigate chronic stress-induced alterations on Th1 lymphocyte subset distribution and corresponding cytokine secretion patterns. Oral administration of chemically standardized and identified aqueous fraction of W. somnifera root (WS) at the graded doses of 25, 50, 100 and 200 mg/kg p.o. caused significant increase in the stress-induced depleted T-cell population and increased the expression of Th1 cytokines in chronically stressed mice.

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This may explain why I've noticed a renewed stiffness over the last week or so. I started taking withania 9 days ago. I shall reduce the dose to 4 x 125mg per day which is hardly anything and try to get the Th2 enhancers, trichosanthes kirilowii and xanthii fructus above in my chinese tea.

Just seen the Chinese doctor and I can't wait to receive the new formulas. Most excitingly the ren shen yang rong tang ingredients reminded him of the formulas which his Chinese professor had used in the treatment of MS many years ago. He looked it up and saw that they both were very similar. So the ren shen yang rong tang has been ordered. Meanwhile he is going to remove the inducer of EBV, achyranthes bidentatae, from the tea formula and maybe replace it with one of the Th2 upregulators mentioned above. Can't wait to see which herbs he comes up with. Am very excited! For the time being I am going to stop the indian ginseng and gentiana tea and see if the stiffness dissipates.

17/6/2008
So I stopped the withania and gentiana tea and it seemed like the stiffness dissipated. But more recently I have increased the boswellia and it seems like the stiffness has increased. However there can be no doubt that the heat is up in London. On the whole I guess that the increased boswellia is increasing my stiffness as I noted severe foot cramps a few weeks back when I increased the dose but I think it's the right thing to do. This is because I think I feel better off now with increased boswellia than with previous dose of boswellia and withania. I think my body needs time to adjust to the increased boswellia but that in time its anti-inflammatory properties will serve me well. All a bit of guess though. I just managed 500meters unaided. Tomorrow I have my hormones tested for DHEA, progesterone etc as well as a liver and kidney function test. If I pass the latter at least I'll know my max dose of curcumin and boswellia are okay on the internal organs, whilst if I'm low on DHEA I'll add in some of that and genistein which is a kv1.3 blocker.

Interesting, my wife takes currently for other reasons synthetic progesterone but in her last blood tests had low DHEA levels (1,9mcg/mL when normal levels are between 0,5-5,4 according to the lab).
Plus the progesterone she uses hasn't the neuroprotective effects pubmed mentions and can't easily converted to estrogens which is crucial as the key word here is hormone balance rather high levels of one or other hormone!

Here's some information on genistein and kv1.3:

1: J Membr Biol. 2005 May;205(2):71-9. Links
Genistein inhibits the activity of kv1.3 potassium channels in human T lymphocytes.Teisseyre A, Michalak K.
Department of Biophysics, Wrocław Medical University, ul. Chałubińskiego 10, Wrocław, Poland. ateiss@biofiz.am.wroc.pl

In the present study, the whole-cell patch-clamp technique was applied to follow the inhibitory effect of genistein--a tyrosine kinase inhibitor and a natural anticancer agent--on the activity of voltage-gated potassium channels Kv1.3 expressed in human T lymphocytes (TL). Obtained data provide evidence that genistein application in the concentration range of 1-80 microM reversibly decreased the whole-cell potassium currents in TL in a concentration-dependent manner to about 0.23 of the control value. The half-blocking concentration range of genistein was from 10 to 40 microM. The current inhibition was correlated in time with a significant decrease of the current activation rate. The steady-state activation of the currents was unchanged upon application of genistein, as was the inactivation rate. The inhibitory effect of genistein on the current amplitude and activation kinetics was voltage-independent. The current inhibition was not changed significantly in the presence of 1 mM of sodium orthovanadate, a tyrosine phosphatase inhibitor. Application of daidzein, an inactive genistein analogue, did not affect significantly either the current amplitudes or the activation kinetics. Possible mechanisms of the observed phenomena and their significance for genistein-induced inhibition of cancer cell proliferation are discussed.

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why block kv1.3?

1: J Biol Chem. 2008 Jan 11;283(2):988-97. Epub 2007 Nov 5. Links
The D-diastereomer of ShK toxin selectively blocks voltage-gated K+ channels and inhibits T lymphocyte proliferation.Beeton C, Smith BJ, Sabo JK, Crossley G, Nugent D, Khaytin I, Chi V, Chandy KG, Pennington MW, Norton RS.
Department of Physiology & Biophysics, University of California, California, Irvine, 92697-4560, USA.

The polypeptide toxin ShK is a potent blocker of Kv1.3 potassium channels, which are crucial in the activation of human effector memory T cells (T(EM)); selective blockers constitute valuable therapeutic leads for the treatment of autoimmune diseases mediated by T(EM) cells, such as multiple sclerosis, rheumatoid arthritis, and type-1 diabetes. The critical motif on the toxin for potassium channel blockade consists of neighboring lysine and tyrosine residues. Because this motif is sufficient for activity, an ShK analogue was designed based on D-amino acids. D-allo-ShK has a structure essentially identical with that of ShK and is resistant to proteolysis. It blocked Kv1.3 with K(d) 36 nm (2,800-fold lower affinity than ShK), was 2-fold selective for Kv1.3 over Kv1.1, and was inactive against other K(+) channels tested. D-allo-ShK inhibited human T(EM) cell proliferation at 100-fold higher concentration than ShK. Its circulating half-life was only slightly longer than that of ShK, implying that renal clearance is the major determinant of its plasma levels. D-allo-ShK did not bind to the closed state of the channel, unlike ShK. Models of D-allo-ShK bound to Kv1.3 show that it can block the pore as effectively as ShK but makes different interactions with the vestibule, some of which are less favorable than for native ShK. The finding that an all-D analogue of a polypeptide toxin retains biological activity and selectivity is highly unusual. Being resistant to proteolysis and nonantigenic, this analogue should be useful in K(+) channel studies; all-d analogues with improved Kv1.3 potency and specificity may have therapeutic advantages.

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1: J Immunol. 2007 Oct 1;179(7):4563-70. Links
Characterization of the functional properties of the voltage-gated potassium channel Kv1.3 in human CD4+ T lymphocytes.Hu L, Pennington M, Jiang Q, Whartenby KA, Calabresi PA.
Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA.

Previous studies have shown that central memory T (T(CM)) cells predominantly use the calcium-dependent potassium channel KCa3.1 during acute activation, whereas effector memory T (T(EM)) cells use the voltage-gated potassium channel Kv1.3. Because Kv1.3-specific pharmacological blockade selectively inhibited anti-CD3-mediated proliferation, whereas naive T cells and T(CM) cells escaped inhibition due to up-regulation of KCa3.1, this difference indicated a potential for selective targeting of the T(EM) population. We examined the effects of pharmacological Kv1.3 blockers and a dominant-negative Kv1.x construct on T cell subsets to assess the specific effects of Kv1.3 blockade. Our studies indicated both T(CM) and T(EM) CD4+ T cells stimulated with anti-CD3 were inhibited by charybdotoxin, which can block both KCa3.1 and Kv1.3, whereas margatoxin and Stichodactyla helianthus toxin, which are more selective Kv1.3 inhibitors, inhibited proliferation and IFN-gamma production only in the T(EM) subset. The addition of anti-CD28 enhanced proliferation of freshly isolated cells and rendered them refractory to S. helianthus, whereas chronically activated T(EM) cell lines appeared to be costimulation independent because Kv1.3 blockers effectively inhibited proliferation and IFN-gamma regardless of second signal. Transduction of CD4+ T cells with dominant-negative Kv1.x led to a higher expression of CCR7+ T(CM) phenotype and a corresponding depletion of T(EM). These data provide further support for Kv1.3 as a selective target of chronically activated T(EM) without compromising naive or T(CM) immune functions. Specific Kv1.3 blockers may be beneficial in autoimmune diseases such as multiple sclerosis in which T(EM) are found in the target organ

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and

1: Neurosci Lett. 2008 Jun 13;438(1):116-20. Epub 2008 Apr 20.Links
Genistein attenuates oxidative stress and neuronal damage following transient global cerebral ischemia in rat hippocampus.Liang HW, Qiu SF, Shen J, Sun LN, Wang JY, Bruce IC, Xia Q.
Department of Physiology, Zhejiang University School of Medicine, 388 Yuhangtang Road, Hangzhou 310058, China.

Oxidative stress is believed to contribute to neuronal damage induced by cerebral ischemia/reperfusion (I/R) injury. The present study was undertaken to evaluate the possible antioxidant neuroprotective effect of genistein against neuronal death in hippocampal CA1 neurons following transient global cerebral ischemia in the rat. Transient global cerebral ischemia was induced in male Sprague-Dawley rats by four-vessel-occlusion for 10min. At various times of reperfusion, the histopathological changes and the levels of mitochondria-generated reactive oxygen species (ROS), malondialdehyde (MDA), cytosolic cytochrome c and caspase-3 activity in hippocampus were measured. We found extensive neuronal death in the CA1 region at day 5 after I/R. The ischemic changes were preceded by increases in ROS generation and MDA concentration and followed by increased cytosolic cytochrome c, and subsequently caspase-3 activation and apoptosis. Treatment with genistein (15mg/kg, i.p.) significantly attenuated ischemia-induced neuronal death. Genistein administration also decreased ROS generation, MDA concentration and the apoptotic indices. These results suggest that genistein protects neurons from transient global cerebral I/R injury in rat hippocampus by attenuating oxidative stress, lipid peroxidation and the signaling cascade leading to apoptotic cell death.

PMID: 18467029 [PubMed - in process]

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1: J Neurosci Res. 2005 Feb 1;79(3):310-7. Links
Enhancement of Schwann cell myelin formation by K252a in the Trembler-J mouse dorsal root ganglion explant culture.Liu N, Varma S, Shooter EM, Tolwani RJ.
Department of Neurobiology, School of Medicine Stanford University, 299 Campus Drive, Fairchild Building D225, Stanford, CA 94305, USA. nliu@cmgm.stanford.edu

The Trembler-J (TrJ) mouse, containing a point mutation in the peripheral myelin protein 22 gene, is characterized by severe hypomyelination and is a representative model of Charcot-Marie-Tooth 1A disease/Dejerine-Sottas Syndrome. Previous studies have shown that protein kinase inhibitor K252a enhances wild-type Schwann cell myelination in culture. We used a dorsal root ganglion (DRG) explant culture system from the heterozygous TrJ/+ mouse to investigate if myelination could be enhanced by K252a. The TrJ/+ DRG explant cultures replicated some important features of the TrJ/+ mouse, showing reduced myelin protein accumulation, thinner myelin sheaths, and shortened myelin internodes. K252a increased myelin protein accumulation and myelin sheath thickness but did not substantially increase myelin internode length. Furthermore, the TrJ/+ DRG explant culture and sciatic nerves continued to respond to K252a during the stage when myelination is complete in the wild type. A general tyrosine kinase inhibitor, genistein, but not inhibitors of serine/threonine protein kinase inhibitors, had a similar effect to K252a. K252a is therefore able to partially overcome hypomyelination by enhancing mutant Schwann cell myelin formation in the TrJ/+ mouse.

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1: Eur J Immunol. 1998 Nov;28(11):3523-9. Links
Tyrphostin AG490, a tyrosine kinase inhibitor, blocks actively induced experimental autoimmune encephalomyelitis.Constantin G, Brocke S, Izikson A, Laudanna C, Butcher EC.
Department of Pathology, Stanford University School of Medicine, Veterans Administration Medical Center, Palo Alto, USA. constant@borgoroma.univr.it

Migration of lymphocytes from blood into the brain is a critical event in the pathogenesis of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). Previous observations made in our laboratory showed that protein tyrosine kinase inhibitors were able to block lymphocyte adhesion to brain endothelium and prevent the entry of encephalitogenic T cell lines into the brain of SJL/J mice. Here we show that systemic administration of the protein tyrosine kinase inhibitor, tyrphostin AG490, blocks the development of actively induced EAE in a dose-dependent manner. Administration of 1 mg of drug daily significantly decreased the severity of the disease, while 3 mg of AG490 daily totally blocked the disease in 62% of treated animals, and in those that developed the disease, paralysis was delayed and clinical score was significantly reduced. Blood leukocytes isolated from mice treated with tyrphostin AG490 were less adhesive on VCAM-1 and fibronectin, when compared with control animals. AG490 treatment had no effect on the proliferation by antigen-stimulated peripheral lymph nodes cells. Interestingly, cells obtained from draining lymph nodes in AG490-treated animals and stimulated with antigen secreted two times more IFN-gamma and four times more IL-10, when compared with control animals, whereas no difference was observed in TNF-alpha production. Our results suggest that tyrphostin AG490 may have therapeutic potential by blocking tyrosine kinase activities involved in key mechanisms leading to demyelinating diseases of the central nervous system.

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One other positive thing I have noted since around mid-March 08 is that I no longer have itchiness around my front, arms or face and I used to get that a lot before when on antibiotics and initially for a few weeks after the steroids they were very noticeable but now I hardly notice this at all.

an old article on EBV and DHEA...all in all looks like DHEA should be in the supplement regime.

1: Carcinogenesis. 1981;2(7):683-6. Links
Dehydroepiandrosterone and 16 alpha-bromo-epiandrosterone: inhibitors of Epstein-Barr virus-induced transformation of human lymphocytes.Henderson E, Schwartz A, Pashko L, Abou-Gharbia M, Swern D.
Dehydroepiandrosterone (DHEA), a major adrenal secretory product in men and women, is a potent inhibitor of mammalian glucose-6-phosphate dehydrogenase (G6PDH). Long-term treatment with this steroid has previously been found to suppress spontaneous breast cancer development in C3H mice. DHEA is now shown to inhibit Epstein-Barr virus (EBV)-induced morphologic transformation and stimulation of DNA synthesis in human lymphocytes. 16 alpha-Br-epiandrosterone, a DHEA analog that is about 60 times as potent as DHEA as an inhibitor of G6PDH, is much more effective as an inhibitor of EBV-induced transformation.

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From wikipedia today:

Dehydroepiandrosterone (DHEA) is a natural steroid prohormone produced from cholesterol by the adrenal glands, the gonads, adipose tissue, brain and in the skin (by an autocrine mechanism). DHEA is the precursor of androstenedione, which can undergo further conversion to produce the androgen testosterone and the estrogens estrone and estradiol. DHEA is also a potent sigma-1 agonist

This pubmed article supports the above view of DHEA as a sigma-1 agonist:

1: Synapse. 2007 Jul;61(7):540-6. Links
In vitro and in vivo binding of neuroactive steroids to the sigma-1 receptor as measured with the positron emission tomography radioligand [18F]FPS.Waterhouse RN, Chang RC, Atuehene N, Collier TL.
Department of Psychiatry, Columbia University, New York, New York, USA. rikki_waterhouse@merck.com

Sigma-1 receptors are widely expressed in the mammalian brain and also in organs of the immune, endocrine and reproductive systems. Based on behavioral and pharmacological assessments, sigma-1 receptors are important in memory and cognitive processes, and are thought to be involved in specific psychiatric illnesses, including schizophrenia, depression, and drug addiction. It is thought that specific neuroactive steroids are endogenous ligands for these sites. In addition, several sigma-1 receptor binding steroids including progesterone, dihydroepiandrosterone (DHEA), and testosterone are being examined clinically for specific therapeutic purposes; however, their mechanisms of action have not been clearly defined. We previously described the high affinity sigma-1 receptor selective PET tracer [(18)F]FPS. This study examines the effect of neuroactive steroids on [(18)F]FPS binding in vitro and in vivo. Inhibition constants were determined in vitro for progesterone, testosterone, DHEA, estradiol, and estriol binding to the [(18)F]FPS labeled receptor. The affinity order (K(i) values) for these steroids ranged from 36 nM for progesterone to >10,000 nM for estrodiol and estriol. Biodistribution studies revealed that i.v. coadministration of progesterone (10 mg/kg), testosterone (20 mg/kg), or DHEA (20 mg/kg) significantly decreased [(18)F]FPS uptake (%ID/g) by up to 50% in nearly all of eight brain regions examined. [(18)F]FPS uptake in several peripheral organs that express sigma-1 receptors (heart, spleen, muscle, lung) was also reduced (54-85%). These studies clearly demonstrate that exogenously administered steroids can occupy sigma-1 receptors in vivo, and that [(18)F]FPS may provide an effective tool for monitoring sigma-1 receptor occupancy of specific therapeutic steroids during clinical trials.

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Of what import sigma-1? This from wikipedia today:

The sigma-1 receptor is a transmembrane protein expressed in many different tissue types. It is particularly concentrated in certain regions of the central nervous system.[1] It has been implicated in myriad phenomena, including cardiovascular function, schizophrenia, clinical depression, the effects of cocaine abuse, and cancer.[2][3] Furthermore, although much is known about the binding affinity of hundreds of compounds to the sigma-1 receptor, an endogenous ligand has never been conclusively identified.

A variety of specific physiological functions have been attributed to the sigma-1 receptor. Chief among these are modulation of Ca2+ release, modulation of cardiac myocyte contractility, and inhibition of voltage gated K+ channels.[6] The reasons for these effects are not well understood, even though sigma-1 receptors have been linked circumstantially to a wide variety of signal transduction pathways. Links between sigma-1 receptors and G-proteins have been suggested, but there is also some evidence against this hypothesis.[7] The sigma-1 receptor has been shown to appear in a complex with voltage gated K+ channels (Kv 1.4 and Kv 1.5), leading to the idea that sigma-1 receptors are auxiliary subunits.[8] Sigma-1 receptors apparently co-localize with IP3 receptors on the endoplasmic reticulum.[9] Also, sigma-1 receptors have been shown to appear in galactoceramide enriched domains at the endoplasmic reticulum of mature oligodendrocytes.[10] The wide scope and effect of ligand binding on sigma-1 receptors has led some to believe that sigma-1 receptors are intracellular signal transduction amplifiers.[5]

This article from pubmed supports the view of the sigma-1 receptor involvement in potassium channel blocking:

1: J Pharmacol Exp Ther. 2005 Jun;313(3):1387-96. Epub 2005 Mar 11. Links
sigma Receptor activation blocks potassium channels and depresses neuroexcitability in rat intracardiac neurons.Zhang H, Cuevas J.
Department of Pharmacology and Therapeutics, University of South Florida College of Medicine, Tampa 33612, USA.

The sigma receptors have been implicated in the regulation of the cardiovascular system, and sigma-1 receptor transcripts have been found in parasympathetic intracardiac neurons. However, the cellular function of sigma-1 receptors in these cells remains to be determined. Effects of sigma receptor activation on voltage-activated K(+) channels and action potential firing were studied in isolated intracardiac neurons using whole-cell patch-clamp recording techniques. Activation of sigma receptors reversibly blocked delayed outwardly rectifying potassium channels, large conductance Ca(2+)-sensitive K(+) channels, and the M-current with maximal inhibition >80%. The inhibition of K(+) channels by sigma ligands was dose-dependent, and the rank order potency of (+)-pentazocine > ibogaine > 1,3-di-O-tolyguanidin (DTG) suggests that the effect is mediated by sigma-1 receptor activation. Preincubation of neurons with the irreversible sigma receptor antagonist metaphit blocked DTG-induced inhibition of K(+) channels, confirming that the effect is mediated by sigma receptor activation. Although bath application of sigma ligands depolarized intracardiac neurons, the number of action potentials fired by the cells in response to depolarizing current pulses was decreased in the presence of these drugs. Neither dialysis of the neurons nor application of intracellular 5'-O-(2-thiodiphosphate) trilithium salt inhibited the effect of sigma receptors on K(+) channels, which suggests that the signal transduction pathway does not involve a diffusible cytosolic second messenger or a G protein. Together, these data suggest that sigma-1 receptors are directly coupled to K(+) channels in intracardiac neurons. Furthermore, activation of sigma-1 receptors depresses the excitability of intracardiac neurons and is thus likely to block parasympathetic input to the heart.

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This article implies voltage-gated potassium channels as opposed to voltage-activated potassium channels are the same thing but can't be sure there:

1: J Pharmacol Exp Ther. 2004 Dec;311(3):1105-14. Epub 2004 Jul 26. Links
Inhibition of tumor cell proliferation by sigma ligands is associated with K+ Channel inhibition and p27kip1 accumulation.Renaudo A, Watry V, Chassot AA, Ponzio G, Ehrenfeld J, Soriani O.
UNSA Centre National de la Recherche Scientifique UMR 6078, Laboratoire de Physiologie des Membranes Cellulaires, Bāt. Jean Maetz, La Darse, 284, Chemin du Lazaret, 06230 Villefranche-sur-Mer, France.

Previous studies have shown that sigma receptors are overexpressed in tumor cells. However, the role of sigma receptors remains enigmatic. Recently, we and others have demonstrated that sigma-1 receptor modulates K+ channels in pituitary. In the present report, patch-clamp and Western blot assays were used in small cell lung cancer (SCLC, NCI-H209, and NCI-H146) and leukemic (Jurkat) cell lines to investigate the effects of sigma ligands on voltage-gated K+ channels and cell proliferation. The sigma ligands (+)-pentazocine, igmesine, and 1,3-di(2-tolyl)guanidine (DTG) all reversibly inhibited voltage-activated K+ currents in both cell lines. The potency of sigma ligand-induced inhibition (10 microM) was igmesine = (+)-pentazocine > DTG, pointing to the involvement of sigma-1 receptors. Addition of the K+ channel blockers tetraethylammonium (TEA) and 4-aminopyridin or one of cited sigma ligands in the culture media reversibly inhibited Jurkat cell growth. Interestingly, K+ channel blockers and sigma ligands caused an accumulation of the cyclin-dependent kinase inhibitor p27kip1 and a decrease in cyclin A expression in Jurkat and SCLC cells, whereas no effect could be detected on p21cip1. Moreover, sigma ligands and TEA had no effect on caspase 3 activity. Accordingly, incubation of cells with sigma ligands did not provoke DNA laddering. These data demonstrate that sigma ligands and voltage-dependent channel blockers inhibit cell growth through a cell cycle arrest in the G1 phase but not via an apoptotic mechanism. Altogether, these results indicate that the sigma-1 receptor-induced inhibition of the cell cycle is, at least in part, the consequence of the inhibition of K+ channels.

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All of which brings us back to:

1: Ann Neurol. 2006 Nov;60(5):586-96. Links
Block of neural Kv1.1 potassium channels for neuroinflammatory disease therapy.Beraud E, Viola A, Regaya I, Confort-Gouny S, Siaud P, Ibarrola D, Le Fur Y, Barbaria J, Pellissier JF, Sabatier JM, Medina I, Cozzone PJ.
Service d'Immunologie, Faculté de Médecine, Université de la Méditerranée, Marseille, France. evelyne.beraud@univmed.fr

OBJECTIVE: We asked whether blockade of voltage-gated K+ channel Kv1.1, whose altered axonal localization during myelin insult and remyelination may disturb nerve conduction, treats experimental autoimmune encephalomyelitis (EAE). METHODS: Electrophysiological, cell proliferation, cytokine secretion, immunohistochemical, clinical, brain magnetic resonance imaging, and spectroscopy studies assessed the effects of a selective blocker of Kv1.1, BgK-F6A, on neurons and immune cells in vitro and on EAE-induced neurological deficits and brain lesions in Lewis rats. RESULTS: BgK-F6A increased the frequency of miniature excitatory postsynaptic currents in neurons and did not affect T-cell activation. EAE was characterized by ventriculomegaly, decreased apparent diffusion coefficient, and decreased (phosphocreatine + beta-adenosine triphosphate)/inorganic phosphate ratio. Reduced apparent diffusion coefficient and impaired energy metabolism indicate astrocytic edema. Intracerebroventricularly BgK-F6A-treated rats showed attenuated clinical EAE with unexpectedly reduced ventriculomegaly and preserved apparent diffusion coefficient values and (phosphocreatine + beta-adenosine triphosphate)/inorganic phosphate ratio. Thus, under BgK-F6A treatment, brain damage was dramatically reduced and energy metabolism maintained. INTERPRETATION: Kv1.1 blockade may target neurons and astrocytes, and modulate neuronal activity and neural cell volume, which may partly account for the attenuation of the neurological deficits. We propose that Kv1.1 blockade has a broad therapeutic potential in neuroinflammatory diseases (multiple sclerosis, stroke, and trauma).

PMID: 17044011 [PubMed - indexed for MEDLINE]

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1: J Rehabil Res Dev. 2006 Jan-Feb;43(1):111-22.Links
Voltage-gated potassium channels in multiple sclerosis: Overview and new implications for treatment of central nervous system inflammation and degeneration.Judge SI, Lee JM, Bever CT Jr, Hoffman PM.
Department of Veterans Affairs (VA) Multiple Sclerosis Center of Excellence East, Baltimore, MD, USA. sjudge@umaryland.edu

Inflammatory tissue damage and the presence of reactive immunocompetent T lymphocytes, macrophages, microglia, and dendritic cells (DCs) are characteristic features in the human chronic inflammatory demyelinating disease, multiple sclerosis (MS). Together, these cells orchestrate the inflammation and immunopathogenesis underlying the MS autoimmune disease processes and all up-regulate the same voltage-gated potassium (K(v)) channel, K(v)1.3, when fully activated. Only microglia, which mediate central nervous system (CNS) inflammatory processes (possibly playing a dual role of CNS protection and mediation of neuroinflammation/ neurodegeneration), and DC, which are pivotal to the induction of T cell responses, express the distinct K(v)1.5 prior to K(v)1.3 up-regulation. Although the precise functional roles of first K(v)1.5 and then K(v)1.3 channels are unclear, their differential expression is likely a common mechanism used by both microglia and DC, revealing K(v)1.5 (in addition to K(v)1.3) as a potentially important target for the development of new immunomodulatory therapies in MS.

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All of which means drinking red wine is the way to go...

1: J Membr Biol. 2006;214(3):123-9. Epub 2007 Jun 5. Links
Inhibition of the activity of human lymphocyte Kv1.3 potassium channels by resveratrol.Teisseyre A, Michalak K.
Department of Biophysics, Wrocław Medical University, ul. Chałubińskiego 10, 50-368, Wrocław, Poland. ateiss@biofiz.am.wroc.pl

The whole-cell patch-clamp technique was applied to study the modulatory effect of resveratrol on voltage-gated potassium channel Kv1.3 expressed in human lymphocytes. Results demonstrate that application of resveratrol in the concentration range 1-200 muM: inhibited the channel activity in a concentration-dependent manner to about 18% of the control value. The half-blocking concentration of resveratrol was 40.9 microM: , whereas the Hill coefficient was 1.05. The inhibition was time-dependent and slowly reversible. The inhibitory effect of resveratrol was correlated in time with a significant slowing of the current activation, whereas the inactivation rate remained unaffected upon application of resveratrol. The inhibition of Kv1.3 channels was voltage-independent. The steady-state activation of the currents remained unchanged upon resveratrol application. The magnitude of the inhibitory effect of resveratrol was not altered when resveratrol was coapplied with genistein. The possible mechanism of the inhibitory effect and its significance for biological activity of resveratrol are discussed.

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Given all the above data I have added today 3 grammes of reserveratrol to be taken at the same time as the bioperine to aid absobancy as again this compound is hard to absorb. I want to get this up to 6 grammes daily but will see if there is any effect of 3g and the chinese tea, one of which has arrived and consists of the following:
40 rehmannia radix
25 angelica sinensis radix
25 astragali radix
20 poria
20 paeoniae radix alba
20 atractylodis marcocephalae
15 codonopsis radix
15 ginseng radix
15 shisandra fructus
15 polygalae radix
15 citri reticulatae percarpium
15 jujubae fructus
10 cinnamoni cortex
10 glycyrrhize radix preparata
10 zingiberis rhizomatis cortex

Phewee that's along list! I wonder if this is the ren shen yang rong tang.
Here's a web formula

ren shen yang rong tang 人 參 養 榮 湯

Edited and translated by: Joe Hing Kwok Chu

Name of Formula: ren shen yang rong tang (source: He Ju Ji Fang)

Application: for qixu and blood deficiency

Formula:

bai shao 18 g, dang gui 15 g, chen pi 12 g, huang qi 30 g, rou gui 6 g, ren shen 15 g (boil first), bai zhu 15 g, zhi gan cao 9 g, shu di 15 g, wu wei zi 12 g, fu ling 15 g, yuan zhi 9 g, he shou wu 30 g, dan shen 30 g, ji xue teng 30 g, sheng jiang 6 g, da zao 7 pieces. Add 1000 c.c. of water. Simmer till 200 ~ 300 c.c. Make into 2 serving. Drink while warm.

Apart from the he shou wu and ji xue teng this list is the same as the ingredients although the weights may be different...

Interesting gibbledygook just received the Polygala (radix polygalae preparata) root extract and according to the seller my wife should take almost 3 gramms per day, much higher quantity than all the ingredients together of your "ren shen yang rong tang"!
On the other hand are the euxanthones from polygala (similar with mango's xanthones) that promote nerve regeneration.
He suggested me to give her 2-3 times x 1gram daily with hot water or with meals, what about yours?

It's rather hard to say how much of each constituent I'll get but I'm to take 2 teaspoons 3 times a day with honey. I'll get my weighing machine out and see if it will record these rather small amounts. I would guess that you are right that I'll be getting much less polygala than 3 grams but it might not be far off. It rather depends how much a spoonful weighs!! Not sure if my weighing machine will be sensitive enough but will try tomorrow. I must admit that with most of the herbs I've looked at a minimum of about 3g is required in humans so I'll be rather disappointed if I get much less than that. From my recollection, the last tea worked out at about 3g a day for the main ingredient which in this case would be the rehmannia preparata. I will be getting another tea shortly so wonder if there will be more polygala in that one.

My weighing machine has worked! Each heaped spoon is about 5g. So in total I take 30g of the herbs a day. Using the above ratios I only take 1.7g of the polygala but 4.4g of the rehmannia. Still, I take more polygala than cinnamoni. I'll just have to see if I feel an effect and so far so good. I slept really well last night and woke up to a pretty unstiff leg but that is probably random.

The weekend produced mixed results vis a vis leg function but it's probably a little early for any effect from the tea and reservatrol. On Friday night I celebrated a dinner with friends in Oxford. It was very humid and I was wearing boots which I haven't tried in at least a year. Walking was very tricky and nearly impossible after a brandy and roll-up cigarette. The following day was much less humid, so despite drinking almost as much alcohol and again having a tobacco cigarette the walking was much easier. Clearly there is plenty of damage there but it's manifestation varies according to humidity. Unless the tea and reservatrol miraculously kicked in on Saturday!

26/6/08
I have been taking the ren shen yang rong tang and the resveratrol for nearly a week and am disappointed that I can't really detect much of a difference. When I started high dose curcumin with moderate dose boswellia I really noticed a change.
I typed "spinal cord chinese" into pubmed and made some further discoveries:

1: J Ethnopharmacol. 2008 May 22;117(3):451-6. Epub 2008 Mar 4. Links
BYHWD rescues axotomized neurons and promotes functional recovery after spinal cord injury in rats.Chen A, Wang H, Zhang J, Wu X, Liao J, Li H, Cai W, Luo X, Ju G.
Department of Anatomy & Neurobiology, Xiangya School of Medicine, Central South University, Changsha 410013, China; Department of Anatomy, Hunan Traditional Chinese Medicine University, Changsha 410007, China.

ETHNOPHARMACOLOGICAL RELEVANCE: Buyang Huanwu Decoction (BYHWD), a Chinese prescription that has been used for hundreds of years to treat paralysis, has gained attention recently due to its significant neuroprotective properties. AIM OF THE STUDY: This study was to investigate whether BYHWD treatment protected axotomized rubrospinal neurons (RN) following spinal cord injury (SCI) in rats. MATERIALS AND METHODS: Adult rats received a right lateral funiculus transection at the level between C3 and C4, and were either treated with BYHWD or with distilled water (DW) via gastrogavage. Effects on RN viability and atrophy were determined by Nissl staining, axon regeneration was examined by biotinylated dextran amine (BDA) tracing techniques and functional recovery was studied by a test of forelimb usage during spontaneous vertical exploration. RESULTS: RN cell number and mean somal size were 20% and 29% higher, respectively, in BYHWD-treated rats relative to DW-treated rats. There were a small number of BDA-labeled axons in the caudal of injury site in BYHWD-treated rats, whereas no caudal axonal regeneration was detected in DW-treated rats. BYHWD-treated rats used the injured forelimb more often than rats treated with DW. CONCLUSIONS: These results indicate that administration of BYHWD following SCI protects injured neurons, promotes regeneration, and enhances functional recovery.

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1: Zhongguo Zhong Xi Yi Jie He Za Zhi. 1994 Feb;14(2):74-6, 67.Links
[Clinical and experimental research of buyang huanwu tang granule in treatment of ischemic apoplexy][Article in Chinese]


Zha LL, Shen ZY, Zhang P.
Institute of the Integration of TCM-WM, Shanghai Medical University.

38 cases of ischemic apoplexy were randomly divided into three groups. Among them 26 cases were treated with type I and type III of Buyang Huanwu Tang Granule (BYHWTG) for 10 weeks, respectively. The other 12 cases served as a control group. The results showed that clinical cure and markedly effective rate were 42.3%, the total effective rate was 88.5% in BYHWTG group. The effective rate of BYHWTG type I for the treatment of ischemic apoplexy was 100% and it was superior to type III (84.6). BYHWTG could significantly improve hemorheologic indexes in the patients of ischemic apoplexy. The activity of RBC sodium pump was markedly raised from 0.210 +/- 0.003 to 0.250 +/- 0.008 1/h (P < 0.001) in BYHWTG type I. The results of this study suggested that BYHWTG had evident efficacy in the treatment of ischemic apoplexy.

http://www.ncbi.nlm.nih.gov/pubmed/8044011

The way my private English/Irish quack laughed about ren shen yang rong tang is symptomatic of Western medicine. Manifestly, however, the herbs are bioactive.

Yesterday I had rather a serendipidous moment when I rescued a young Chinese lady hobbling in agony down the road - her walking was worse than mine - and so I took her to the local hospital. She hadn't been able to do this because she had run out of money and she couldn't get hold of her husband who was...working as a Chinese medical practitioner in the King's road. I paid for the taxi and helped her fill in the forms at the hospital. Knowing a little of the Asian honour code I may have made a very fortuitous or possibly problematic connection! In Japan it is considered bad form to help strangers as then they are indebted to them. Ridiculous! That poor girl could barely manage a few inches as it transpires she had broken her foot. Can the Japanese really walk past people in such agony and refuse to help because of honour? Well, she was Chinese at least.

1: Chin J Physiol. 2007 Aug 31;50(4):151-6.Links
Effects of Buyang Huanwu Decoction on neurite outgrowth and differentiation of neuroepithelial stem cells.Sun JH, Gao YM, Yang L, Wang X, Bao LH, Liu WJ, Yew D.
Institute of Anatomy and Histology & Embryology, School of Medicine, Shandong University, Jinan 250012, Shandong, P.R. China. sunjinhao@sdu.edu.cn

To determine the effects of Buyang Huanwu Decoction (BYHWD), a traditional Chinese medicine, on neurite outgrowth and differentiation of neuroepithelial stem cells (NEPs), NEPs were isolated from embryonic neural tube and cultured in medium with rat serum containing BYHWD, which was prepared from rats administrated orally with BYHWD. The average neurite length of NEPs grew significantly longer in rat serum containing BYHWD than in control serum without BYHWD. More neurofilament (NF) positive cells and glial fibrillary acidic protein (GFAP) positive cells were detected in NEPs cultured in the presence of BYHWD. Besides, when cultured NEPs were loaded with Fluo-3-AM, the fluorescence intensity obtained from NEPs cultured in serum with BYHWD was significantly lower than that from NEPs cultured in control serum without BYHWD. Our results indicate that BYHWD could exert a promotion effect on neurite outgrowth and differentiation of NEPs.

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1: Zhong Xi Yi Jie He Za Zhi. 1989 Mar;9(3):164-6, 134.Links
[Anti-inflammatory and immunologic actions of buyang huanwu tang][Article in Chinese]


Duan JY.
Orally administered with Buyang Huanwu Tang (BHT) markedly inhibited swelling of mice's ear induced by xylene and significantly depressed the increase of capillary permeability induced by acetic acid in mice. The carrageenin induced edema of hind paws and the proliferation of granuloma induced by subcutaneous implantation of plastic ring in rats were inhibited by BHT. The results indicated that BHT possessed a marked anti-acute and chronic inflammatory effects. The weights of spleen and thymus, and clearance rate of charcoal particles by intravenous in mice could be increased by oral administration of BHT. It markedly promoted phagocytosis of the peritoneal macrophages of mice and hemolysin reaction. The above data revealed that anti-inflammatory effect of BHT could relatively improve immunological functions.

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but what is it? Well after digging around and paying 30bucks I discovered that it consists of radix astragalis seu hedysari, radix angelicae sinensis, radix paeoniae rubra, rhizoma ligustici chuanxiong, flos carthami semen persicae, pheretima. The ratio in the experiment for which I have a pdf file if anyone wants was 120:6:4.5:3:3:3:3.