[/img]<shortened url>1: J Pharmacol Sci. 2007 Sep;105(1):34-40. Links
Protective effects of Guizhi-Fuling-Capsules on rat brain ischemia/reperfusion injury.Li TJ, Qiu Y, Mao JQ, Yang PY, Rui YC, Chen WS.
Department of Pharmacology, School of Pharmacy, Second Military Medical University, 325 GuoHe Road, Shanghai 200433, China.
Previous studies revealed that Guizhi-Fuling-Capsules (GZFLC), a traditional Chinese medical (Kampo) formulation composed of five kinds of medicinal plants, Cinnamomum cassia BLUME (Cinnamomi Cortex), Paeonia lactiflora PALL. (Peonies Radix), Paeonia suffruticosa ANDREWS (Moutan Cortex), Prunus persica BATSCH (Persicae Semen), and Poria cocos WOLF (Hoelen), exerts a protective effect against vascular injury and has a protective effect against glutamate- or nitro oxide-mediated neuronal damage. In the present study, the effect of GZFLC in a rat in vivo model of focal cerebral ischemia and reperfusion was investigated. Administration of GZFLC (0.3 and 0.9 g/kg, p.o.) after focal cerebral ischemia significantly decreased brain infarction and water contents in rats subjected to 2-h ischemia followed by 24-h reperfusion from 31.72 +/- 2.49%, 84.76 +/- 1.63% in the model group to 17.31 +/- 3.66%, 82.51 +/- 1.36% and 8.30 +/- 3.73%, 81.35 +/- 1.73%, respectively. Furthermore, analysis of inflammatory cytokines in ischemic brain showed that GZFLC treatment significantly down-regulated expressions of pro-inflammatory cytokines including interleukin (IL)-1beta and tissue necrosis factor-alpha and markedly up-regulated expressions of anti-inflammatory cytokines IL-10 and IL-10R both in mRNA and protein levels. The serum levels of these inflammatory cytokines were also regulated the same way. These results suggested that GZFLC may be beneficial for the treatment of brain ischemia-reperfusion injury partly due to its anti-inflammatory properties.
<shortened url>1: Brain Res. 2005 Feb 28;1035(2):206-10. Epub 2005 Jan 22. Links
Phenidone, a dual inhibitor of cyclooxygenases and lipoxygenases, ameliorates rat paralysis in experimental autoimmune encephalomyelitis by suppressing its target enzymes.Moon C, Ahn M, Wie MB, Kim HM, Koh CS, Hong SC, Kim MD, Tanuma N, Matsumoto Y, Shin T.
Department of Veterinary Medicine, Aradong 1, Cheju National University, Jeju 690-756, South Korea.
This study examined whether phenidone, a dual inhibitor of cyclooxygenase (COX) and lipoxygenase (LOX), affects the clinical symptoms of experimental autoimmune encephalomyelitis (EAE) in the rat, and the expression of both COX-1/-2 and 5-LOX in EAE spinal cords. Oral phenidone (200 mg/kg) significantly suppressed the incidence and clinical severity of EAE paralysis. Western blot analysis showed that phenidone significantly inhibited the increases in COX-1/-2 and 5-LOX in the spinal cords of rats with EAE. This finding was paralleled by immunohistochemical observations. Overall, these findings suggest that COX-1/-2 and 5-LOX are important inflammatory mediators in the pathogenesis of EAE, and that the inhibition of both COX and LOX ameliorates the autoimmune disorder of the central nervous system.
<shortened url>1: Brain Res. 2004 Sep 17;1021(1):140-5. Links
Experimental allergic encephalomyelitis is exacerbated in mice deficient for 12/15-lipoxygenase or 5-lipoxygenase.Emerson MR, LeVine SM.
Department of Molecular and Integrative Physiology, Ralph L. Smith Mental Retardation Research Center, University of Kansas Medical Center, Kansas City, KS 66160, USA. firstname.lastname@example.org
12/15-Lipoxygenase (12/15-LO) produces 15-hydroxyeicosatetraenoic acid (15-HETE) and 13-hydroxyoctadecadienoic acid (13-HODE) which are agonists for peroxisome proliferator-activated receptor-gamma (PPARgamma). PPARgamma agonists reduce clinical severity of experimental allergic encephalomyelitis (EAE), an animal model of multiple sclerosis. In contrast, 5-lipoxygenase (5-LO) produces the generally proinflammatory leukotrienes (LTs) which would be expected to worsen EAE. We tested the hypotheses that EAE severity would be exacerbated in 12/15-LO-deficient mice and attenuated in 5-LO-deficient mice. 12/15-LO deficiency conferred a significantly worse disease course, and surprisingly, 5-LO deficiency also caused significantly more severe EAE compared to control mice. These data suggest that PPARgamma-regulated gene expression and that 5-LO production of certain LTs have the ability to diminish EAE. Continued analysis will provide insight into the endogenous LO-generated effectors that assist in tempering EAE.
<shortened url>1: J Neuroimmunol. 2005 Sep;166(1-2):55-64. Links
Involvement of 5-lipoxygenase in spinal cord injury.Genovese T, Mazzon E, Rossi A, Di Paola R, Cannavò G, Muià C, Crisafulli C, Bramanti P, Sautebin L, Cuzzocrea S.
Dipartimento Clinico Sperimentale di Medicina e Farmacologia, Facoltà di Medicina e Chirurgia, Università di Messina, Italy.
A traumatic spinal cord injury (SCI) induces a sequelae of events which conduce biochemical and cellular alterations. Here we compare the degree of spinal cord injury caused by the application of vascular clips, in mice lacking the 5-lipoxygenase and in the corresponding wild-type mice. Biochemical, immunohistochemical and functional studies revealed respectively an increase of neutrophils infiltration, of IL-1beta, TNF-alpha immunoreactivity, apoptosis (measured by Annexin-V staining) and loss of hind legs movement in SCI operated 5-LO wild-type mice. In contrast, the degree of (1) neutrophil infiltration at different time points, (2) cytokine expression (TNF-alpha and IL-1beta), (3) histological damage, (4) apoptosis, was markedly reduced in the tissues obtained from SCI operated 5-LO deficient mice and (5) the motor recovery was ameliorated.
<shortened url>1: Arzneimittelforschung. 1998 Jun;48(6):668-74.Links
Effects of boswellic acids extracted from a herbal medicine on the biosynthesis of leukotrienes and the course of experimental autoimmune encephalomyelitis.Wildfeuer A, Neu IS, Safayhi H, Metzger G, Wehrmann M, Vogel U, Ammon HP.
Department of Pathology, Medical Faculty, University of Ulm, Germany.
Mixed acetylboswellic acids, pentacyclic triterpenes extracted from the gum resin of Boswellia serrata Roxb., significantly inhibited the ionophore-stimulated release of the leukotrienes (LT) B4 and C4 from intact human polymorphonuclear neutrophil leukocytes (PMNLs), with IC50 values of 8.48 micrograms/ml and 8.43 micrograms/ml, respectively. Purified acetyl-11-keto-beta-boswellic acid was about three times more potent as inhibitor of the formation of both LTB4 (IC50 = 2.53 micrograms/ml) and LTC4 (IC50 = 2.26 micrograms/ml) from human PMNLs in the same assay. The comparative agent MK 886 (3-[1-(4-chlorobenzyl)-3-t-butyl-thio-5-isopropylindol-2-yl]- 2,2-dimethylpropanoic acid, L-663,536, CAS 118, 414-82-7) was about 10 to 100-fold more active than the boswellic acids in inhibiting the formation of 5-lipoxygenase products in human PMNLs, with IC50 values of 0.0068 microgram/ml (LTB4) and 0.49 microgram/ml (LTC4). After daily intraperitoneal dosage the extract of mixed acetylboswellic acids (20 mg/kg) significantly reduced the clinical symptoms in guinea pigs with experimental autoimmune encephalomyelitis (EAE) between days 11 and 21. However, the inflammatory infiltrates in the brain and the spinal cord were not significantly less extensive in the treated animals than in the respective control group. The multiple intraperitoneal application of boswellic acids did not inhibit the ionophore-challenged ex vivo release of leukotrienes B4 and C4 from PMNLs separated from the blood of guinea pigs with EAE. The boswellic acids have thus been characterized as selective, non-redox and potent inhibitors of the biosynthesis of leukotrienes in vitro
<shortened url>1: Lipids. 1997 Nov;32(11):1173-80.Links
Effect of curcumin and capsaicin on arachidonic acid metabolism and lysosomal enzyme secretion by rat peritoneal macrophages.Joe B, Lokesh BR.
Department of Biochemistry and Nutrition, Central Food Technological Research Institute, Mysore, India.
The inflammatory mediators secreted by macrophages play an important role in autoimmune diseases. Spice components, such as curcumin from turmeric and capsaicin from red pepper, are shown to exhibit antiinflammatory properties. The influence of these spice components on arachidonic acid metabolism and secretion of lysosomal enzymes by macrophages was investigated. Rat peritoneal macrophages preincubated with 10 microM curcumin or capsaicin for 1 h inhibited the incorporation of arachidonic acid into membrane lipids by 82 and 76%: prostaglandin E2 by 45 and 48%; leukotriene B4 by 61 and 46%, and leukotriene C4 by 34 and 48%, respectively, but did not affect the release of arachidonic acid from macrophages stimulated by phorbol myristate acetate. However, the secretion of 6-keto PG F1 alpha was enhanced by 40 and 29% from macrophages preincubated with 10 microM curcumin or capsaicin, respectively, as compared to those produced by control cells. Curcumin and capsaicin also inhibited the secretion of collagenase, elastase, and hyaluronidase to the maximum extent of 57, 61, 66%, and 46, 69, 67%, respectively. These results demonstrated that curcumin and capsaicin can control the release of inflammatory mediators such as eicosanoids and hydrolytic enzymes secreted by macrophages and thereby may exhibit antiinflammatory properties.
<shortened url>1: Proc Natl Acad Sci U S A. 2007 Jun 12;104(24):10146-51. Epub 2007 Jun 4. Links
Central histamine H3 receptor signaling negatively regulates susceptibility to autoimmune inflammatory disease of the CNS.Teuscher C, Subramanian M, Noubade R, Gao JF, Offner H, Zachary JF, Blankenhorn EP.
Departments of Medicine and Pathology, University of Vermont, Burlington, VT 05405, USA. email@example.com
Histamine (HA), a biogenic amine with a broad spectrum of activities in both physiological and pathological settings, plays a key regulatory role in experimental allergic encephalomyelitis, the autoimmune model of multiple sclerosis. HA exerts its effect through four G protein-coupled receptors designated HA receptor H1, H2, H3, and H4. We report here that, compared with wild-type animals, mice with a disrupted HA H3 receptor (H3RKO), the expression of which is normally confined to cells of the nervous system, develop more severe disease and neuroinflammation. We show that this effect is associated with dysregulation of blood-brain barrier permeability and increased expression of MIP-2, IP-10, and CXCR3 by peripheral T cells. Our data suggest that pharmacological targeting of the H3R may be useful in preventing the development and formation of new lesions in multiple sclerosis, thereby significantly limiting the progression of the disease.
<shortened url>1: J Immunol. 2006 Jan 1;176(1):17-26. Links
A key regulatory role for histamine in experimental autoimmune encephalomyelitis: disease exacerbation in histidine decarboxylase-deficient mice.Musio S, Gallo B, Scabeni S, Lapilla M, Poliani PL, Matarese G, Ohtsu H, Galli SJ, Mantegazza R, Steinman L, Pedotti R.
Immunology and Muscular Pathology Unit, National Neurological Institute "C. Besta," Milan, Italy.
Histamine can modulate the cytokine network and influence Th1 and Th2 balance and Ab-isotype switching. Thus, pharmacological blockade or genetic deletion of specific histamine receptors has been shown to reduce the severity of experimental autoimmune encephalomyelitis (EAE), a prototypic Th1-mediated disease with similarities to human multiple sclerosis. To study the comprehensive contribution of endogenous histamine to the expression of EAE, we attempted to induce EAE in histidine decarboxylase-deficient mice, which are genetically unable to make histamine. In this study, we show that EAE is significantly more severe in HDC-/-, histamine-deficient mice, with diffuse inflammatory infiltrates, including a prevalent granulocytic component, in the brain and cerebellum. Unlike splenocytes from wild-type mice, splenocytes from HDC-/- mice do not produce histamine in response to the myelin Ag, whereas production of IFN-gamma, TNF, and leptin are increased in HDC-/- splenocytes in comparison to those from wild-type mice. Endogenous histamine thus appears to regulate importantly the autoimmune response against myelin and the expression of EAE, in this model, and to limit immune damage to the CNS. Understanding which receptor(s) for histamine is/are involved in regulating autoimmunity against the CNS might help in the development of new strategies of treatment for EAE and multiple sclerosis.
<shortened url>1: Neurosci Lett. 1999 Aug 6;270(3):181-4. Links
Activation of sensory nerves participates in stress-induced histamine release from mast cells in rats.Huang ZL, Mochizuki T, Watanabe H, Maeyama K.
Department of Pharmacology, Ehime University School of Medicine, Onsen-gun, Japan.
To elucidate the mechanism by which stress induces rapid histamine release from mast cells, Wistar rats, pretreated as neonates with capsaicin, were subjected to immobilization stress for 2 h, and histamine release was measured in paws of anesthetized rats by using in vivo microdialysis after activation of sensory nerves by electrical or chemical stimulation. Immobilization stress studies indicated that in control rats stress induced a 2.7-fold increase in the level of plasma histamine compared to that in freely moving rats. Whereas pretreatment with capsaicin significantly decreased stress-induced elevation of plasma histamine. Microdialysis studies showed that electrical stimulation of the sciatic nerve resulted in a 4-fold increase of histamine release in rat paws. However, this increase was significantly inhibited in rats pretreated with capsaicin. Furthermore, injection of capsaicin into rat paw significantly increased histamine release in a dose-dependent manner. These results suggest that activation of sensory nerves participates in stress-induced histamine release from mast cells.
<shortened url>1: Adv Exp Med Biol. 2007;601:423-30.Links
Mast cells, T cells, and inhibition by luteolin: implications for the pathogenesis and treatment of multiple sclerosis.Theoharides TC, Kempuraj D, Iliopoulou BP.
Department of Pharmacology, Internal Medicine and Biochemistry, Immunology Program, Tufts University School of Medicine, Tufts-New England Medical Center, Boston, MA, USA. firstname.lastname@example.org
Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) mainly mediated by Th1, but recent evidence indicates that Th2 T cells, mostly associated with allergic reactions, are also involved. Mast cells are involved in allergic and inflammatory reactions because they are located perivascularly and secrete numerous proinflammatory cytokines. Brain mast cells are critically placed around the blood-brain barrier (BBB) and can disrupt it, a finding preceding any clinical or pathological signs of MS. Moreover, mast cells are often found close to MS plaques, and the main MS antigen, myelin basic protein (MBP), can activate human cultured mast cells to release IL-8, TNF-alpha, tryptase, and histamine. Mast cells could also contribute to T cell activation since addition of mast cells to anti-CD3/anti-CD28 activated T cells increases T cell activation over 30-fold. This effect requires cell-to-cell contact and TNF, but not histamine or tryptase. Pretreatment with the flavone luteolin totally blocks mast cell stimulation and T cell activation. Mast cells could constitute a new unique therapeutic target for MS.
<shortened url>1: Neurology. 2006 Feb 28;66(4):572-5. Links
Allergy, histamine 1 receptor blockers, and the risk of multiple sclerosis.Alonso A, Jick SS, Hernán MA.
Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA. email@example.com
BACKGROUND: It is unclear whether allergic diseases are associated with multiple sclerosis (MS), but histamine 1 receptor blockers, used in the treatment of allergic conditions, decreased the severity of experimental autoimmune encephalomyelitis (an animal model of MS). OBJECTIVE: To assess the association of allergy history and use of histamine 1 receptor blockers with the risk of MS. METHODS: Using a case-control study nested in the United Kingdom-based General Practice Research Database cohort, the authors identified 163 incident cases of MS with at least 3 years of follow-up before their first symptoms (index date). Up to 10 controls matched to the cases by age, sex, general practice, and time in the cohort were selected. Previous history of allergic disease and use of histamine 1 receptor blockers in the 3 years before the index date were assessed through computerized medical records. RESULTS: History of any allergic condition in the 3 years before the index date was not associated with MS risk (adjusted odds ratio [OR] 1.2, 95% CI 0.8 to 1.. However, use of sedating histamine 1 receptor blockers was associated with decreased MS risk (adjusted OR 0.2, 95% CI 0.1 to 0.. CONCLUSION: These results do not support a strong link between allergic conditions and multiple sclerosis (MS) risk but suggest a possible beneficial effect of antihistamines on the onset of MS.
<shortened url>1: Int J Immunopathol Pharmacol. 2005 Oct-Dec;18(4):771-8.Links
A pilot, open label, clinical trial using hydroxyzine in multiple sclerosis.Logothetis L, Mylonas IA, Baloyannis S, Pashalidou M, Orologas A, Zafeiropoulos A, Kosta V, Theoharides TC.
Department of Neurology, Aristotle University, AHEPA Hospital, Thessaloniki, Greece.
Multiple sclerosis (MS) is an autoimmune disorder of myelin destruction. Blood-brain-barrier (BBB) disruption precedes pathological or clinical findings and could involve mediators from perivascular brain mast cells, such as histamine and vascular endothelial growth factor (VEGF). Mast cells could be activated by many triggers, including acute stress that has been correlated with MS exacerbations. We considered that the histamine-1 (H1) receptor antagonist hydroxyzine, which also partially inhibits brain mast cells and has anxiolytic properties, may reduce MS symptoms. This open label, pilot, clinical trial investigated the effect on MS of an oral solution of hydroxyzine (100 mg per day), together with caffeine (200 mg per day) to reduce sedation. Twenty patients (8 males; 12 females) with relapsing-remitting or relapsing-progressive MS completed the study (12 +/- 1 months) and were evaluated using disability scales. Most patients on hydroxyzine (75%) remained stable or improved neurologically and all but one showed improved mood. Hydroxyzine could be used as an adjuvant in MS, but the small number of patients enrolled and the short duration of the study precludes any definitive conclusions. A double-blind, placebo-controlled study is warranted.
<shortened url>1: Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):1867-72. Epub 2003 Feb 7. Links
Multiple elements of the allergic arm of the immune response modulate autoimmune demyelination.Pedotti R, DeVoss JJ, Youssef S, Mitchell D, Wedemeyer J, Madanat R, Garren H, Fontoura P, Tsai M, Galli SJ, Sobel RA, Steinman L.
Department of Neurology and Neurological Science, Stanford University Medical Center, Stanford, CA 94305, USA.
Analysis of mRNA from multiple sclerosis lesions revealed increased amounts of transcripts for several genes encoding molecules traditionally associated with allergic responses, including prostaglandin D synthase, histamine receptor type 1 (H1R), platelet activating factor receptor, Ig Fc epsilon receptor 1 (Fc epsilon RI), and tryptase. We now demonstrate that, in the animal model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), mediated by T helper 1 (Th1) T cells, histamine receptor 1 and 2 (H1R and H2R) are present on inflammatory cells in brain lesions. Th1 cells reactive to myelin proteolipid protein expressed more H1R and less H2R than Th2 cells. Pyrilamine, an H1R antagonist, blocked EAE, and the platelet activating factor receptor antagonist CV6209 reduced the severity of EAE. EAE severity was also decreased in mice with disruption of the genes encoding Ig Fc gamma RIII or both Fc gamma RIII and Fc epsilon RI. Prostaglandin D synthase and tryptase transcripts were elevated in EAE brain. Taken together, these data reveal extensive involvement of elements of the immune response associated with allergy in autoimmune demyelination. The pathogenesis of demyelination must now be viewed as encompassing elements of both Th1 responses and "allergic" responses.
Mepyramine (INN, also known as pyrilamine)  is a first generation antihistamine, targeting the H1 receptor. However, it rapidly permeates the brain and so often causes drowsiness as a side effect.
It is used in over-the-counter combination products for colds and menstrual symptoms.
Side effects may include sedation/drowsiness, muscle weakness, and insomnia.
<shortened url>1: Neuroreport. 2002 Aug 7;13(11):1407-10. Links
Activation of histamine H2 receptors ameliorates experimental allergic encephalomyelitis.Emerson MR, Orentas DM, Lynch SG, LeVine SM.
Department of Molecular and Integrative Physiology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA.
Experimental allergic encephalomyelitis (EAE), a model of multiple sclerosis, is an autoimmune, demyelinating disease of the CNS. Pro-inflammatory cytokines (e.g. tumour necrosis factor-alpha (TNF-alpha) and interleukin (IL)-12) and reactive oxygen species are implicated in promoting EAE. Since histamine H(2) receptor activation suppresses production of O(2)*-, TNF-alpha, and IL-12 by inflammatory cells, we tested the hypothesis that dimaprit, an H(2) agonist, would reduce the clinical severity and pathology of EAE. Dimaprit treatment significantly reduced clinical signs compared to vehicle in both C57BL/6 and iNOS deficient EAE mice. Furthermore, dimaprit significantly reduced CNS staining for lectin-positive macrophages and decreased extravasated albumin staining, an indicator of blood-brain barrier leakage. These data provide a rationale for exploring H2 receptor activation for therapeutic value in multiple sclerosis.
<shortened url>1: Int J Immunopharmacol. 2000 Sep;22(9):673-84. Links
Hydroxyzine inhibits experimental allergic encephalomyelitis (EAE) and associated brain mast cell activation.Dimitriadou V, Pang X, Theoharides TC.
Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, MA 02111, USA.
Experimental allergic encephalomyelitis (EAE) has been used as an animal model for the human demyelinating disease multiple sclerosis (MS). In acute MS or EAE, early disruption in the integrity of the blood-brain-barrier (BBB) precedes brain infiltration by inflammatory cells or any clinical evidence of disease. BBB permeability could be affected by vasoactive mediators and cytokines released from perivascular brain mast cells. We investigated the number and degree of activation of brain mast cells in EAE and the effect of the heterocyclic histamine-1 receptor antagonist hydroxyzine, a piperazine compound known to also block mast cells. Acute EAE was induced in Lewis rats by immunization with whole guinea pig spinal cord homogenate and complete Freund's adjuvant (CFA). A second group of animals were treated orally with hydroxyzine for one day before immunization and then continuously for 14 days. Control rats were treated with CFA or hydroxyzine alone. The clinical progression of EAE was assessed on days 10, 12 and 14 after immunization. The number of metachromatic mast cells and the degree of degranulation was assessed in the thalamus with light microscopy. At day 14, there was a three-fold increase in the number of brain mast cells with EAE, as compared to controls. These cells were positive for the immunoglobulin E binding protein (FcepsilonRI), while those from control rats were not. Over 40% of all thalamic mast cells studied in EAE showed partial staining or extruded secretory granule indicative of secretion. Hydroxyzine treatment inhibited (p<0.05) the progression and severity of EAE by 50% and the extent of mast cell degranulation by 70% (p<0.05). These findings indicate that brain mast cells are associated with EAE development and that inhibition of their activation correlates positively with the clinical outcome.
<shortened url>1: Life Sci. 2007 Apr 3;80(17):1553-63. Epub 2007 Jan 27. Links
Capsicum ethanol extracts and capsaicin enhance interleukin-2 and interferon-gamma production in cultured murine Peyer's patch cells ex vivo.Takano F, Yamaguchi M, Takada S, Shoda S, Yahagi N, Takahashi T, Ohta T.
Department of Pharmacognosy and Chemistry of Natural Products, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan. firstname.lastname@example.org
We investigated the effects of red pepper (Capsicum annuum Lin.) extracts (capsicum extract) and its main pungent capsaicin on T helper 1 (Th1) and 2 (Th2) cytokine production in cultured murine Peyer's patch (PP) cells in vitro and ex vivo. Direct administration of capsicum extract (1 and 10 mug/ml) and capsaicin (3 and 30 muM) resulted in suppression of interleukin (IL)-2, interferon (IFN)-gamma, IL-4 and IL-5 production. In an ex vivo experiment using PP cells removed from the mice after oral administration of capsicum extract (10 mg/kg/day for 4 consecutive days), IL-2, IFN-gamma and IL-5 increased in response to concanavalin A (Con A). Oral administration of 3 mg/kg/day capsaicin, one active constituent of the extract, also enhanced IL-2, INF-gamma and IL-4 production in response to Con A stimulation but did not influence the production of IL-5. Orally administered capsazepine (3 mg/kg/day), a selective transient receptor potential vanilloid 1 (TRPV1) antagonist, slightly enhanced IL-2 production also irrespective of Con A stimulation. The capsaicin-induced enhancement of both IL-2 and IFN-gamma production was not reduced by oral administration of capsazepine (3 mg/kg/day), suggesting a TRPV1 receptor-independent mechanism. Flow cytometric analysis revealed that the population of CD3(+) cells in the PP cells was significantly reduced while CD19(+) cells increased after oral administration of capsicum extract (1 and 10 mg/kg/day) and capsaicin (0.3 and 3 mg/kg/day). Capsazepine (3 mg/kg/day) weakly but significantly reversed these effects. Orally administered capsicum extract and capsaicin did not change the T cell subset (CD4(+) and CD8(+)), Th1 (IFN-gamma(+)) and T2 (IL-4(+)) ratio. These findings indicate that capsicum extract and capsaicin modulate T cell-immune responses, and their immunomodulatory effects on murine PP cells are partly due to both TRPV1-dependent and -independent pathway.
Concanavalin A is a lectin protein originally extracted from the jack-bean Canavalia ensiformis. It binds specifically to certain structures found in various sugars, namely internal and nonreducing terminal alpha-mannosyl groups. It is used in biology and biochemistry to characterize glycoproteins and other sugar-containing entities. It is also used in lectin affinity chromatography.
Concanavalin A is also a lymphocyte mitogen.
It has also been shown as a stimulator of several matrix metalloproteinases (MMPs).
<shortened url>1: J Neuroimmunol. 2006 Feb;171(1-2):110-9. Epub 2005 Oct 18. Links
Arvanil inhibits T lymphocyte activation and ameliorates autoimmune encephalomyelitis.Malfitano AM, Matarese G, Pisanti S, Grimaldi C, Laezza C, Bisogno T, Di Marzo V, Lechler RI, Bifulco M.
Dipartimento di Scienze Farmaceutiche, Universita' di Salerno, Via Ponte don Melillo 84084 Fisciano (Salerno), Italy.
This study examined the immunomodulatory effect of arvanil, a synthetic capsaicin-anandamide hybrid. Arvanil inhibits lymphocyte proliferation and IFN-gamma production. The phenotype of activated CD4+T cells treated with arvanil shows a down-regulation of T cell activation markers such as CD25, HLA-DR and CD134/OX40. Arvanil and anandamide do not induce apoptosis on CD4+T cells. Arvanil blocks the G1/S phase transition of the cell cycle in stimulated peripheral blood mononuclear cells, inducing activation of p21waf-1/cip-1 and phosphorylation of Akt/PKB. In vivo, arvanil ameliorates experimental autoimmune encephalomyelitis in the SJL/J mouse. Our findings have relevance for the use of arvanil and related compounds as a novel immunotherapeutic approach in the treatment of multiple sclerosis.
<shortened url>1: Br J Pharmacol. 2003 Nov;140(6):1077-87. Epub 2003 Oct 6. Links
Signal transduction for inhibition of inducible nitric oxide synthase and cyclooxygenase-2 induction by capsaicin and related analogs in macrophages.Chen CW, Lee ST, Wu WT, Fu WM, Ho FM, Lin WW.
Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.
1. Although capsaicin analogs might be a potential strategy to manipulate inflammation, the mechanism is still unclear. In this study, the effects and action mechanisms of vanilloid analogs on iNOS and COX-2 expression were investigated in RAW264.7 macrophages. 2. Capsaicin and resiniferatoxin (RTX) can inhibit LPS- and IFN-gamma-mediated NO production, and iNOS protein and mRNA expression with similar IC50 values of around 10 microm. 3. Capsaicin also transcriptionally inhibited LPS- and PMA-induced COX-2 expression and PGE2 production. However, this effect exhibited a higher potency (IC50: 0.2 microm), and RTX failed to elicit such responses at 10 microm. 4. Interestingly, we found that capsazepine, a competitive TRPV1 antagonist, did not prevent the inhibition elicited by capsaicin or RTX. Nevertheless, it mimicked vanilloids in inhibiting iNOS/NO and COX-2/PGE2 induction with an IC50 value of 3 microm. RT-PCR and immunoblotting analysis excluded the expression of TRPV1 in RAW264.7 macrophages. 5. The DNA binding assay demonstrated the abilities of vanilloids to inhibit LPS-elicited NF-kappaB and AP-1 activation and IFN-gamma-elicited STAT1 activation. The reporter assay of AP-1 activity also supported this action. 6. The kinase assay indicated that ERK, JNK, and IKK activation by LPS were inhibited by vanilloids. 7. In conclusion, vanilloids can modulate the expression of inflammatory iNOS and COX-2 genes in macrophages through interference with upstream signalling events of LPS and IFN-gamma. These findings provide new insights into the potential benefits of the active ingredient in hot chilli peppers in inflammatory conditions.
<shortened url>1: Pharmacology. 2005 Nov;75(3):116-21. Epub 2005 Sep 2. Links
ERK and STAT3 phosphorylation in sensory neurons during capsaicin-induced impairment and nerve growth factor treatment.Donnerer J, Liebmann I, Schicho R.
Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria. email@example.com
Distinct signal transduction pathways have been shown to regulate injury responses and regeneration in peripheral nerves. In the present investigation, the time courses of the induction of phospho-MAPK/ERK1/2 and of phospho-STAT3 were investigated in the dorsal root ganglia (DRG) and in the sciatic nerve of rats following a systemic capsaicin treatment without or with concomitant intraplantar NGF injections. Western blots were probed with polyclonal antibodies that specifically detect phosphorylated ERK 1/2 and STAT3. Phosphorylation of ERK clearly peaked in the sciatic nerve and in the lumbar DRGs at 6 and 10 h after the capsaicin treatment. In the following 8 days phospho-ERK decreased to very low levels and was found recovered to basal values at the time point 16 days. An additional intraplantar nerve growth factor (NGF) injection at time points 20, 44 and 92 h after the capsaicin treatment, and collection of tissues 4 h later, markedly increased the level of phospho-ERK in the sciatic nerve as well as in the DRG, as compared to the samples taken from rats at the same time points with a capsaicin treatment only. Posphorylated STAT3, which was almost non-detectable in the control sciatic nerve, clearly peaked at 6 h after the capsaicin treatment and decreased again during the following days to almost undetectable levels. The intraplantar NGF injections slightly stimulated phosho-STAT3 in the sciatic nerve. A basal level of phosphorylated STAT3 was present in DRGs of control animals, it remained at a high level up to 6 h after the capsaicin treatment, then markedly decreased and recovered on day 8 and day 16. NGF increased STAT3 phosphorylation in DRG on day 1 and day 2 above the level observed in samples taken from rats at the same time points with a capsaicin treatment only. The present study demonstrates that a capsaicin impairment of small diameter primary sensory neurons followed by an NGF treatment evokes a characteristic pattern of ERK and STAT3 activation indicative of neuronal degeneration and regeneration. Copyright (c) 2005 S. Karger AG, Basel.
<shortened url>1: Int J Cancer. 2003 Feb 10;103(4):475-82. Links
Roles of JNK-1 and p38 in selective induction of apoptosis by capsaicin in ras-transformed human breast epithelial cells.Kang HJ, Soh Y, Kim MS, Lee EJ, Surh YJ, Kim HR, Kim SH, Moon A.
College of Pharmacy, Duksung Women's University, 4129 Ssangmun-dong, Tobong-ku, Seoul 132-714, Korea.
Efforts have been made to develop a chemoprevention strategy that selectively triggers apoptosis in malignant cancer cells. Previous studies showed that capsaicin, the major pungent ingredient of red pepper, had differential effect between normal and transformed cells. As an approach to unveil the molecular mechanism by which capsaicin selectively induces apoptosis in transformed cells, we investigated the effect of capsaicin in nontransformed and ras-transformed cells of a common origin: parental (MCF10A) and H-ras-transformed (H-ras MCF10A) human breast epithelial cells. Here, we show that capsaicin selectively induces apoptosis in H-ras-transformed cells but not in their normal cell counterparts. The capsaicin-induced apoptosis, which is dependent on ras transformation, involves the activity of DEVDase (caspase-3 like). In H-ras MCF10A cells, capsaicin treatment markedly activated c-Jun N-terminal protein kinase (JNK)-1 and p38 matigen-activated protein kinase (MAPK) while it deactivated extracellular signal-regulated protein kinases (ERKs). The use of kinase inhibitors and overexpression of dominant-negative forms of MAPKs demonstrated a role of JNK-1 and p38, but not that of ERKs, in apoptosis induced by capsaicin in H-ras-transformed MCF10A cells. Based on the present study, we propose that capsaicin selectively induces apoptosis through modulation of ras-downstream signaling molecules in ras-activated MCF10A cells. Taken in conjunction with the fact that uncontrolled ras activation is probably the most common genetic defect in human cancer cells, our finding may be critical to the chemopreventive potential of capsaicin and for developing a strategy to induce tumor cell-specific apoptosis. Copyright 2002 Wiley-Liss, Inc
<shortened url>1: Pain. 2004 Oct;111(3):278-85. Links
Peripheral and central p38 MAPK mediates capsaicin-induced hyperalgesia.Sweitzer SM, Peters MC, Ma JY, Kerr I, Mangadu R, Chakravarty S, Dugar S, Medicherla S, Protter AA, Yeomans DC.
Department of Anesthesia, Stanford University School of Medicine, Stanford, CA 94305, USA. firstname.lastname@example.org
The stress-activated mitogen-activated protein kinase (MAPK) p38 is emerging as an important mediator of pain. The present study examined the possible involvement of peripheral and spinal p38 MAPK in capsaicin-induced thermal hyperalgesia. Topical capsaicin produced phosphorylation of p38 MAPK in the skin from the affected hindpaw as well as the corresponding lumbar spinal cord in a time dependent manner. Topical capsaicin produced robust C-fiber mediated thermal hyperalgesia that was inhibited by systemic, local peripheral, or central intrathecal pre-treatment with the p38 MAPK inhibitor, SD-282. Intraperitoneal SD-282 (10-60 mg/kg) significantly and dose-dependently attenuated capsaicin-induced C-fiber mediated thermal hyperalgesia. Similarly, 0.1-5mg/kg subcutaneous SD-282 in the hindpaw dose-dependently attenuated capsaicin-induced thermal hyperalgesia. Intrathecal administration of 1microg SD-282 was also anti-hyperalgesic in this model. Functionally, SD-282 decreased capsaicin-induced release of calcitonin gene related peptide in an in vitro skin release assay, consistent with a role for p38 MAPK in peripheral nerve function. These results suggest that p38 MAPK plays a role in the development of hyperalgesic states, exerting effects both centrally in the spinal cord and peripherally in sensory C fibers.
PMID: 15363871 [PubMed - indexed for MEDLINE]
<shortened url>1: J Neurochem. 2007 Apr;101(2):364-76. Epub 2007 Jan 22. Links
A novel role of glia maturation factor: induction of granulocyte-macrophage colony-stimulating factor and pro-inflammatory cytokines.Zaheer A, Zaheer S, Sahu SK, Knight S, Khosravi H, Mathur SN, Lim R.
Veterans Affair Medical Center, Iowa City, Iowa, USA. email@example.com
The glia maturation factor (GMF), which was discovered in our laboratory, is a highly conserved protein predominantly localized in astrocytes. GMF is an intracellular regulator of stress-related signal transduction. We now report that the overexpression of GMF in astrocytes leads to the destruction of primary oligodendrocytes by interactions between highly purified cultures of astrocytes, microglia, and oligodendrocytes. We infected astrocytes with a replication-defective adenovirus carrying the GMF cDNA. The overexpression of GMF caused the activation of p38 MAP kinase and transcription factor NF-kappaB, as well as the induction of granulocyte-macrophage colony-stimulating factor (GM-CSF) mRNA and protein in astrocytes. Small interfering RNA-mediated GMF knockdown completely blocked the GMF-dependent activation of p38 mitogen-activated protein kinase (MAPK), NF-kappaB, and enhanced expression of GM-CSF by astrocytes. Inhibition of p38 MAPK or NF-kappaB by specific inhibitors prevented GM-CSF production. The cell-free conditioned medium from overexpressing GMF astrocytes contained 320 +/- 33 pg/mL of GM-CSF, which was responsible for enhanced production and secretion of TNF-alpha, IL-1beta, IL-6, and IP-10 by microglia. Presence of these inflammatory cytokines in the conditioned medium from microglia efficiently destroyed oligodendrocytes in culture. These results suggest that GMF-induced production of GM-CSF in astrocytes is depending on p38 MAPK and NF-kappaB activation. The GM-CSF-dependent expression and secretion of inflammatory cytokine/chemokine, TNF-alpha, IL-1beta, IL-6, and IP-10, is cytotoxic to oligodendrocytes, the myelin-forming cells in the central nervous system, and as well as neurons. Our results suggest a novel pathway of GMF-initiated cytotoxicity of brain cells, and implicate its involvement in inflammatory diseases such as multiple sclerosis.
<shortened url>1: Eur J Immunol. 2002 Jun;32(6):1753-63. Links
Immunosuppressive activity of capsaicinoids: capsiate derived from sweet peppers inhibits NF-kappaB activation and is a potent antiinflammatory compound in vivo.Sancho R, Lucena C, Macho A, Calzado MA, Blanco-Molina M, Minassi A, Appendino G, Muñoz E.
Departamento de Biología Celular, Fisiología e Inmunología, Universidad de Córdoba, Córdoba, Spain.
Capsiate and its dihydroderivatives are the major capsaicinoids of sweet pepper. These new capsaicinoids do not activate the vanilloid receptor type 1 (VR1) but they share with capsaicin (CPS)some biological activities mediated in a VR1-independent fashion. In this study we show that CPS and nordihydrocapsiate (CPT) inhibit early and late events in T cell activation, including CD69, CD25 and ICAM-1 cell surface expression, progression to the S phase of the cell cycle and proliferation in response to TCR and CD28 co-engagement. Moreover, both CPS and CPT inhibit NF-kappaB activation in response to different agents including TNF-alpha. CPS itself does not affect the DNA-binding ability of NF-kappaB but it prevents IkappaB kinase activation and IkappaBalpha degradation in a dose-dependent manner, without inhibiting the activation of the mitogen-activated protein kinases, p38, extracellular regulated kinase and c-Jun N-terminal protein kinase. Moreover, intraperitoneal pretreatment with CPT prevented mice from lethal septic shock induced by lipopolysaccharide. In a second model of inflammation CPT pretreatment greatly reduced the extensive damage in the glandular epithelium observed in the bowel of DSS-treated mice. Taken together, these results suggest that CPT and related synthetic analogues target specific pathways involved in inflammation, and hold considerable potential for dietary health benefits as well as for pharmaceutical development.
<shortened url>1: J Immunol. 2006 Oct 1;177(7):4322-9. Links
Transient receptor potential vanilloid subtype 1 mediates microglial cell death in vivo and in vitro via Ca2+-mediated mitochondrial damage and cytochrome c release.Kim SR, Kim SU, Oh U, Jin BK.
Brain Disease Research Center, Ajou University School of Medicine, Suwon 443-479, Korea.
The present study examined the expression of transient receptor potential vanilloid subtype 1 (TRPV1) in microglia, and its association with microglial cell death. In vitro cell cultures, RT-PCR, Western blot analysis, and immunocytochemical staining experiments revealed that rat microglia and a human microglia cell line (HMO6) showed TRPV1 expression. Furthermore, exposure of these cells to TRPV1 agonists, capsaicin (CAP) and resiniferatoxin (RTX), triggered cell death. This effect was ameliorated by the TRPV1 antagonists, capsazepine and iodo-resiniferatoxin (I-RTX), suggesting that TRPV1 is directly involved. Further examinations revealed that TRPV1-induced toxicity was accompanied by increases in intracellular Ca(2+), and mitochondrial damage; these effects were inhibited by capsazepine, I-RTX, and the intracellular Ca(2+) chelator BAPTA-AM. Treatment of cells with CAP or RTX led to increased mitochondrial cytochrome c release and enhanced immunoreactivity to cleaved caspase-3. In contrast, the caspase-3 inhibitor z-DEVD-fmk protected microglia from CAP- or RTX-induced toxicity. In vivo, we also found that intranigral injection of CAP or 12-hydroperoxyeicosatetraenoic acid, an endogenous agonist of TRPV1, into the rat brain produced microglial damage via TRPV1 in the substantia nigra, as visualized by immunocytochemistry. To our knowledge, this study is the first to demonstrate that microglia express TRPV1, and that activation of this receptor may contribute to microglial damage via Ca(2+) signaling and mitochondrial disruption.
Microglia are a type of glial cell that acts as the first and main form of active immune defense in the central nervous system (CNS). Microglia constitute 20% of the total glial cell population within the brain. Unlike astrocytes, individual microglia are distributed in large non-overlapping regions throughout the brain and spine. Microglia are constantly moving and analyzing the CNS for damaged neurons, plaques, and infectious agents. The brain and spine are considered “immune privileged” organs in that they are separated from the rest of the body by a series of endothelial cells known as the blood-brain barrier, which prevents most infections from reaching the vulnerable nervous tissue. In the case where infectious agents are directly introduced to the brain or cross the blood-brain barrier, microglial cells must react quickly to increase inflammation and destroy the infectious agents before they damage the sensitive neural tissue. Due to the unavailability of antibodies from the rest of the body (antibodies are too large to cross the blood-brain barrier), microglia must be able to recognize foreign bodies, swallow them, and act as antigen-presenting cells activating T-cells. Since this process must be done quickly to prevent potentially fatal damage, microglia are extremely sensitive to even small pathological changes in the CNS. They achieve this sensitivity in part by having unique potassium channels that respond to even small changes in extracellular potassium.
<shortened url>1: Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 1995 Aug;17(4):269-73.Links
[The role of substance P in immunosuppression induced by Tripterygium wilfordii][Article in Chinese]
Liu Y, Wang W, Zhu G, Chen J, Xu C.
Institute of Basic Medical Sciences, CAMS, Beijing.
The effects of T II (extracted from Tripterygium wilfordii) and substance P (SP) on imunoregulation were investigated. It has been shown that Tripterygium wilfordii is an immunosuppresive. In order to assess the immunosuppression elicited by T II was mediated by SP in spinal dorsal horn, Wistar rats were injected intrathecally with capsaicin (CAP) to deplete SP in spinal dorsal horn prior to T II given orally. The level of interleukin 2 (IL-2) produced by splenic lymphocytes of rats and the contents of SP in some brain areas and spinal cord in mice were assayed after T II treatment. Our findings were as follows: 1. The level of IL-2 was decreased significantly after T II treatment only. However the level of IL-2 was increased markedly after CAP was given intrathecally. Moreover, CAP administration also enhanced the level of IL-2 even in immunosuppression group induced by T II treatment. 2. SP contents in spinal cord, hypothalamus and brain stem of mice were increased dramatically during immunosuppression produced by T II. The results suggested that SP in spinal dorsal horn was involved in regulation of cellular immunity, the suppressive effect of T II on cellular immunity might be mediated by SP in spinal dorsal horn.
http://www.ncbi.nlm.nih.gov/pubmed/93889891: Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 1996 Jun;18(3):183-8.Links
[The role of substance P in the spinal dorsal horn in the pathogenesis of autoimmune diseases][Article in Chinese]
Chen J, Li S, Liu Y, Wu S, Ji H.
Institute of Basic Medical Sciences, CAMS, Beijing.
The aim of the present study is to explore the role of immunosuppression mediated by substance P (SP) in spinal dorsal horn (SDH) in the pathogenesis of the autoimmune diseases. The experimental allergic neuritis (EAN), experimental allergic encephalomyelitis (EAE) and adjuvant arthritis (AA) animal models were established in the guinea pigs and Wistar rats, respectively. The effects of alteration of SP activity in SDH on immune responses and the pathogenesis of the autoimmune diseases were observed. The results showed that decreasing activity of SP in SDH by pretreatment of capsaicin or intrathecal SP antagonist could enhance cellular and humoral immune responses and aggravate the autoimmune diseases, while intrathecal SP agonist could suppress the immunity and alleviate clinical signs. The contents of SP in SDH was elevated dramatically at the peak of immune responses. These results suggest that SDH SP might participate in the pathogenesis of the autoimmune diseases. The increase of SP contents in SDH may inhibit the immune system via unknown pathway and ease clinical severity of the autoimmune disease, where SP might act as neurotransmitter in the immunoregulation of the negative feedback. To elevate SP content in SDH might be beneficial to the autoimmune diseases.
The prophylactic and therapeutic effects of dietary n-3 polyunsaturated fatty acids and antiinflammatory spice principles—curcumin and capsaicin on adjuvant induced arthritis in rats were studied. Rats fed codliver oil (1 mL/day/rat or 8 wt % in the diet) rich in n-3 fatty acids were found to have a decreased incidence of adjuvant induced arthritis as compared with those observed in coconut oil- or groundnut oil-fed animals. The inflammation in animals which developed adjuvant arthritis in codliver oil-fed animals was also significantly lower than that observed in the other two groups. Additional feeding of spice principles—capsaicin (from red pepper) (5 mg/kg bw/day) or curcumin (from turmeric) (30 mg/kg bw/day) along with dietary lipids delayed the onset of the disease and also lowered the extent of inflammation in arthritis arrested further progression of the disease. Curcumin and capsaicin feeding to arthritic rats also lowered paw inflammation. This beneficial effect of spice principles was observed irrespective of the nature of the dietary lipids fed to the rats. These studies indicated that the dietary n-3 polyunsaturated fatty acids, capsaicin, and curcumin can decrease the incidence, delay the onset and reduce the extent of inflammation of adjuvant-induced arthritis in rats.
1: Front Biosci. 2007 Jan 1;12:1615-28.Links
Corticotropin-releasing hormone and the blood-brain-barrier.Theoharides TC, Konstantinidou AD.
Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine and Tufts-New England Medical Center, 136 Harrison Avenue, Boston, MA 02111, USA. firstname.lastname@example.org
Increased blood-brain-barrier (BBB) permeability precedes any clinical or pathologic signs and is critical in the pathogenesis of multiple sclerosis (MS) and brain metastases. CD4+ TH1 cells mediate demyelination in MS, but how they get sensitized and enter the brain to induce brain inflammation remains obscure. TH2 cytokines associated with allergic disorders have recently been implicated in MS, while genes upregulated in MS plaques include the mast cell-specific tryptase, the IgE receptor (Fc-epsilon-RI) and the histamine-1 receptor. Mast cell specific tryptase is elevated in the CSF of MS patients, induces microvascular leakage and stimulates protease-activated receptors (PAR), leading to widespread inflammation. BBB permeability, MS and brain metastases appear to worsen in response to acute stress that leads to the local release of corticotropin-releasing hormone (CRH), which activates brain mast cells to selectively release IL-6, IL-8 and vascular endothelial growth factor (VEGF). Acute stress increases BBB permeability that is dependent on CRH and mast cells. Acute stress shortens the time of onset of experimental alleric encephalomyelitis (EAE) that does not develop in W/W mast cell deficient or CRH -/- mice. Brain mast cell inhibition and CRHR antagonists offer novel therapeutic possibilities.
<shortened url>1: J Immunol. 2005 May 1;174(9):5407-13. Links
Corticotropin-releasing hormone contributes to the peripheral inflammatory response in experimental autoimmune encephalomyelitis.Benou C, Wang Y, Imitola J, VanVlerken L, Chandras C, Karalis KP, Khoury SJ.
Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Peripheral corticotropin-releasing hormone (CRH) is thought to have proinflammatory effects. We used the model of experimental autoimmune encephalomyelitis (EAE) to study the role of CRH in an immune-mediated disease. We showed that CRH-deficient mice are resistant to EAE, with a decrease in clinical score as well as decreased cellular infiltration in the CNS. Furthermore, Ag-specific responses of primed T cells as well as anti-CD3/anti-CD28 TCR costimulation were decreased in crh(-/-) mice with decreased production of Th1 cytokines and increased production of Th2 cytokines. Wild-type mice treated in vivo with a CRH antagonist showed a decrease in IFN-gamma production by primed T cells in vitro. This effect of CRH is independent of its ability to increase corticosterone production, because adrenalectomized wild-type mice had similar disease course and severity as control mice. We found that IkappaBalpha phosphorylation induced by TCR cross-linking was decreased in crh(-/-) T cells. We conclude that peripheral CRH exerts a proinflammatory effect in EAE with a selective increase in Th1-type responses. These findings have implications for the treatment of Th1-mediated diseases such as multiple sclerosis.
PMID: 15843539 [PubMed - indexed for MEDLINE]
<shortened url>1: Ann Neurol. 2004 Jan;55(1):37-45. Links
Impaired hypothalamus-pituitary-adrenal axis activity and more severe multiple sclerosis with hypothalamic lesions.Huitinga I, Erkut ZA, van Beurden D, Swaab DF.
Netherlands Institute for Brain Research, Amsterdam, The Netherlands. email@example.com
In this postmortem study, we investigated the relationship between multiple sclerosis (MS) lesions in the hypothalamus and the state of activity of corticotropin-releasing hormone (CRH)-producing neurons that control the hypothalamus-pituitary-adrenal (HPA) axis. A high incidence (15/16) of MS lesions was found in the hypothalamus, of which more than 50% was active, that is, contained activated macrophages. MS patients have increased numbers of CRH-immunoreactive neurons coexpressing vasopressin (CRH/VP neurons), a sign of chronic activation of CRH neurons and increased CRH mRNA expression. Active MS lesions correlated with a low number of hyperactive CRH/VP neurons. High human leukocyte antigen (HLA)-DR, -DP, -DQ expression, a measure for macrophage and microglial activation, correlated with low CRH mRNA expression. The nearer the HLA expression was situated to the CRH neurons, the stronger the inhibiting effect, suggesting that activated microglial cells or macrophages suppress these neurons. The more active MS lesions were present in the hypothalamus, the shorter was the disease duration until the moment of death, indicating an unfavorable course of the disease. Thus, MS patients have a chronically activated CRH system, but, in the subgroup of patients with active MS lesions in the hypothalamus, this activation is impaired and the disease course is worse.
<shortened url>1: J Pharmacol Exp Ther. 2002 Dec;303(3):1061-6. Links
Corticotropin-releasing hormone and brain mast cells regulate blood-brain-barrier permeability induced by acute stress.Esposito P, Chandler N, Kandere K, Basu S, Jacobson S, Connolly R, Tutor D, Theoharides TC.
Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, New England Medical Center, Boston, Massachusetts 02111, USA.
Stress activates the hypothalamic-pituitary-adrenal axis through release of corticotropin releasing hormone (CRH), leading to production of glucocorticoids that down-regulate immune responses. Acute stress, however, also has proinflammatory effects that seem to be mediated through the activation of mast cells. Stress and mast cells have been implicated in the pathophysiology of various inflammatory conditions, including some in the central nervous system, such as multiple sclerosis in which disruption of the blood-brain barrier (BBB) precedes clinical symptoms. We previously showed that acute restraint stress increases rat BBB permeability to intravenous 99Tc gluceptate and that administration of the "mast cell stabilizer" disodium cromoglycate (cromolyn) inhibits this effect. In this study, we show that the CRH-receptor antagonist Antalarmin blocks stress-induced 99Tc extravasation, whereas site-specific injection of CRH in the paraventricular nucleus (PVN) of the hypothalamus mimics acute stress. This latter effect is blocked by pretreatment of the PVN with cromolyn; moreover, restraint stress cannot disrupt the BBB in the diencephalon and cerebellum of W/W(v) mast cell-deficient mice. These results demonstrate that CRH and mast cells are involved in regulating BBB permeability and, possibly, brain inflammatory disorders exacerbated by acute stress.
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1949285As a medical student in the early 1960s, trained at Bart’s Hospital (founded in 1123), I was extremely frustrated by some aspects of the teaching of clinical medicine. What I wanted to learn was exciting facts about the causes of illness, modern biochemistry, and the latest treatments. A number of years later when I worked as an intern for the late Dr Alan Spence, I felt confident enough to express my concerns. He replied that “50% of what I would have taught you would be wrong by the time you are middle aged, and biochemical tests change every 10 years.” His job, he thought, was to teach me to use clinical judgment and to keep asking why does this happen, why are we doing this? I asked myself what motivated physicians in the past to carry out procedures, such as total dental extraction for colitis and rheumatoid arthritis!
Perhaps the most important person to ask “why” was William Harvey, the first physician appointed in Bart’s. For the first 500 years of Bart’s existence, they thought they could make do without physicians, running the hospital with nurses and administrators. At that time, Galenic philosophy was deeply carved in stone and taught as the basis of human physiology. Harvey, with only minimal support and apparatus, provided about 90% of the proof that blood circulates. It is difficult to understand that the idea of a heart acting as a pump was totally foreign at the time.
Analogously, I am certain there are many things that are wrong in modern medicine, even though great breakthroughs have been made in genetics, transplants, electrophysiology, and so on. In particular, I have a gut feeling that we have shied away from truly confronting the origins of a great puzzle—the so-called autoimmune diseases.
For the last 100 years, little progress has been made in understanding the true etiology and specific treatment of autoimmune diseases, such as rheumatoid arthritis, ulcerative colitis, Crohn disease, and disseminated lupus. These illnesses are thrown into a rat bag labeled “auto-immune.” While admittedly there are design flaws in the human body, it does seem unusual that evolution has allowed the continuation of a mechanism whereby the body attacks itself. (In passing, some thought should be given to the concept that most organisms have a purpose. Bacteria and viruses, although they might kill the host, do carry out the basic tenet of nature: they reproduce and spread, thus fulfilling their goal. Such a goal is missing in all forms of cancer, which kill the host, and in the self-destructive autoimmune diseases.)
Over the last 80 years or more, great attention has been focused on the inflammatory cascade mechanisms of autoimmune disorders. We have nonsteroidal anti-inflammatory drugs, which suppress some of the pathology, disease-modifying agents that inhibit inflammation, and now the new anti–tumour necrosis factor agents. These all focus on the inflammation underlying auto-immune disorders, but none of them really address the underlying cause, the specific triggers that set the self-destructive autoimmune process in motion. The common factor in autoimmune diseases is that their true etiology remains unknown—we might be on the wrong track and persist in going down the wrong road.
A typical example of this frustrating situation is rheumatoid arthritis. Why is it symmetrical in distribution? It’s not likely that the joints classically affected differ in cartilage structure from those that aren’t. Moreover, why does a stroke prevent the development of the disease in the paralyzed limb? In animal studies, either surgically or chemically destroying the afferent nerves to joints prevents the appearance of arthritis in those joints.1 As Harvey might have noted, the same blood circulates around these joints—so why the sparing? I was surprised to observe that a great many papers in the peer-reviewed medical literature refer to a phenomenon that is virtually ignored in clinical medicine—the neurogenic origins of arthritis.2
The final stimulus that motivated me to write this letter was encountering reports from the early part of the 20th century that sectioning the sympathetic nervous system often provided amazing relief in arthritis. Not double-blind studies, but great work by great medical scientists.
There is considerable evidence that substance P (SP) is a key trigger for arthritic inflammation.3,4 Substance P is found in the terminals of afferent nerves densely innervating the joints affected by rheumatoid arthritis. The puzzle that no one can solve is why small afferent nerves carry 2-way traffic—sending sensory impulses centrally while at the same time releasing vesicles of SP antidromically. (The author will donate a case of wine for the first correct answer!) In rodents, neonatal depletion of SP from afferent joint nerve endings markedly reduces the induction of arthritis with Freund adjuvant—the classic experimental model of auto-immune arthritis.2,5,6
The neurogenic theory of arthropathy might explain why anticonvulsants often appear to exert a positive effect on so-called autoimmune diseases. Patients with epilepsy taking phenytoin seem to be at lower risk for autoimmune disorders.7 Scleroderma, very difficult to treat, was reported to respond to anticonvulsant drugs in studies conducted in the 1970s.8,9 Moreover, scleroderma might not afflict paralyzed limbs; a similar observation has been made with psoriasis.10
Our treatment of the so-called inflammatory cascade is passable: it provides pain relief and some disease modification—but it does not deal with the underlying cause of the cascade. Animal experimentation points clearly to the direct effect of a neurogenic influence, which I would humbly suggest is the initial stimulus. All of our attention in the past has been focused on the inflammatory cascade—its effect on blood chemistry and its response to therapeutic agents, such as steroids or nonsteroidal anti-inflammatory drugs—but we continue to ignore the cause.
Perhaps the greatest defect in modern medicine is that once we have gone down the wrong path, it is difficult to change direction or admit failure. Better sooner than later! Most have forgotten that for centuries we got the circulation of the blood wrong. A modern example is the hilarity and disdain that greeted the scientists who dared to propose that infection with Helicobacter pylori was the fundamental cause of ulcers. To quote a popular song—When will we ever learn?
The critical test is to electrically stimulate the afferent nerves innervating joints in animals to see if this can trigger inflammatory arthropathy—a very fast, very cheap experiment. Would anticonvulsant drugs provide protection also?
References References1.Glick EN. Asymmetrical rheumatoid arthritis after poliomyelitis. BMJ. 1967;3:26–9. [PubMed]
2.Levine JD, Dardick SJ, Roizen MF, Helms C, Basbaum AI. Contribution of sensory afferents and sympathetic efferents to joint injury in experimental arthritis. J Neurosci. 1986;6(12):3423–9. [PubMed]
3.Holzer P. Local effector functions of capsaicin-sensitive sensory nerve endings: involvement of tachykinins, calcitonin gene-related peptide and other neuropeptides. Neuroscience. 1988;24(3):739–68. [PubMed]
4.Levine JD, Moskowitz MA, Basbaum AI. The contribution of neurogenic inflammation in experimental arthritis. J Immunol. 1985;135(2 Suppl):843s–7s. [PubMed]
5.Maggi CA, Meli A. The sensory-efferent function of capsaicin-sensitive sensory neurons. Gen Pharmacol. 1988;19(1):1–43. [PubMed]
6.Niissalo S, Hukkanen M, Imai S, Tornwall J, Konttinen YT. Neuropeptides in experimental and degenerative arthritis. Ann N Y Acad Sci. 2002;966:384–99. [PubMed]
7.Bobrove AM. Possible beneficial effects of phenytoin for rheumatoid arthritis. Arthritis Rheum. 1983;26:118–9. [PubMed]
8.Morgan RJ. Scleroderma: treatment with diphenylhydantoin. Cutis. 1971;8:278–82.
9.Neldner HK. Treatment of localized linear scleroderma with phenytoin. Cutis. 1978;22:569–72. [PubMed]
10.Sethi S, Sequeira W. Sparing effect of hemiplegia on scleroderma. Ann Rheum Dis. 1990;49(12):999–1000. [PubMed]
url link not specific1: J Neurosurg. 2005 Mar;102(3):522-5.Links
Selective ablation of nociceptive neurons for elimination of hyperalgesia and neurogenic inflammation.Tender GC, Walbridge S, Olah Z, Karai L, Iadarola M, Oldfield EH, Lonser RR.
Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892-1414, USA.
OBJECT: Neuropathic pain is mediated by nociceptive neurons that selectively express the vanilloid receptor 1 (VR1). Resiniferatoxin (RTX) is an excitotoxic VR1 agonist that causes destruction of VR1-positive neurons. To determine whether RTX can be used to ablate VR1-positive neurons selectively and to eliminate hyperalgesia and neurogenic inflammation without affecting tactile sensation and motor function, the authors infused it unilaterally into the trigeminal ganglia in Rhesus monkeys. METHODS: Either RTX (three animals) or vehicle (one animal) was directly infused (20 microl) into the right trigeminal ganglion in Rhesus monkeys. Animals were tested postoperatively at 1, 4, and 7 weeks thereafter for touch and pain perception in the trigeminal distribution (application of saline and capsaicin to the cornea). The number of eye blinks, eye wipes, and duration of squinting were recorded. Neurogenic inflammation was tested using capsaicin cream. Animals were killed 4 (one monkey) and 12 (three monkeys) weeks postinfusion. Histological and immunohistochemical analyses were performed. Throughout the duration of the study, response to high-intensity pain stimulation (capsaicin) was selectively and significantly reduced (p < 0.001, RTX-treated compared with vehicle-treated eye [mean +/- standard deviation]): blinks, 25.7 +/- 4.4 compared with 106.6 +/- 20.8; eye wipes, 1.4 +/- 0.8 compared with 19.3 +/- 2.5; and squinting, 1.4 +/- 0.6 seconds compared with 11.4 +/- 1.6 seconds. Normal response to sensation was maintained. Animals showed no neurological deficit or sign of toxicity. Neurogenic inflammation was blocked on the RTX-treated side. Immunohistochemical analysis of the RTX-treated ganglia showed selective elimination of VR1-positive neurons. CONCLUSIONS: Nociceptive neurons can be selectively ablated by intraganglionic RTX infusion, resulting in the elimination of high-intensity pain perception and neurogenic inflammation while maintaining normal sensation and motor function. Analysis of these findings indicated that intraganglionic RTX infusion may provide a new treatment for pain syndromes such as trigeminal neuralgia as well as others.
PMID: 15796388 [PubMed - indexed for MEDLINE]
Resiniferatoxin (RTX) is a naturally occurring, ultrapotent capsaicin analog that activates the vanilloid receptor in a subpopulation of primary afferent sensory neurons involved in nociception (the transmission of physiological pain). RTX causes a novel ion channel in the plasma membrane of sensory neurons — the transient receptor potential vanilloid 1 — to become permeable to cations, most particularly the calcium cation; this evokes a powerful irritant effect followed by desensitization and analgesia.
<shortened url>1: Neuroscience. 2008 Jun 23;154(2):621-30. Epub 2008 Apr 1. Links
Capsaicin-induced neuronal death and proliferation of the primary sensory neurons located in the nodose ganglia of adult rats.Czaja K, Burns GA, Ritter RC.
Department of Veterinary, Comparative Anatomy, Pharmacology, and Physiology, College of Veterinary Medicine, G7 Wegner Hall, Washington State University, Pullman, WA 99163-6520, USA.
To evaluate the potential for neuronal replacement following destruction of vagal afferent neurons, we examined nodose ganglia following i.p. capsaicin treatment of adult rats. Rats received capsaicin or vehicle followed by a regimen of 5'-bromo-2'-deoxyuridine injections (BrdU) to reveal DNA replication. Nodose ganglia were harvested at various times post-treatment and processed for 4',6-diamidino-2-phenylindole (DAPI) nuclear staining and immunofluorescence to estimate neuronal numbers and to determine vanilloid receptor, cleaved caspase 3, TUNEL, BrdU, the neuron-selective marker protein gene product (PGP) -9.5 and neurofilament-M-immunoreactivity. Twenty-four hours after capsaicin approximately 40% of nodose ganglion neurons expressed cleaved caspase 3-immunoreactivity and 16% revealed TUNEL staining, indicating that primary sensory neurons are killed by the capsaicin treatment of adult rats. The occurrence of neuronal death was confirmed by counts of DAPI-stained neuronal nuclei, which revealed >/=50% reduction of nodose neuron number by 30 days post-capsaicin. However, by 60 days post-capsaicin, the total numbers of neuronal nuclei in nodose ganglia from capsaicin-treated rats were not different from controls, suggesting that new neurons had been added to the nodose ganglia. Neuronal proliferation was confirmed by significant BrdU incorporation in nuclei of nodose ganglion cells immunoreactive for the neuron-specific antigen PGP-9.5 revealed 30 and 60 days post-capsaicin. Collectively, these observations suggest that in adult rats massive scale neurogenesis occurs in nodose ganglia following capsaicin-induced neuronal destruction. The adult nodose ganglion, therefore, provides a novel system for studying neural plasticity and adult neurogenesis after peripheral injury of primary sensory neurons.
PMID: 18456414 [PubMed - in process]
<shortened url>1: Gut. 2008 Jul;57(7):923-9. Epub 2008 Feb 5. Links
Gut. 2008 Jul;57(7):882-4.
Increased capsaicin receptor TRPV1-expressing sensory fibres in irritable bowel syndrome and their correlation with abdominal pain.Akbar A, Yiangou Y, Facer P, Walters JR, Anand P, Ghosh S.
Department of Gastroenterology, Imperial College London, UK.
OBJECTIVE: The capsaicin receptor TRPV1 (transient receptor potential vanilloid type-1) may play an important role in visceral pain and hypersensitivity states. In irritable bowel syndrome (IBS), abdominal pain is a common and distressing symptom where the pathophysiology is still not clearly defined. TRPV1-immunoreactive nerve fibres were investigated in colonic biopsies from patients with IBS, and this was related to abdominal pain. METHODS: Rectosigmoid biopsies were collected from 23 IBS patients fulfilling Rome II criteria, and from 22 controls. Abdominal pain scores were recorded using a validated questionnaire. TRPV1-, substance P- and neuronal marker protein gene product (PGP) 9.5-expressing nerve fibres, mast cells (c-kit) and lymphocytes (CD3 and CD4) were quantified, following immunohistochemistry with specific antibodies. The biopsy findings were related to the abdominal pain scores. RESULTS: A significant 3.5-fold increase in median numbers of TRPV1-immunoreactive fibres was found in biopsies from IBS patients compared with controls (p<0.0001). Substance P-immunoreactive fibres (p = 0.01), total nerve fibres (PGP9.5) (p = 0.002), mast cells (c-kit) (p = 0.02) and lymphocytes (CD3) (p = 0.03) were also significantly increased in the IBS group. In multivariate regression analysis, only TRPV1-immuno-reactive fibres (p = 0.005) and mast cells (p = 0.008) were significantly related to the abdominal pain score. CONCLUSIONS: Increased TRPV1 nerve fibres are observed in IBS, together with a low-grade inflammatory response. The increased TRPV1 nerve fibres may contribute to visceral hypersensitivity and pain in IBS, and provide a novel therapeutic target.
<shortened url>1: Trends Pharmacol Sci. 2008 Jan;29(1):29-36. Epub 2007 Dec 4. Links
The emerging role of TRPV1 in diabetes and obesity.Suri A, Szallasi A.
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
The capsaicin receptor transient receptor potential vanilloid subfamily member 1 (TRPV1) is highly expressed on sensory nerve fibers innervating the pancreas. Indeed, the role of TRPV1 in mediating pain during pancreatitis is well established. The initial excitation of these nerves by capsaicin is followed by a reversible refractory state (desensitization) or, under certain conditions such as neonatal treatment, neurotoxicity. Interestingly, ablation of TRPV1-positive fibers by subcutaneous capsaicin treatment not only ameliorates pancreatitis pain but also diminishes aging-associated weight gain and improves glucose tolerance both in mice on a high-fat diet and in rat models of type 2 diabetes. New evidence implies an unexpected, pivotal role for TRPV1 in type 1 (autoimmune) diabetes. Non-obese diabetic (NOD) mice carry a hypofunctional TRPV1 mutant. Ablation of nerves carrying this mutant TRPV1 by capsaicin prevents immune-mediated destruction of islet beta cells despite the persistence of diabetogenic T cells. Collectively, these findings establish a crucial link among sensory nerves, obesity and diabetes and identify pharmacological TRPV1 blockade as a novel therapeutic approach for diabetes prevention and weight control.
http://www.ncbi.nlm.nih.gov/sites/entrez think the url link is down1: Cell. 2006 Dec 15;127(6):1123-35. Links
Cell. 2006 Dec 15;127(6):1097-9.
TRPV1+ sensory neurons control beta cell stress and islet inflammation in autoimmune diabetes.Razavi R, Chan Y, Afifiyan FN, Liu XJ, Wan X, Yantha J, Tsui H, Tang L, Tsai S, Santamaria P, Driver JP, Serreze D, Salter MW, Dosch HM.
Neurosciences and Mental Health Program, The Hospital for Sick Children, Research Institute, University of Toronto, Toronto, ON, Canada, M5G 1X8.
In type 1 diabetes, T cell-mediated death of pancreatic beta cells produces insulin deficiency. However, what attracts or restricts broadly autoreactive lymphocyte pools to the pancreas remains unclear. We report that TRPV1(+) pancreatic sensory neurons control islet inflammation and insulin resistance. Eliminating these neurons in diabetes-prone NOD mice prevents insulitis and diabetes, despite systemic persistence of pathogenic T cell pools. Insulin resistance and beta cell stress of prediabetic NOD mice are prevented when TRPV1(+) neurons are eliminated. TRPV1(NOD), localized to the Idd4.1 diabetes-risk locus, is a hypofunctional mutant, mediating depressed neurogenic inflammation. Delivering the neuropeptide substance P by intra-arterial injection into the NOD pancreas reverses abnormal insulin resistance, insulitis, and diabetes for weeks. Concordantly, insulin sensitivity is enhanced in trpv1(-/-) mice, whereas insulitis/diabetes-resistant NODxB6Idd4-congenic mice, carrying wild-type TRPV1, show restored TRPV1 function and insulin sensitivity. Our data uncover a fundamental role for insulin-responsive TRPV1(+) sensory neurons in beta cell function and diabetes pathoetiology.
(S.E. Jordt and B. E, Ehrlich, Yale University; TRP Channels in Disease). This is the opposite to the first abstract on diabetes and isn't mentioned in the second abstract on diabetes which is the source of the Yale reseach. MMMMMM! What to make of it all. I shall have to get Razavi and Chan's full text."The authors could show that application of exogenous substance P to the pancreas delays the onset of diabetes in NOD mice, proving that substance P is a crucial mediator in this feedback mechanism. When substance P is withdrawn, or sensory neurons are eliminated by injections of large doses of capsaicin, the autoimmune response proceeds, resulting in beta cell damage and diabetes."
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