an old article on EBV and DHEA...all in all looks like DHEA should be in the supplement regime.
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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:
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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:
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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.comSigma-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:
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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:
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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:
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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:
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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.frOBJECTIVE: 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.eduInflammatory 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...
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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.plThe 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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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.
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!
