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Multiple sclerosis is a chronic inflammatory disease affecting the central nervous system. As reported by clinical observations, variation in hormonal levels might alter disease susceptibility and progression. Specifically, decreased levels of testosterone in males are reported to be permissive for disease onset. Accordingly, testosterone seems to exert protective effects in experimental autoimmune encephalomyelitis (EAE). In this context, it is important to highlight that testosterone is further metabolized into 17β-estradiol or dihydrotestosterone (DHT). In this study, we aimed to explore the protective effects of DHT treatment in EAE Dark Agouti rats (i.e. an experimental model showing a protracted relapsing EAE). Data obtained 45 days after EAE induction showed that DHT exerts a beneficial effect on clinical scores, coupled with decreased gliosis (i.e. glial fibrillary acidic protein and major histocompatibility complex of class II staining) and inflammation (i.e. translocator protein 18 kDa, interleukin-1β, Toll-like receptor 4 and nuclear factor-κB expression) in the spinal cord. Moreover, parameters linked to oxidative stress and tissue damage, like thiobarbituric acid-reactive substance levels and Bcl-2-associated X protein expression, and to mitochondrial activity (i.e. content of mitochondrial DNA and proteins), were improved after DHT administration. This neuroactive steroid may be further metabolized into 3α- or 3β-diol. However, assessment of the levels of these metabolites after DHT treatment seems to suggest that the protective effects observed here are due to DHT itself. Altogether, the present results indicate that DHT was effective in reducing the severity of chronic EAE and, consequently, may represent an interesting perspective for multiple sclerosis treatment.

Observations so far obtained in experimental autoimmune encephalomyelitis (EAE) have revealed the promising neuroprotective effects exerted by progesterone (PROG). The findings suggest that this neuroactive steroid may potentially represent a therapeutic tool for multiple sclerosis (MS). However, up to now, the efficacy of PROG has been only tested in the acute phase of the disease, whereas it is well known that MS expresses different features depending on the phase of the disease. Accordingly, we have evaluated the effect of PROG treatment in EAE induced in Dark Agouti rats (i.e. an experimental model showing a protracted relapsing EAE). Data obtained 45 days after EAE induction show that PROG treatment exerts a beneficial effect on clinical score, confirming surrogate parameters of spinal cord damage in chronic EAE (i.e. reactive microglia, cytokine levels, activity of the Na(+) ,K(+) -ATPase pump and myelin basic protein expression). An increase of the levels of dihydroprogesterone and isopregnanolone (i.e. two PROG metabolites) was also observed in the spinal cord after PROG treatment. Taken together, these results indicate that PROG is effective in reducing the severity of chronic EAE and, consequently, may have potential with respect to MS treatment., (© 2012 The Authors. Journal of Neuroendocrinology © 2012 Blackwell Publishing Ltd.)

Erythropoietin (Epo), the principal regulator of erythroids progenitor cells, greatly improves neuronal survival. A wide variety of experimental studies have shown that both Epo and the EpoR are functionally expressed in the nervous system and that this cytokine exerts a remarkable neuroprotection both in vitro against different neurotoxicants and in animal models of nervous system disorders. Aim of this review is to summarize the neuroprotective properties of Epo and to outline the molecular mechanisms involved in order to point out the signal transduction pathway which may represent the potential basis for future strategies against neuronal injury.

Erythropoietin, the principal regulator of erythroids progenitor cells, also promotes neuronal survival. Using primary cultures of rat hippocampal neurons, we investigated whether erythropoietin could mediate neuroprotection favouring the transcription of brain-derived neurotrophic factor (BDNF). Erythropoietin 2.7 nm reduced by approximately 50% the neuronal death triggered by the prototypic neurotoxicant trimethyltin (TMT) and time-dependently induced BDNF mRNA. This effect resulted in an increased production of biologically active BDNF, which led to a sustained activation of the specific BDNF receptor tyrosine kinase B (TrkB). Reduction of TMT-induced neuronal death by erythropoietin was specifically prevented by a neutralizing anti-BDNF antibody (15 microg/mL), indicating the involvement of this neurotrophin in erythropoietin neuroprotective effect. Intracerebroventricular administration of erythropoietin in mice significantly increases BDNF mRNA expression in brain, supporting the idea of the involvement of this neurotrophin in erythropoietin action within the CNS. BDNF expression in neuronal cells is induced by activation of voltage Ca(2+)-channels and recruitment of Ca(2+)-sensitive transcription factors. Consistently, 2.7 nm erythropoietin increased intracellular Ca(2+) in 5 min and cAMP response element binding protein (CREB) phosphorylation at Ser 133 in 30 min. Both effects were abolished by 1 microm nitrendipine, a selective blocker of L-type voltage Ca(2+)-channels. These data demonstrate that erythropoietin activates the CREB transcription pathway and increases BDNF expression and production, which contributes to erythropoietin mediated neuroprotection.