Dihydrotestosterone as a Protective Agent in Chronic Experimental Autoimmune Encephalomyelitis

Abstract

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 17ß-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-1ß, 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 3a- or 3ß-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.

Sex Hormones and Multiple Sclerosis

“…Dihydrotestosterone has been effective in reducing the severity of chronic EAE in Dark Agouti rats (an experimental model showing a protracted relapsing EAE). Decreased gliosis and inflammation in the spinal cord has also been observed [96]. These results are in line with previous findings of Dalal et al [97] who reported a less severe course of EAE in dihydrotestosterone treated female SJL mice.…”

The role of testosterone in MS risk and course

“…Because some of the benefits of testosterone in EAE models may result from its aromatization to estradiol, testosterone preparations, as opposed to the downstream DHT product, have been initially explored. However, a recent study in EAE demonstrated a benefit of DHT, 51 obviating the need for further comparative studies.…”

A Unique TGFB1-Driven Genomic Program Links Astrocytosis, Low-Grade Inflammation and Partial Demyelination in Periplaques of Spinal Cords from Progressive Multiple Sclerosis Patients

“…Interestingly, even when excluding males from our study, the AR was still co-expressed with GJA1/Cx43. As androgens are known to prevent astrocytosis [29][30][31][32][33][34], our results raise the possibility that in males and females suffering from progressive forms of MS, activation of the AR is somehow defective and fails to downregulate a large set of progliotic genes induced by the TGFB/SMAD1/SMAD2 pathway. This could be due to an age-related decrease of circulating testosterone or of the circulating androgen precursors (Dehydroepiandrosterone and Androstendiol) that can be intracellularly metabolized into testosterone [54][55][56][57].…”

“…On the other hand, the androgen receptor (AR), which was also found to co-express with Cx43/GJA1, was previously shown to inhibit reactive astrocytosis under varied CNS conditions [29][30][31][32][33][34]. Of note, AR co-expressed also with Cx43/GJA1 when excluding the 2 male patients from our analysis (data supplement 3).…”