Abstract
Gonadal steroid hormones are neurotrophic and neuroprotective. These effects are modulated by local metabolism of the hormones within the brain. Such control is necessary to maintain normal function, as several signaling pathways that are activated by gonadal steroid hormones in the brain can also become dysregulated in disease. Metabolites of the gonadal steroid hormones—particularly 3α-hydroxy, 5α-reduced neurosteroids—are synthesized in the brain and can act through different mechanisms from their parent steroids. These metabolites may provide a mechanism for modulating the responses to their precursor hormones, thereby providing a regulatory influence on cellular responses. In addition, there is evidence that the 3α-hydroxy, 5α-reduced neurosteroids are neuroprotective in their own right, and therefore may contribute to the overall protection conferred by their precursors. In this review article, the rapidly growing body of evidence supporting a neuroprotective role for this class of neurosteroids will be considered, including a discussion of potential mechanisms that may be involved. In addition, we explore the hypothesis that differences between males and females in local neurosteroid production may contribute to sex differences in the development of neurodegenerative disease.
Highlights
Many neurodegenerative diseases—conditions that are characterized by progressive deterioration of cognition, mood, executive function, etc. due to loss of neurons in the central nervous system (CNS)—exhibit sex differences in incidence, onset and severity
Limbic brain concentrations of 3α-diol increase with age in wild-type and 3xTg-Alzheimer’s disease (AD) male mice (Caruso et al, 2013a). Consistent with these results, a divergence between plasma levels of allopregnanolone and 3α-diol has been reported in patients with AD, the former being significantly reduced in patients with the disease, while the latter does not appear to change, compared to normal age-matched controls (Smith et al, 2006)
In male Sprague-Dawley rats given streptozotocin injections to induce diabetic neuropathy, Ro5-4864 increased levels of pregnenolone, progesterone and DHT in the sciatic nerves, while reversing impairments in nerve conduction velocity, thermal threshold, skin innervation density, protein 0 (P0) mRNA levels, and activity of Na+/K+-ATPase (Giatti et al, 2009). As many of these factors were improved in the same way following treatment with DHT or 3α-diol in a previous study (Calabrese et al, 2014), it seems likely that the effects of Ro5-4864 in this study were due to its regulation of endogenous neurosteroidogenesis
Summary
Gonadal steroid hormones are neurotrophic and neuroprotective These effects are modulated by local metabolism of the hormones within the brain. Such control is necessary to maintain normal function, as several signaling pathways that are activated by gonadal steroid hormones in the brain can become dysregulated in disease. Metabolites of the gonadal steroid hormones— 3α-hydroxy, 5α-reduced neurosteroids—are synthesized in the brain and can act through different mechanisms from their parent steroids. These metabolites may provide a mechanism for modulating the responses to their precursor hormones, thereby providing a regulatory influence on cellular responses.
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