Abstract
Aims: We have previously shown that the neurosteroid androstenediol (ADIOL) promotes remyelination following gliotoxin-induced demyelination. However, the impact of this ADIOL on axonal recovery is not yet known. In the present study, we investigated the impact of ADIOL on axonal integrity following a focal demyelination in the corpus callosum.Methods: A 2 μl solution of either ethidium bromide (EB; 0.04%) or pyrogen-free saline were stereotaxically injected into the corpus callosum of Sprague Dawley rats. Each of these two rat groups was divided into two subgroups and received daily subcutaneous injections of either ADIOL (5 mg/kg) or vehicle. The brains were collected at 2, 7 and 14 days post-stereotaxic injection. Immunofluorescent staining was used to explore the impact of ADIOL on axonal integrity (neurofilament (NF)-M) and microglial activation (ionized calcium binding adapter molecule 1, Iba1). The inducible nitric oxide synthase (iNOS) and arginase-1 (arg-1), two major markers of microglial polarization towards the proinflammatory M1 and the regulatory M2 phenotypes respectively, were monitored using western blot.Results: ADIOL increased the density of NF fibers and decreased the extent of axonal damage in the vicinity of the demyelination lesion. ADIOL-induced decrease in axonal damage was manifested by decreased number of axonal spheroids at both 2 and 7 days post-demyelination insult. This reduced axonopathy was associated with decreased expression of iNOS and enhanced expression of arg-1 during the acute phase.Conclusion: These data strongly suggest that ADIOL reduces demyelination-induced axonal damage, likely by dampening the local inflammatory response in the white matter and shifting microglial polarization towards a reparative mode.
Highlights
Myelin is a lipid membrane that enwraps a large portion of axons within the nervous system
Compared to salineinjected corpus callosum, ethidium bromide (EB)-injected corpus callosum showed a significant reduction in the density of NF+ fibers (Sal-O; n = 4, EB-O; n = 4, p < 0.05; Figure 1A upper panel, Figure 1B)
We monitored the number of axonal spheroids per area which are indicative of axonal damage (Sternberger and Sternberger, 1983)
Summary
Myelin is a lipid membrane that enwraps a large portion of axons within the nervous system It enhances the speed of propagation of nerve impulses and provides axons with trophic support (Franklin et al, 2012). MS is a disease characterized by the development of a wide range of disabilities depending on the area of the central nervous system affected (Crawford et al, 2013). These deficits include sensory, motor, autonomic and cognitive dysfunctions (Procaccini et al, 2015). Limiting axonal damage can potentially reduce the severity of the disease
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