Abstract
AimExperimental studies have shown that the progesterone metabolite, allopregnanolone, is endowed with promyelinating effects. The mechanisms underlying these promyelinating effects are not well understood. Therefore, we explored the impact of allopregnanolone's synthetic analogue, ganaxolone, on remyelination and microglial activation following focal demyelination in the corpus callosum of ovariectomized rats.MethodsOvariectomized adult Sprague Dawley rats received a stereotaxic injection of 2 µL of 1% lysolecithin solution in the corpus callosum followed by daily injections of either ganaxolone (intraperitoneal injection [i.p.], 2.5 mg/kg) or vehicle. The demyelination lesion was assessed 3 and 7 days postdemyelination insult using Luxol fast blue staining and transmission electron microscopy. The expression levels of myelin proteins (MBP, MAG, MOG, CNPase) were explored using Western blot. The inflammatory response and clearance of damaged myelin were evaluated using immunofluorescent staining (Iba1, dMBP, GFAP) and multiplex enzyme‐linked immunosorbent assay (IL‐1β, TNF‐α, IL‐4, IL‐10, IL‐6).ResultsSystemic administration of ganaxolone promoted remyelination of lysolecithin‐induced demyelination, upregulated the expression of major myelin proteins, and enhanced microglial clearance of damaged myelin. Astrocytosis, as well as locally produced pro‐ and antiinflammatory cytokines, was not affected by ganaxolone treatment.ConclusionGanaxolone promotes remyelination in response to focal demyelination of the corpus callosum of ovariectomized rats. This effect is, at least in part, mediated by enhancing microglial clearance of myelin debris, which creates a conducive environment for a successful remyelination process.
Highlights
Several experimental studies suggest that allopregnanolone (ALLO), a metabolite of progesterone, is endowed with neuro‐ protective effects,[1] likely due to its GABAA receptor‐mediated antiinflammatory action.[2]
To avoid the systemic inflammatory response associated with encepha‐ lomyelitis (EAE) model, we explored the effect of GNX on lysolecithin‐ induced focal demyelination of the corpus callosum of OVX rats
We show that systemic administration of GNX, the synthetic analogue of ALLO, enhances remyelination following a focal demyelination lesion in the corpus callosum of OVX rats
Summary
Several experimental studies suggest that allopregnanolone (ALLO), a metabolite of progesterone, is endowed with neuro‐ protective effects,[1] likely due to its GABAA receptor‐mediated antiinflammatory action.[2]. The aim of this study was to investigate the effect of GNX on remyelination and the inflammatory response associated with de‐ myelination, which involves the activation of microglia and astro‐ cytes.[13,14] To avoid the systemic inflammatory response associated with EAE model, we explored the effect of GNX on lysolecithin‐ induced focal demyelination of the corpus callosum of OVX rats. Lysolecithin is a detergent‐like gliotoxin that causes the dissolution of oligodendrocyte membranes causing their death and subsequent demyelination.[15] Our data show that GNX enhances remyelination in the corpus callosum of OVX rats. It upregulates the expression of key myelin proteins, increases axonal myelination, and enhances clear‐ ance of damaged myelin by microglia
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