Resveratrol enhances myelin protein expression following a demyelinating insult by promoting an anti-inflammatory environment

Caloric restriction, defined as a sustained reduction in calorie intake, has been shown to attenuate demyelination and promote remyelination. Resveratrol (3,4′,5-trihydroxystilbene, RSV) is a caloric restriction mimetic, with reported neuroprotective properties. Here, we evaluated the effects of RSV on myelin production upon demyelinating conditions in vivo in adult male mice and its effects in vitro, in microglia, astrocytes and oligodendrocyte precursor cells (OPCs), three key players involved in remyelination, in mice of both sexes. RSV enhanced myelin basic protein (MBP) expression ex vivo and augmented proteolipid protein expression (PLP) after focal demyelination in vivo. Analysis of oligodendroglial lineage cells revealed no differences in their proliferation and differentiation in vivo. In contrast, the highest dose of RSV directly promoted OPC differentiation to myelin-producing oligodendrocytes in vitro . Moreover, microglia-conditioned medium containing RSV, enhanced OPC differentiation, indicating the crucial role of microglia in the maturation of oligodendrocytes. RSV further increased the density of TREM2 expressed on alternatively activated microglia, following LPC-induced demyelination. In line with this, RSV caused a significant elevation in the secretion of the anti-inflammatory cytokine IL-10 and a reduction of the pro-inflammatory mediator iNOS in mouse primary microglia in vitro , indicating a shift toward an anti-inflammatory phenotype. In astrocytes, RSV increased astrogliosis in vivo , as evident by the increased GFAP density, while it upregulated both IL-10 and TNF-α in vitro , which might reflect an intermediate state of astrocytic activation. Overall, our findings support the hypothesis that RSV promotes an anti-inflammatory environment, thus enhancing myelin expression after a demyelinating insult.