Niacin-mediated rejuvenation of macrophage/microglia enhances remyelination of the aging central nervous system:

"These results identify niacin as a novel stimulator of macrophage/microglia phagocytosis in culture that acts through Hcar2 to upregulate CD36 culminating in myelin engulfment.

We conclude that niacin is not affecting circulating monocytes or the recruitment of macrophages/microglia into lesions in middle-aged animals, but that it promotes the intralesional phagocytic clearance of inhibitory myelin debris.

These results demonstrate that systemic treatment with niacin improves remyelination in the aging CNS, specifically in larger caliber axons that otherwise would not be remyelinated in aging after lysolecithin-induced demyelination.

Recently, it was shown that the ability for macrophages/microglia to export phagocytosed cholesterol is important for preventing the formation of cholesterol crystals and lysosomal rupture within macrophages/microglia in demyelinated lesions, and that this is reduced in aging.

As niacin has an extensive clinical history when used in dyslipidemia and is well tolerated, we examined whether systemic niacin treatment would be effective in improving the deficient remyelination observed in middle-aged mice.

Indeed, daily treatment with niacin enhanced myelin debris clearance, promoted OPC recruitment, as well as enhanced remyelination in lesions.

Altogether, these results identify a novel clinically approved medication that is able to significantly stimulate the innate immune system to enhance remyelination in the aging central nervous system.

These cells have also been shown to be detrimental through the secretion of free radicals and reactive oxygen species in addition to the release of potentially harmful pro-inflammatory cytokines [40].

As we found that niacin was able to significantly upregulate the secretion of several pro-inflammatory cytokines in vitro, including TNF-α which has been shown to be toxic in its soluble form through TNFR1 on oligodendrocytes [4], we were concerned that niacin treatment in middle-aged mice may exacerbate neurotoxicity. We do not think that this is the case, however, as we found no difference in axonal density with niacin treatment.

Furthermore, niacin treatment of mice induced with experimental autoimmune encephalomyelitis, an inflammatory model of MS, improved disease score and minimized the degree of inflammatory infiltrates in the CNS [52].

As pro-inflammatory macrophages/microglia have been previously shown to be important for remyelination [1, 26, 30], we may be harnessing the beneficial aspects of these cells without causing significant cell death or neurotoxicity.

It is also reassuring that we did not find elevation of pro-inflammatory monocytes in the circulation of niacin-treated mice, suggesting its safety in patients with inflammatory demyelinating diseases including MS.

Altogether, these results further emphasize the potential clinical utility of using niacin for remyelination.

We have identified niacin as a novel clinically approved medication that enhances macrophage/microglia phagocytosis of inhibitory debris, resulting in increased OPC recruitment and ultimately remyelination in the aging CNS."