J. Neurochem. (2011) 116, 508–521. Abstract Th1 cytokine‐induced loss of oligodendrocytes (OLs) is associated with axonal loss in CNS demyelinating diseases such as multiple sclerosis (MS)that contributes to neurological disabilities in affected individuals. Recent studies indicated that, in addition to Th1‐phenotype cytokines including tumor necrosis factor (TNF)‐α, Th17 phenotype cytokine, interleukin (IL)‐17 also involved in the development of MS. In this study, we investigated the direct effect of IL‐17 on the survival of OLs in the presence of TNF‐α and individually in vitro settings. Our findings suggest that IL‐17 alone, however, was not able to affect the survival of OLs, but it exacerbates the TNF‐α‐induced OL apoptosis as compared with individual TNF‐α treatment. This effect of cytokines was ascribed to an inhibition of cell‐survival mechanisms, co‐localization of Bid/Bax proteins in the mitochondrial membrane and caspase 8 activation mediated release of apoptosis inducing factor from mitochondria in treated OLs. In addition, cytokine treatment disturbed the mitochondrial membrane potential in OLs with corresponding increase in the generation of reactive oxygen species, which were attenuated by N‐acetyl cysteine treatment. In addition, combining of these cytokines induced cell‐cycle arrest at G1/S phases in OL‐like cells and inhibited the maturation of OL progenitor cells that was attenuated by peroxisome proliferator‐activated receptor‐γ/‐β agonists. Collectively, these data provide initial evidence that IL‐17 exacerbates TNF‐α‐induced OL loss and inhibits the differentiation of OL progenitor cells suggesting that antioxidant‐ or peroxisome proliferator‐activated receptor agonist‐based therapies have potential to limit CNS demyelination in MS or other related demyelinating disorders.

Impaired remyelination due to degeneration of both postmitotic oligodendrocytes and oligodendrocyte progenitors (OPs) is the major hallmark of inflammatory demyelination in multiple sclerosis (MS) lesions and experimental autoimmune encephalomyelitis (EAE). Here, we have demonstrated the potential of lovastatin, a HMG‐CoA reductase inhibitor, for the restoration of impaired remyelination mediated through enhanced survival and differentiation of OPs in the spinal cord of treated EAE animals. Lovastatin treatment significantly increased the level of myelin lipids in the spinal cord of treated EAE animals, coinciding with the attenuation of disease severity and inflammatory demyelination as compared with untreated EAE animals. The increased expression of myelin proteins and transcription factors associated with differentiating oligodendrocytes along with the increase in number of NG2 ⁺ /BrdU ⁻ and NG2 ⁺ /BrdU ⁺ cells, and the expression of proliferating OP‐specific proteins, demonstrated the restoration of remyelination in the spinal cord of lovastatin‐treated EAE animals. Corresponding to this, in vitro studies further corroborated the increased survival and differentiation of OPs in lovastatin‐treated activated mixed glial cells suggesting that lovastatin protects against the degeneration of OPs and enhances their differentiation through induction of a pro‐remyelinating environment in the spinal cord of treated EAE animals. Together, these data demonstrate that lovastatin has the potential to augment remyelination in MS lesions and other neuroinflammatory diseases. Paintlia, A. S., Paintlia, M. K., Khan, M., Vollmer, T., Singh, A. K., Singh, I. HMG‐CoA reductase inhibitor augments survival and differentiation of oligodendrocyte progenitors in animal model of multiple sclerosis. FASEB J. 19, 1407–1421 (2005)