HMG‐CoA reductase inhibitor augments survival and differentiation of oligodendrocyte progenitors in animal model of multiple sclerosis

Abstract

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.

Therapeutic potential of statins in multiple sclerosis: immune modulation, neuroprotection and neurorepair

“…However, recent clinical and experimental studies have documented a variety of statins' pleiotropic effects, such as anti-inflammatory, antiproliferative, antithrombotic and antioxidant activities in various pathological conditions [7][8][9][10][11][12][13][14][15][16][17].…”

“…However, the precise role of these factors in the loss of oligodendrocytes and myelin in MS is not well understood. Recent studies reporting reduced loss of myelin proteins and lipids in the brains and spinal cord of animals with EAE treated with lovastatin [10], or a lovastatin and 5 aminoimidazole-4-carboxamide ribonucleoside (AICAR) combination [68], suggest the possible neuroprotective activity of lovastatin against loss of oligodendrocytes and myelin in EAE.…”

“…The expression of antibodies against oligodendrocytes and their progenitors [64,65], and activation of AMPA/kainite receptors by increased amounts of glutamate [66], are some of the factors that are reported to account for the observed demyelination in inflammatory areas in MS plaques. Reparative therapies with a potential to enhance remyelination, such as statins, provide a promising approach for myelin repair [10,68,69]. Higher numbers of oligodendrocyte progenitors in the spinal cords of animals with EAE treated with lovastatin and their observed proliferation and differentiation into myelin-producing cells document the potential of statins to repair demyelinated lesions [10].…”

“…Recent observations of statin-mediated protection of neuroprogenitor cells from inflammatory insult and the resulting enhanced remyelination during experimental allergic encephalomyelitis (EAE), an animal model of MS, suggest that, in addition to immunomodulatory activity [8,9], statins mediate neuroprotection and possibly neuroregeneration [10]. They affect BBB integrity and inhibit the infiltration of inflammatory cells into the CNS [7].…”

“…They affect BBB integrity and inhibit the infiltration of inflammatory cells into the CNS [7]. They also prevent neurodegenerative changes and may promote neurorepair in EAE [10]. Therefore, statins represent a promising monotherapy, as well as a combination therapy with presently approved and new experimental therapies for MS.…”