Neuroprotection and Myelin Repair Mechanisms in Multiple Sclerosis

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DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is central nervous system (CNS) inflammatory, demyelinating disease that affects individuals in their most productive ages. MS is prevalent in US veterans due to their prior residence or socioeconomics status during their service as risk factor is more in northern tire states than southern tire states. So far MS lacks effective treatment: current FDA-approved drugs focus on attenuating the progression of peripheral immune responses and do not emphasize neuro-repair in the injured brain. The present proposal is planned to evaluate the role of AMP-activated protein kinase (AMPK), a phylogenetically conserved, intracellular energy sensor switch which helps regulate glucose and lipid metabolism, in the context of the survival and differentiation of oligodendrocyte (OP) progenitor cells (OPCs) in an experimental autoimmune encephalomyelitis (EAE) model of MS. In line with this, AMPK has previously been implicated in the protection and differentiation of neurons against various inflammatory insults. Specifically, AMPK has been studied with respect to myelin repair and neuroprotection in EAE. Data suggest that the differentiation of OPCs into myelin-forming OLs is essential for myelin repair and maintenance during CNS demyelinating diseases. Our recent studies established that AMPK activation by 5-aminoimidazole-4-carboxamide-1-2-D-ribofuranoside (AICAR) or metformin attenuates EAE disease and provides neuro-protection via immunomodulation and protection of the blood brain barrier (BBB). Moreover, AMPK-11 gene knockout mice had more severe EAE than wild-type mice, suggesting a role for AMPK in EAE attenuation. These anti-inflammatory activities of AMPK were also evident in lipopolysaccharide (LPS)-stimulated astrocytes in vitro as well as in endotoxemia model. Recent studies established that AMPK is important in the regulation of peroxisome proliferator-activated receptor (PPAR) activity in various cell types and this was ascribed to direct PPAR phosphorylation or increased bio-availability of their endogenous activators. PPARs are nuclear receptors which regulate the growth and differentiation of various cell types. Similar to AMPK, PPAR activation is reported to participate in the attenuation of EAE as a function of immunomodulatory and BBB protection activities, whereas the inflammatory response tends to downregulate PPAR cellular expression. Importantly, PPAR activation has been shown to induce the differentiation of OPCs into myelin-forming OLs. Based upon these studies, we hypothesized that activated AMPK-mediated regulation of PPAR activity may participate in the differentiation of OPCs to promote myelin repair in EAE. Elucidation of this mechanism will permit us to design new therapeutics to promote myelin repair and limit the progression of MS in affected individuals. Therefore, the focus of this proposal will be to determine the regulation of PPAR subtype activity using activated AMPK in OPCs, which may participate in their survival and differentiation (Aim 1). Next we will therapeutically evaluate the AMPK activator metformin alone or in combination with an agonist of PPAR subtypes to promote neuro-repair in an EAE model (Aim 2). The novelty of the study is the promise of new therapeutic targets for induction of myelin repair for improved treatment and management of neurodegenerative diseases such as MS. Therapeutic targeting of neural cell mechanisms in inflammatory demyelinating model is an innovative approach. PUBLIC HEALTH RELEVANCE: MS is highly prevalent in US veterans due to their prior residence or socioeconomics status during their service as risk factor is more in northern tire states than southern tire states of US. Epidemiological studies demonstrated that the high rate of MS occurrence in all veterans who served in World War II, the Korean conflict and the Gulf war in 1991 due to the environmental factors or the precipitation of the disease. Therefore, an effective therapy for MS is required to treat veterans working at this time period of war and different environmental conditions in Iraq and Afghanistan. In spite of the current therapeutics for MS targeting immune response, the disease often progresses leading to demyelination thus physical disability in affected individuals. Lack of effective treatment for MS represents a significant gap for controlling it. Therefore, the understanding of proposed mechanism of AMPK mediated regulation of PPARs by metformin in oligodendrocyte progenitor cells will identify novel therapeutic for induction of myelin repair (remyelination) by targeting the endogenous precursor cells in MS patients.