Multiple sclerosis (MS) is an inflammatory demyelinating disease leading to loss of oligodendrocytes, myelin and axons and neurodegenerative lesion formation. Present day drugs developed to target immunomodulatory mechanisms provide limited efficacy since CNS disease progression continues despite treatment. Studies from various laboratories including ours have provided evidence of functional abnormality of mitochondria and peroxisomes as a cause of CNS disease pathologies in EAE (experimental autoimmune encephalomyelitis) and MS but very little, if any, about the mechanisms leading to these pathologies. The present proposal is designed to understand the mechanisms of mitochondrial and peroxisomal dysfunction and to determine the efficacy of drugs targeting these pathologies for neuroprotection and neurorepair in EAE. Recently, we have described that RhoA-Rock-PPAR mediated activity of statins as well as activation of AMP activated protein kinase (AMPK) protects oligodendrocytes against inflammatory insult in EAE and that a combination of lovastatin and AICAR, a specific activator AMPK, greatly improved the efficacy against EAE disease thus indicating the potential efficacy of these drugs against the CNS disease of EAE. AMPK is a cellular energy sensor playing an essential role in biogenesis, dynamics, and autophagic clearance of peroxisomes and mitochondria. Moreover, a recent phase-II double blind placebo controlled study of 140 patients with the progressive form of MS, a disease with no approved drug, reporting efficacy of simvastatin treatment as 50% reduction in brain atrophy over two years also supports the efficacy of statins against CNS disease of MS. Based on these findings, we hypothesize that drugs targeting RhoA-Rock-PPAR signaling mechanisms (lovastatin) and AMPK/PGC-1?-mTOR signaling mechanisms with AMPK activator (AICAR) in EAE/MS disease provides greater neuroprotection and accelerated neurorepair and hence improved efficacy in EAE/MS. Therefore, the proposed studies will investigate the mechanisms underlying mitochondrial and peroxisomal abnormalities using both cultured neurons and oligodendrocytes under EAE disease conditions, and mouse models of EAE.
Aim 1 : To investigate the mechanisms of mitochondrial and peroxisomal biogenesis and autophagic clearance in cultured neurons and oligodendrocytes under EAE conditions.
Aim 2 : To evaluate the therapeutic potential of RhoA/PPAR-mediated mechanisms using lovastatin and AMPK/PGC-1?-mediated mechanisms using AICAR for neuroprotection and neurorepair in EAE mice. The novelty of the study is the premise of a new therapeutic approach targeting CNS disease mechanisms of EAE and MS. The proposed studies will use state-of-the-art methodologies to address the proposed goals. Statins are the most commonly used drugs for hypercholesterolemia; therefore, translational potential of such a novel oral therapy of statin alone or in combination with activator of AMPK is reasonably high.
Multiple Sclerosis (MS), a debilitating neurological disorder affecting nearly 2 million adults, affects individuals in their most productive age, but currently approved drugs developed to target immune disease have limited efficacies for central nervous system (CNS) disease, thus underscoring a need for drug(s) targeting the critical CNS disease mechanisms. Secondly, MS is a complex disease involving multiple mechanisms and several cell types, thus drug targeting single mechanism/activity may not provide the needed efficacy. Based on the observed efficacy of a novel statin and bioenergy sensor AMPK activator (AICAR) combination, the present proposal is to delineate the underlying mechanisms for neuroprotection and neurorepair, and to evaluate the therapeutic potential of these drug combinations in EAE (experimental autoimmune encephalomyelitis), an animal model of MS, and thus develop novel neuroprotective and neurorepair based therapeutics for MS.
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