Parkinson's disease (PD) is one of the most devastating neurodegenerative disorders in humans. Despite intense investigations, no effective therapy is available. Although its etiology remains unknown, it is believed that complex interaction between environmental and genetic factors leads to activation of glia and induction of broad-spectrum inflammatory reactions followed by degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Consistently, enhanced expression of inducible nitric oxide synthase (iNOS) and pro inflammatory cytokines (IL-1a, IL-6 and TNF-a) has been found in association with glial cells in the SNpc of patients with PD. We have found that lovastatin, a drug approved for hypercholesterolemia, and sodium phenylacetate (NaPA), a drug approved for urea cycle disorders in children, inhibit the expression of iNOS and pro inflammatory cytokines in glial cells by inhibiting Ras - NF-kB. Our recent studies have shown that drinking water containing NaPA markedly inhibits the disease process of experimental allergic encephalomyelitis (EAE), an animal model of Multiple Sclerosis (MS), as well as the expression of proinflammatory molecules in the CNS of EAE mice. Similarly sodium phenylbutyrate (NaPB), a synthetic precursor of NaPA and a FDA-approved drug, also inhibited the inflammatory disease process of EAE. Consistently, it has been also shown that lovastatin inhibits the disease process of EAE in different animal models. These results raise the possibility that lovastatin, NaPA and NaPB may turn out to be antineuroinflammatory drugs. Unlike MS, PD is not an autoimmune disorder. However, similar to MS, inflammation within the CNS plays a major role in the loss of dopaminergic neurons in SNpc of PD patients. Therefore, it is of worth trying if oral administration of lovastatin, NaPA and NaPB attenuates the expression of proinflammatory molecules (iNOS and cytokines) and the loss of dopaminergic neurons in an animal model of PD. A positive outcome of this grant proposal will further attest the anti neuroinflammatory role of lovastatin, NaPA and NaPB, and enhance the possibility of treating PD patients with these FDA approved drugs as primary or adjunct therapy.
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