NET-PD LS-1 Nicotine and Neuroprotection in Parkinson's Disease

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DESCRIPTION (provided by applicant): About 1.2 million patients suffer from Parkinson's Disease (PD) and > 100,000 patients are diagnosed with PD every year. The occurrence of PD may only increase in the future adding to the personal suffering of numerous families as well as an increase in the health care cost for the family and the nation. The etiology of PD is not known. Progressive degeneration of the midbrain dopaminergic neurons is the main pathological finding in human PD. Factors that cause of progressive nigral degeneration are not known. Experimental evidence suggests that mitochondrial dysfunction may be the seminal factor inducing apoptosis of nigral neurons. Mitochondria play a major role in energy synthesis and calcium homeostasis. Damage to mitochondria will lead to decreased energy synthesis, altered calcium homeostasis, and increased oxidative stress and these factors will trigger cell death through mitochondrial-mediated cascades of apoptosis. The factors inducing mitochondrial distress in human PD are unknown. Exogenous (MPTP and rotenone) and endogenous neurotoxins (increased free radicals) induce severe damage to Complex I of the electron transfer chain of the mitochondria, contributing to mitochondrial stress and cell death. Mutations of several genes do cause inherited forms of PD. The proteins derived from many of the PD related genes are localized in the matrix, the inner and outer membranes of the mitochondria and contribute to the structural and functional integrity of mitochondria. Some mutations cause an accumulation of protein (alpha-synuclein) and result in cell death. Mutations of other genes may induce loss of neuro- and mitochondrial protection and decrease mitochondrial biogenesis, (e.g.. Parkin) Mutations of genes of proteins localized to membranes and matrix induce loss of mitochondrial structural and functional integrity and lead to cell death. The long-term objective of the NET-PD consortium is to identify agents that are mitochondrial protectants. LS1 is a multi-center. Phase 3, double-blind clinical trial that tests the hypothesis that daily administration of creatine (10gm/day) is more effective than placebo in slowing clinical decline in PD between baseline and the 5 year follow-up visit against the background of dopaminergic therapy and best PD care.