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Neuroprotective Effects of A2A Antagonists in Rodent Models of Motor Function and Dyskinesia

The principal feature of Parkinson's disease is a progressive death of dopamine neurons in the substantia nigra. Pharmacological therapies that enhance dopamine activity effectively treat the rigidity and bradykinesia (slowing and difficulty initiating movement) associated with PD. However, the efficacy of current dopaminergic therapies diminishes over time because of the associated development of interfering motor complications and ultimately because dopamine neurons continue to degenerate. Novel pharmacologic strategies are being sought to improve motor symptoms without the risk for long-term motor complications and, more importantly, to provide neuroprotection. Adenosine A2A receptor antagonists represent one such class of drugs that exhibit antiparkinsonian efficacy in both preclinical models and early clinical trials, and that may lead to minimal motor complications with extended use. Importantly, A2A antagonists might also slow degeneration of dopamine neurons. Epidemiological studies link consumption of caffeine, a nonselective adenosine receptor antagonist, to a reduced risk of developing PD. Pre-clinical studies show that caffeine and more selective A2A antagonists reduce neurotoxin-induced degeneration of DA neurons when administered prophylactically, i.e. before or during infusion of different dopamine-specific neurotoxins. Despite this evidence, the neuroprotective potential of A2A antagonists has yet to be assessed in a clinically driven design where the drug is given after the incremental loss of DA neurons exceeds a threshold where PD symptoms begin to manifest (with approximately 50 percent loss of dopamine neurons). This is the pathological state at which patients first seek treatment and achieving this same state in animal models may be an important requirement for assessing neuroprotection. In the present proposal, we will use a clinically driven design to test whether novel A2A antagonist molecules modify disease progression (motor behavior and number of surviving DA neurons) after an initial Symptoms & Side Effects loss of DA neurons is first achieved. These studies will provide a better understanding of whether A2A antagonists might in fact modify early PD progression and may help to guide preclinical selection of drug candidates in which both antiparkinsonian and neuroprotective actions, among other characteristics (e.g. potency, selectivity and metabolic profile), have been optimized.


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