The pathophysiological mechanisms for slow and progressive dopaminergic neuronal cell death in Parkinson's disease (PD) are currently unknown: therefore, only limited therapeutic options are available. Dopamine replacement therapy has been the mainstay of antiparkinson treatment for the past three decades. Nevertheless, no real progress has been made to intervene in the progressive neurodegenerative process underlying Parkinson's disease. Glutamate-mediate excitotoxic mechanisms have been suggested to contribute to the progressive neurodegenerative process by leading to excessive activation of cortical glutamatergic input into the basal ganglia. The concept that NMDA receptor blockage could be beneficial in neurodegenerative disorders is pursued actively, to date, has been limited by toxicity of the glutamate antagonists. The current proposal focuses on developing an innocuous neuro-protective agent by indirectly modulating rather than merely blocking the NMDA receptor. In preliminary studies, we have identified two novel strychnine-insensitive glycine (NMDA)/glycine site antagonists acting on the NMDA receptors that are active in attenuating NMDA-induced dopamine neuronal injuries in vitro. These compounds also show neuroprotection in an animal model of PD. The objectives of the current proposal are: (i) to characterize a series of novel quinoxalinediones, which have preferential selectivity for NMDA/glycine sites, for their neuroprotective properties against NMDA and glutamate-induced dopaminergic neurotoxicity in primary mesencephalic neuronal culture, (ii) to further evaluate their effectiveness in attenuating degeneration of dopaminergic neurons in a mouse model of MPTP-induced PD, (iii) to examine the ability of these novel compounds for mitigating the NMDA receptor mediated oxidative stress, (iv) to determine the long-term tolerability of these compounds, and , (v) to investigate the safety and neuroprotective efficacy of these NMDA/ glycine site antagonists in a non-human primate model (marmosets) of PD. Together, this systematic approach should lead to significant advances in the development of a rationale-based neuroprotective therapy for the treatment of Parkinson's disease.
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