Identification of Neuroprotective Compounds of Caenorhabditis elegans Dopaminergic Neurons Against 6-OHDA

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Abstract

Parkinson's disease (PD) is a severe debilitating disorder, characterized by progressive and selective dopaminergic (DAergic) neuron degeneration within the substantia nigra pars compacta. Although current pharmacological treatments are effective in early stages of the disease, with time, most patients fail to respond to medications and develop serious motor complications. Therefore, devising novel and efficacious therapeutics that address not only the symptoms of PD, but also the cause, are of great importance. Unfortunately, many obstacles are associated with current PD research in mammalian-based systems, which limit the rate of progress. One solution is to investigate mechanisms of PD in model genetic organisms like Caenorhabditis elegans. In general, striking and profound similarities underlie the basic cellular and molecular processes between the worm and humans. The use of C. elegans over traditional mammalian-based systems holds the promise of an enhanced rate of discovery with lower associated costs. Here, we have utilized C. elegans to screen a variety of compounds, including specific dopamine (DA), GABA, and NMDA receptor agonists, as well as antagonists to identify those that protect against 6-OHDA-induced DAergic toxicity. Two DA D2 receptor agonists, bromocriptine and quinpirole, were found to protect against 6-OHDA toxicity in a dose-dependent manner. Surprisingly, these protective effects appear to involve receptor-independent mechanisms. Given the high degree of conservation of cellular processes between the worm and mammalian systems, these results are likely relevant and important toward understanding potentially novel mechanisms leading to DAergic neuroprotection in mammalian systems and, ultimately, new therapeutics for PD.

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