An update on the potential role of excitotoxicity in the pathogenesis of Parkinson's disease

The primary cause of the neurodegenerative process that underlies Parkinson's disease (PD) is still unknown. Different mechanisms probably contribute to triggering neuronal death in the nigrostriatal pathway, including mitochondrial defects, oxidative stress and proteolytic stress. Glutamate-mediated excitotoxicity may be a further contributor. Glutamate is the predominant fast excitatory neurotransmitter in the central nervous system and, in the presence of specific conditions, a potential neurotoxin. Although excitotoxicity per se is unlikely to act as a major causative agent in PD pathogenesis, glutamate-mediated intracellular changes may contribute, in a more subtle way, to the mechanisms that trigger the neurodegenerative process in the substantia nigra pars compacta (SNc). It is, therefore, likely that synergistic interactions between mitochondrial defects, oxidative stress and glutamatergic stimulation take place at the SNc level. These interactions may create the conditions for the development of the nigrostriatal damage that characterizes PD.