Environmental neurotoxicant-induced dopaminergic neurodegeneration: a potential link to impaired neuroinflammatory mechanisms.

With the increased incidence of neurodegenerative diseases worldwide, Parkinson's disease (PD) represents the second-most common neurodegenerative disease. PD is a progressive multisystem neurodegenerative disorder characterized by a marked loss of nigrostriatal dopaminergic neurons and the formation of Lewy pathology in diverse brain regions. Although the mechanisms underlying dopaminergic neurodegeneration remain poorly characterized, data from animal models and postmortem studies have revealed that heightened inflammatory responses mediated via microglial and astroglial activation and the resultant release of proinflammatory factors may act as silent drivers of neurodegeneration. In recent years, numerous studies have demonstrated a positive association between the exposure to environmental neurotoxicants and the etiology of PD. Although it is unclear whether neuroinflammation drives pesticide-induced neurodegeneration, emerging evidence suggests that the failure to dampen neuroinflammatory mechanisms may account for the increased vulnerability to pesticide neurotoxicity. Furthermore, recent studies provide additional evidence that shifts the focus from a neuron-centric view to glial-associated neurodegeneration following pesticide exposure. In this review, we propose to summarize briefly the possible factors that regulate neuroinflammatory processes during environmental neurotoxicant exposure with a focus on the potential roles of mitochondria-driven redox mechanisms. In this context, a critical discussion of the data obtained from experimental research and possible epidemiological studies is included. Finally, we hope to provide insights on the pivotal role of exosome-mediated intercellular transmission of aggregated proteins in microglial activation response and the resultant dopaminergic neurodegeneration after exposure to pesticides. Collectively, an improved understanding of glia-mediated neuroinflammatory signaling might provide novel insights into the mechanisms that contribute to neurodegeneration induced by environmental neurotoxicant exposure.