Distinct Role for Microglia in Rotenone-Induced Degeneration of Dopaminergic Neurons

Abstract

Increasing evidence has suggested an important role for environmental factors such as exposure to pesticides in the pathogenesis of Parkinson's disease. In experimental animals the exposure to a common herbicide, rotenone, induces features of parkinsonism; mechanistically, rotenone-induced destruction of dopaminergic neurons has been attributed to its inhibition of the activity of neuronal mitochondrial complex I. However, the role of microglia, the resident brain immune cells in rotenoneinduced neurodegeneration, has not been reported. Using primary neuron-enriched and neuron/glia cultures from the rat mesencephalon, we discovered an extraordinary feature for rotenone-induced degeneration of cultured dopaminergic neurons. Although little neurotoxicity was detected in neuronenriched cultures after treatment for 8 d with up to 20 nM rotenone, significant and selective dopaminergic neurodegeneration was observed in neuron/glia cultures 2 d after treatment with 20 nM rotenone or 8 d after treatment with 1 nM rotenone. The greatly enhanced neurodegenerative ability of rotenone was attributed to the presence of glia, especially microglia, because the addition of microglia to neuron-enriched cultures markedly increased their susceptibility to rotenone. Mechanistically, rotenone stimulated the release of superoxide from microglia that was attenuated by inhibitors of NADPH oxidase. Furthermore, inhibition of NADPH oxidase or scavenging of superoxide significantly reduced the rotenone-induced neurotoxicity. This is the first report demonstrating that microglia play a pivotal role in rotenone-induced degeneration of dopaminergic neurons. The results of this study should advance our understanding of the mechanism of action for pesticides in the pathogenesis of Parkinson's disease.

Cytotoxicity of paraquat in microglial cells: Involvement of PKCδ- and ERK1/2-dependent NADPH oxidase

“…In addition, ROS produced by glial cells can cause deleterious effects to neighboring cells including neurons (Abramov et al, 2004;Wilkinson and Landreth, 2006). Neurotoxicity induced by other neurotoxins such as substance P, rotenone and MPTP, can be attenuated upon inhibition of NADPH oxidase by compounds such as DPI and apocynin or by using microglial cells deficient in NADPH oxidase (Block et al, 2006;Gao et al, 2002;Gao et al, 2003a;Wu et al, 2003). In agreement with these earlier studies, DPI and apocynin also inhibited paraquat-induced ROS production and cell death in BV-2 microglial cells.…”

“…In PD patients, the substantia nigra was found to have more than 6-time the number of reactive microglia as compared to the control brains (McGeer et al, 1988a;McGeer et al, 1988b). Microglia activation is involved in the cytotoxicity of neurotoxins such as MPTP, rotenone, substance P, and methamphetamine (Block et al, 2006;Delgado, 2003;Gao et al, 2002;Gao et al, 2003b;Scheller et al, 2005;Thomas et al, 2004;Wu et al, 2003). In the substantial nigra, a brain region enriched in dopaminergic neurons, microglial activation is associated with neurochemical changes such as the decrease in dopamine synthesis (Barcia et al, 2004;Scheller et al, 2005;Wu et al, 2003).…”

Microglia and inflammation-mediated neurodegeneration: Multiple triggers with a common mechanism

“…The enhanced neurotoxicity of A␤ (1-42) was attributed primarily to the activation of microglia and subsequent release of the superoxide free radical. In the case of rotenone, which was initially thought to damage dopaminergic neurons by inhibiting mitochondrial complex I activity, the presence of microglia significantly enhanced its neurotoxicity, and the generation of oxygen free radicals appeared to underlie this increased toxicity (Gao et al, 2002a). Similarly, the destruction of neurons by HIV gp120 and prion proteins also involves the participation of activated microglia (Brown, 2001).…”

Reactive oxygen species generation by the ethylene-bis-dithiocarbamate (EBDC) fungicide mancozeb and its contribution to neuronal toxicity in mesencephalic cells

“…Microglia, the resident immune cells of the brain, have been implicated in neurotoxicity and neurodegeneration via ROS generation (Gao et al, 2002(Gao et al, , 2003bLiu and Hong, 2003;Wu et al, 2003;Zhang et al, 2004;Wu et al, 2005). Microglia are also a major source of NADPH oxidase in the nervous system (Babior et al, 1999;Wu et al, 2003).…”

“…Pesticide exposure in experimental rodent and cell culture models has been linked to ROS generation and/or an inflammatory response that potentiates ROS production. Dopaminergic toxicity by rotenone, a naturally occurring complex I inhibitor and a common herbicide, is caused by oxidative stress and is mediated, in part, by the activation of microglia (Gao et al, 2002(Gao et al, , 2003bSherer et al, 2002;Sherer et al, 2003;Zeevalk and Bernard, 2005). The neurotoxicity of paraquat (PQ), a bipyridial herbicide, mimics PD in experimental models and results in microglia activation and redox cycling via microglial NADPH oxidase (McCormack et al, 2002;Bonneh-Barkay et al, 2005).…”