Abstract
Parkinson’s disease (PD) is the second most common neurodegenerative disease. Although its pathogenesis is still unclear, increasing evidence suggests that mitochondrial dysfunction induced by environmental toxins, such as mitochondrial complex I inhibitors, plays a significant role in the disease process. The microglia in PD brains are highly activated, and inflammation is also an essential element in PD pathogenesis. However, the means by which these toxins activate microglia is still unclear. In the present study, we found that rotenone, a mitochondrial complex I inhibitor, could directly activate microglia via the nuclear factor kappa B (NF-κB) signaling pathway, thereby inducing significantly increased expression of inflammatory cytokines. We further observed that rotenone induced caspase-1 activation and mature IL-1β release, both of which are strictly dependent on p38 mitogen-activated protein kinase (MAPK). The activation of p38 is associated with the presence of reactive oxygen species (ROS) produced by rotenone. Removal of these ROS abrogated the activation of the microglia. Therefore, our data suggest that the environmental toxin rotenone can directly activate microglia through the p38 MAPK pathway.
Highlights
Parkinson’ disease (PD) is one of the most common neurodegenerative diseases [1]
Many studies have suggested that neuroinflammation plays an important role in the pathogenesis of PD [16,17]
To test whether rotenone could activate nuclear factor kappa B (NF-kB) in microglial cells, we first examined the effect of rotenone on IkB kinase (IKK) activation in microglia
Summary
Parkinson’ disease (PD) is one of the most common neurodegenerative diseases [1]. Its pathological hallmarks include the preferential loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) [2]. Some gene mutations have been implicated in the pathogenesis of PD [3,4], most PD cases are sporadic. In these patients, mitochondrial dysfunction induced by environmental toxins is considered a major etiology of PD [5]. Administration of mitochondrial toxins, such as 1-methyl-4-phenyl-1,2,3,4tetrahydropyridine (MPTP) or rotenone, can induce a PD-like syndrome characterized by DA neuronal degeneration [4]. These studies highlight the role of mitochondrial dysfunction in the pathogenesis of PD
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