Microglial activation as a priming event leading to paraquat-induced dopaminergic cell degeneration

Abstract

Dopaminergic cells in the substantia nigra are highly vulnerable to the neurodegenerative process of Parkinson's disease. Therefore, mechanisms that enhance their susceptibility to injury bear important implications for disease pathogenesis. Repeated injections with the herbicide paraquat cause oxidative stress and a selective loss of dopaminergic neurons in mice. In this model, the first paraquat exposure, though not sufficient to induce any neurodegeneration, predisposes neurons to damage by subsequent insults. The purpose of this study was to elucidate the mechanisms underlying this "priming" event. We found that a single paraquat exposure was followed by an increase in the number of cells with immunohistochemical, morphological and biochemical characteristics of activated microglia, including induction of NADPH-oxidase. If this microglial response was inhibited by the anti-inflammatory drug minocycline, subsequent exposures to the herbicide failed to cause oxidative stress and neurodegeneration. On the other hand, if microglial activation was induced by pretreatment with lipopolysaccharide, a single paraquat exposure became capable of triggering a loss of dopaminergic neurons. Finally, mutant mice lacking functional NADPH-oxidase were spared from neurodegeneration caused by repeated paraquat exposures. Data indicate that microglial activation and consequent induction of NADPH-oxidase may act as risk factors for Parkinson's disease by increasing the vulnerability of dopaminergic cells to toxic injury.

Pharmacological inhibition of neuronal NADPH oxidase protects against 1-methyl-4-phenylpyridinium (MPP+)-induced oxidative stress and apoptosis in mesencephalic dopaminergic neuronal cells

“…These studies demonstrate that the neuroprotective properties of DPI and apocynin are not due to inhibition of microglial NADPH oxidase, but rather are due to inhibition of endogenously expressed NADPH oxidase. In animal studies, DPI and apocynin protect against global cerebral ischemia (Wang et al, 2006), and rotenone- (Gao et al, 2003a), paraquat- (Purisai et al, 2006), 6-OHDA- (Yasuhara et al, 2004), MPTP- (Gao et al, 2003b) and IFN-gamma/LPS- (Hirsch et al, 2003a) induced dopaminergic degeneration. In these studies, the neuroprotective properties of apocynin and DPI were associated with inhibition of microglial NADPH oxidase activity, but the role of neuronal NADPH oxidase was not investigated.…”

Paraquat and Parkinson's disease

“…The major source of oxidative stress may in fact, be the resident microglia. In Purisai et al 59 studies there is evidence that a single PQ dose is sufficient to increase the number of cells with immunohistochemical, morphological and biochemical characteristics of activated microglia, including the induction of NADPH oxidase. The anti-inflammatory drug, myocyclin, blocks this microglial response and under these circumstances, PQ fails to cause both oxidative stress and neurodegeneration in subsequent exposures.…”

“…Recent work by Purisai et al 59 has shown that administration of three weekly injections of PQ causes a significant loss of the dopaminergic neurons in the substantia nigra, pars compacta. Along with these findings is the observation that treatment with PQ increases the levels of a-synuclein.…”

“…According to this paradigm, the first injection would sensitize brain cells in a non-lethal way whereas the second injection would trigger irreversible injury. Purisai et al 59 suggest that neurotoxicity of PQ, as well as other pro-oxidants that indeed cross the BBB, may be due to a two-tiered effect, priming (perhaps of microglia) and a secondary injury to the neurons because of the combination of a pro-inflammatory response and a direct neuronal oxidative stress. The major source of oxidative stress may in fact, be the resident microglia.…”

Quantitative determination of paraquat in meconium by sodium borohydride-nickel chloride chemical reduction and gas chromatography/mass spectrometry (GC/MS)

“…Studies on the etiology of Parkinson's disease (PD) suggest that PQ may be an important environmental risk factor in the development of PD [10,11,12,13], due to the strong correlation between the incidence and development of PD and PQ exposure in certain human populations [10,12,14]. PQ is an efficient redox cycler that produces cation radicals in the presence of oxygen, resulting in cellular oxidative stress and eventually cell damage or death [15].…”