Interferon-γ plays a role in paraquat-induced neurodegeneration involving oxidative and proinflammatory pathways

Exposure to environmental contaminants, particularly pesticides, may be an important etiological factor in Parkinson's disease (PD); and evidence suggests a role for microglia-dependent inflammatory and oxidative processes in nigrostriatal pathology induced by such toxins. Yet, the events mediating microglial activation and their effects are not fully known. To this end, we hypothesized that the proinflammatory cytokine, interferon-gamma (IFN-gamma), may be a prime factor in the pathogenesis of PD, given its critical role in regulating microglial responses to pathogens. Indeed, the present investigation demonstrated that genetic deletion of IFN-gamma protected substantia nigra pars compacta (SNc) dopamine (DA) neurons from the toxic effects of the pesticide, paraquat, and normalized changes in inflammatory and oxidative factors within this brain region. Specifically, IFN-gamma knockout prevented the paraquat-induced morphological signs of microglial activation and expression of key nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits, while also preventing time-dependent changes in proinflammatory enzymes (inducible nitric oxide synthase [iNOS], cyclooxygenase-2 [COX-2]), cytokines (interleukin-1 beta [IL-1 beta], tumor necrosis factor-alpha [TNF-alpha]), and signaling factors (c-Jun N-terminal kinase [JNK], p38 MAP kinase [p38], Signal transducer and activator of transcription-1 [STAT1], nuclear factor kappa B [NF-kappa B]). Moreover, paraquat transiently suppressed substantia nigra pars compacta expression of trophic and proneuroplastic factors (cyclic-AMP response element binding protein [CREB], brain-derived neurotrophic factor [BDNF]), and IFN-gamma deficiency again reversed these effects. These data suggest that IFN-gamma is important for paraquat-induced neurodegeneration and the accompanying oxidative, inflammatory, and trophic changes that characterize the response to the toxin. Targeting IFN-gamma could thus have therapeutic implications for PD and other neurodegenerative conditions that involve multiple inflammatory pathways. (C) 2012 Elsevier Inc. All rights reserved.