Viral-toxin interactions and Parkinson's disease: poly I:C priming enhanced the neurodegenerative effects of paraquat.

BACKGROUND: Parkinson's disease (PD) has been linked with exposure to a variety of environmental and immunological insults (for example, infectious pathogens) in which inflammatory and oxidative processes seem to be involved. In particular, epidemiological studies have found that pesticide exposure and infections may be linked with the incidence of PD. The present study sought to determine whether exposure to a viral mimic prior to exposure to pesticides would exacerbate PD-like pathology. METHODS: Mice received a supra-nigral infusion of 5 µg of the double-stranded RNA viral analog, polyinosinic: polycytidylic acid (poly(I:C)), followed 2, 7 or 14 days later by administration of the pesticide, paraquat (nine 10 mg/kg injections over three weeks). RESULTS: As hypothesized, poly(I:C) pre-treatment enhanced dopamine (DA) neuron loss in the substantia nigra pars compacta elicited by subsequent paraquat treatment. The augmented neuronal loss was accompanied by robust signs of microglial activation, and by increased expression of the catalytic subunit (gp91) of the NADPH oxidase oxidative stress enzyme. However, the paraquat and poly(I:C) treatments did not appreciably affect home-cage activity, striatal DA terminals, or subventricular neurogenesis. CONCLUSIONS: These findings suggest that viral agents can sensitize microglial-dependent inflammatory responses, thereby rendering nigral DA neurons vulnerable to further environmental toxin exposure.

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-γ), 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-γ 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-γ 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-1ß [IL-1ß], tumor necrosis factor-α [TNF-α]), 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-κB]). 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-γ deficiency again reversed these effects. These data suggest that IFN-γ is important for paraquat-induced neurodegeneration and the accompanying oxidative, inflammatory, and trophic changes that characterize the response to the toxin. Targeting IFN-γ could thus have therapeutic implications for PD and other neurodegenerative conditions that involve multiple inflammatory pathways.

Behavior and pro-inflammatory cytokine variations among submissive and dominant mice engaged in aggressive encounters: moderation by corticosterone reactivity.

Psychosocial stressors contribute to the pathophysiology of affective disorders and variations of cytokine functioning have been implicated in this process. The present investigation demonstrated, in mice, the impact of stressful aggressive encounters on activity levels, plasma corticosterone and cytokine concentrations, and on cytokine mRNA expression within the prefrontal cortex (PFC) and hippocampus. As glucocorticoids have been tied to cytokine variations, mice were subdivided into low or high corticosterone responders, defined in terms of circulating hormone levels 75 min post-confrontation. Interestingly, stressor-induced effects among low and high responders varied as a function of whether mice were submissive or dominant during the aggressive bout. Agonistic encounters elicited subsequent hyperactivity, particularly among low corticosterone responders and among dominant mice. Plasma levels of corticosterone and interleukin (IL)-6 concomitantly increased after aggressive encounters and varied with dominance status and with the low versus high corticosterone response. Among the low responders corticosterone and IL-6 increases were modest and only apparent among submissive mice, whereas among high responders these elevations were more pronounced and comparable in submissive and dominant mice. Aggressive episodes also increased IL-1ß and IL-6 mRNA brain expression. The IL-1ß rise was greater in the PFC and hippocampus of submissive mice that were low responders. Among high responders IL-1ß and IL-6 increased in both groups, although in the PFC this effect was specific to dominant mice. The data are discussed in terms of their relevance to the impact of aggressive encounters on affective behaviors, and to the role that cytokines might play in this regard.

Inflammatory priming of the substantia nigra influences the impact of later paraquat exposure: Neuroimmune sensitization of neurodegeneration.

Activation of microglia along with the release of inflammatory cytokines and oxidative factors often accompanies toxin-induced degeneration of substantia nigra pars compacta (SNc) dopamine (DA) neurons. Multiple toxin exposure may synergistically influence microglial-dependent DA neuronal loss and, in fact, pre-treatment with one toxin may sensitize DA neurons to the impact of subsequent insults. Thus, we assessed whether priming SNc neurons with the inflammatory agent, lipopolysaccharide (LPS), influenced the impact of later exposure to the pesticide, paraquat, which has been reported to provoke DA loss. Indeed, LPS infusion into the SNc sensitized DA neurons to the neurodegenerative effects of a series of paraquat injections commencing 2 days later. In contrast, LPS pre-treatment actually protected against some of neurodegenerative effects of paraquat when the pesticide was administered 7 days after the endotoxin. These sensitization and de-sensitization effects were associated with altered expression of reactive microglia expressing inducible immunoproteasome subunits, as well as variations of fibroblast growth factor and a time-dependent infiltration of peripheral immune cells. Circulating levels of the inflammatory cytokines, interleukin (IL)-6, IL-2, tumor necrosis factor-alpha and interferon-gamma were also time-dependently elevated following intra-SNc LPS infusion. These data suggest that inflammatory priming may influence DA neuronal sensitivity to subsequent environmental toxins by modulating the state of glial and immune factors, and these findings may be important for neurodegenerative conditions, such as Parkinson's disease (PD).

Cyclooxygenase-2 deficiency modifies the neurochemical effects, motor impairment and co-morbid anxiety provoked by paraquat administration in mice.

Parkinson's disease and other motor disorders of midbrain basal ganglia dopaminergic functioning are often characterized by alterations of brainstem and limbic systems with accompanying co-morbid anxiety and depressive symptoms. Accumulating evidence suggests that inflammatory processes may play an important role in such neurodegenerative and psychiatric pathology. In this regard, inhibition of the inflammatory enzyme cyclooxygenase-2 (COX-2) was reported to limit the impact of stressors as well as the neurodegenerative effects of dopaminergic toxins. The present investigation assessed the impact of the putative dopamine toxin paraquat (a widely used herbicide) upon motor functioning, behavioural indices of anxiety-like states and central monoamine levels and whether these effects were altered in mice lacking COX-2. Indeed, paraquat did induce motor impairment and altered dopamine utilization within the striatum, and COX-2 deletion moderately attenuated these effects. Conversely, COX-2 deficiency enhanced the impact of paraquat upon indices of anxiety (open field exploration) and on serotonergic, noradrenergic and dopaminergic alterations within two brain regions implicated in stressor-related pathologies, namely the dorsal hippocampus and medial prefrontal cortex. These results suggest that COX-2 might differentially influence the motor and psychiatric symptoms associated with environmental toxin exposure. Furthermore, these data indicate that the neurochemical impact of paraquat is not restricted to the nigrostriatal dopamine pathway but also involves stressor-sensitive limbic regions. It is possible that COX-2 may play a dual role by contributing to the motor impairment induced by paraquat, but acting to moderate the effects of paraquat upon processes aligned with anxiety and depression.