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We report a novel in vitro classification system that tracks microglial activation state and their potential neurotoxicity. Mixed live‐cell imaging was used to characterize transition through distinct morphological phenotypes, production of reactive oxygen species (ROS), formation of reactive microglial aggregates, and subsequent cytokine production. Transwell cultures were used to determine microglial migration (control and lipopolysaccharide (LPS) treated) to glutamate pre‐stressed or healthy neurons. This two‐hit paradigm was developed to model the vast evidence that neurodegenerative conditions, like Parkinson's disease (PD), may stem from the collective impact of multiple environmental stressors. We found that healthy neurons were resistant to microglial‐mediated inflammation, whereas glutamate pre‐stressed neurons were highly susceptible and in fact, appeared to recruit microglia. The LPS treated microglia progressed through distinct morphological states and expressed high levels of ROS and formed large cellular aggregates. Recent evidence implicates leucine‐rich repeat kinase 2 (LRRK2) as an important player in the microglial inflammatory state, as well as in the genesis of PD. We found that inhibition of the LRRK2 signaling pathway using the kinase inhibitor cis‐2,6‐dimethyl‐4‐(6‐(5‐(1‐methylcyclopropoxy)‐1H‐indazol‐3‐yl)pyrimidin‐4‐yl)morpholine (MLi2) or inhibition of the actin regulatory protein, Wiskott‐Aldrich syndrome family Verprolin‐homologous Protein‐2 (WAVE2), stunted microglial activation and prevented neurotoxicity. Furthermore, inhibition of LRRK2 kinase activity reduced pro‐inflammatory chemokines including MIP‐2, CRG‐2, and RANTES. These data together support the notion that LRRK2 and WAVE2 are important mediators of cytokine production and cytoskeletal rearrangement necessary for microglial‐induced neurotoxicity. Furthermore, our model demonstrated unique microglial phenotypic changes that might be mechanistically important for better understanding neuron‐microglial crosstalk. [ABSTRACT FROM AUTHOR]

Physical illnesses can be markers for subsequent psychological disturbances, and conversely, mental health problems can be markers of later physical pathologies. More importantly, the presence of one condition can limit [...]

Abstract 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.

Abstract Background The geographic distribution of environmental toxins is generally not uniform, with certain northern regions showing a particularly high concentration of pesticides, heavy metals and persistent organic pollutants. For instance, Northern Canadians are exposed to high levels of persistent organic pollutants like polychlorinated biphenyls (PCB), organochlorine pesticides (OCs) and methylmercury (MeHg), primarily through country foods. Previous studies have reported associations between neuronal pathology and exposure to such toxins. The present investigation assessed whether perinatal exposure (gestation and lactation) of rats to a chemical mixture (27 constituents comprised of PCBs, OCs and MeHg) based on Arctic maternal exposure profiles at concentrations near human exposure levels, would affect brain levels of several inflammatory cytokines Methods Rats were dosed during gestation and lactation and cytokine levels were measured in the brains of offspring at five months of age. Hypothalamic cytokine protein levels were measured with a suspension-based array system and differences were determined using ANOVA and post hoc statistical tests. Results The early life PCB treatment alone significantly elevated hypothalamic interleukin-6 (IL-6) levels in rats at five months of age to a degree comparable to that of the entire chemical mixture. Similarly, the full mixture (and to a lesser degree PCBs alone) elevated levels of the pro-inflammatory cytokine, IL-1b, as well as the anti-inflammatory cytokine, IL-10. The full mixture of chemicals also moderately increased (in an additive fashion) hypothalamic levels of the pro-inflammatory cytokines, IL-12 and tumor necrosis factor (TNF-α). Challenge with bacterial endotoxin at adulthood generally increased hypothalamic levels to such a degree that differences between the perinatally treated chemical groups were no longer detectable. Conclusions These data suggest that exposure at critical neurodevelopmental times to environmental chemicals at concentrations and combinations reflective of those observed in vulnerable population can have enduring consequences upon cytokines that are thought to contribute to a range of pathological states. In particular, such protracted alterations in the cytokine balance within the hypothalamus would be expected to favor marked changes in neuro-immune and hormonal communication that could have profound behavioral consequences.

Major depression is a prevalent illness that increases the risk of several neurological conditions. These include stroke, cardiovascular disease, and dementia including Alzheimer's disease. In this review we ask whether certain types of depression and associated loneliness may be a harbinger of cognitive decline and possibly even dementia. We propose that chronic stress and inflammation combine to compromise vascular and brain function. The resulting increases in proinflammatory cytokines and microglial activation drive brain pathology leading to depression and mild cognitive impairment, which may progress to dementia. We present evidence that by treating the inflammatory changes, depression can be reversed in many cases. Importantly, there is evidence that anti-inflammatory and antidepressant treatments may reduce or prevent dementia in people with depression. Thus, we propose a model in which chronic stress and inflammation combine to increase brain permeability and cytokine production. This leads to microglial activation, white matter damage, neuronal and glial cell loss. This is first manifest as depression and mild cognitive impairment, but can eventually evolve into dementia. Further research may identify clinical subgroups with inflammatory depression at risk for dementia. It would then be possible to address in clinical trials whether effective treatment of the depression can delay the onset of dementia. [ABSTRACT FROM AUTHOR]