Long-term dynamic changes of NMDA receptors following an excitotoxic challenge

Excitotoxicity is a form of neuronal death characterized by the sustained activation of N-methyl-D-aspartate receptors (NMDARs) triggered by the excitatory neurotransmitter glutamate. NADPH-diaphorase neurons [also known as nNOS (+) neurons] are a subpopulation of aspiny interneurons, largely spared following excitotoxic challenges. Unlike nNOS (-) cells, nNOS (+) neurons fail to generate reactive oxygen species in response to NMDAR activation, a key divergent step in the excitotoxic cascade. However, additional mechanisms underlying the reduced vulnerability of nNOS (+) neurons to NMDAR-driven neuronal death have not been explored. Using functional, genetic, and molecular analysis in striatal cultures, we demonstrate that nNOS (+) neurons possess distinct NMDAR properties. These specific features are primarily driven by the peculiar redox milieu of this subpopulation. In addition, we found that nNOS (+) neurons exposed to a pharmacological maneuver set to mimic chronic excitotoxicity alter their responses to NMDAR-mediated challenges. These findings suggest the presence of mechanisms providing long-term dynamic regulation of NMDARs that can have critical implications in neurotoxic settings.

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Long-term exposure to iron and copper in fine particulate air pollution and their combined impact on reactive oxygen species concentration in lung fluid: a population-based cohort study of cardiovascular disease incidence and mortality in Toronto, Canada

International Journal of Epidemiology ◽

10.1093/ije/dyaa230 ◽

2020 ◽

Author(s):

Zilong Zhang ◽

Scott Weichenthal ◽

Jeffrey C Kwong ◽

Richard T Burnett ◽

Marianne Hatzopoulou ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Cardiovascular Disease ◽

Regression Models ◽

Population Based ◽

Sensitivity Analyses ◽

Oxygen Species ◽

Lung Fluid ◽

Fine Particulate ◽

Combined Impact

Abstract Background Exposure to fine particulate (PM2.5) air pollution is associated with increased cardiovascular disease (CVD), but less is known about its specific components, such as metals originating from non-tailpipe emissions. We investigated the associations of long-term exposure to metal components [iron (Fe) and copper (Cu)] in PM2.5 with CVD incidence. Methods We conducted a population-based cohort study in Toronto, Canada. Exposures to Fe and Cu in PM2.5 and their combined impact on the concentration of reactive oxygen species (ROS) in lung fluid were estimated using land use regression models. Incidence of acute myocardial infarction (AMI), congestive heart failure (CHF) and CVD death was ascertained using health administrative datasets. We used mixed-effects Cox regression models to examine the associations between the exposures and health outcomes. A series of sensitivity analyses were conducted, including indirect adjustment for individual-level cardiovascular risk factors (e.g. smoking), and adjustment for PM2.5 and nitrogen dioxide (NO2). Results In single-pollutant models, we found positive associations between the three exposures and all three outcomes, with the strongest associations detected for the estimated ROS. The associations of AMI and CHF were sensitive to indirect adjustment, but remained robust for CVD death in all sensitivity analyses. In multi-pollutant models, the associations of the three exposures generally remained unaltered. Interestingly, adjustment for ROS did not substantially change the associations between PM2.5 and CVD, but attenuated the associations of NO2. Conclusions Long-term exposure to Fe and Cu in PM2.5 and their combined impact on ROS were consistently associated with increased CVD death.

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