Intracellular zinc mobilization is required for nNOS (+) neuron loss. Role of zinc in the excitotoxic cascade

Year 2019, , 5 - 5, 21.06.2019

Alberto Granzotto

https://doi.org/10.37212/jcnos.584662

Cited By: 1

Abstract

NMDA receptor (NMDAR) overstimulation by glutamate promotes massive calcium (Ca2+) entry and initiates a cascade of events leading to the overproduction of Reactive Oxygen Species (ROS), mitochondrial dysfunction, intraneuronal zinc (Zn2+) mobilization, and, ultimately, neuronal demise (Choi 1992).  This glutamate-driven form of neuronal death has been described as excitotoxicity (Olney 1969).  NADPH-diaphorase neurons [nNOS (+) neurons] are a subpopulation of nitric-oxide synthase-overexpressing interneurons that is spared from the NMDAR-mediated neuronal death (Koh and Choi, 1988).  The mechanisms underlying the reduced vulnerability of nNOS (+) neurons to NMDAR-driven neuronal death are still largely unexplored.  In the talk, we will discuss the mechanisms that are involved in the reduced vulnerability of nNOS (+) neurons.  Differences between nNOS (+) and nNOS (-) neurons as far as changes in intracellular Ca2+ levels, mitochondrial functioning, ROS production as well as the intraneuronal accumulation of Zn2+ were investigated.  We found that nNOS (+) neurons differ from nNOS (-) cells by lacking the production of a significant amount of ROS in response to NMDAR activation.  The absence of NMDA-driven oxidative stress shown by the nNOS (+) neurons abolished the neurotoxic accumulation of Zn2+.  Exposure of nNOS (-) neurons to NMDA in the presence of TPEN (a Zn2+ chelator) mimicked the behavior of the nNOS (+) subpopulation and preserved the nNOS (-) population from the excitotoxic damage.  These results indicate that Zn2+ mobilization is the mandatory step of the excitotoxic cascade.  These findings identify the intraneuronal accumulation of Zn2+ as a therapeutic target for the treatment of excitotoxic prone neurological conditions. 

Keywords

NMDA receptor, nNOS

References

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• Koh JY, Choi DW. 1988. Vulnerability of cultured cortical neurons to damage by excitotoxins: differential susceptibility of neurons containing NADPH-diaphorase. J. Neurosci. 8:2153–2163.