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

Authors : Alberto GRANZOTTO

Pages : 5-5

Doi:10.37212/jcnos.584662

View : 10 | Download : 6

Publication Date : 2019-06-21

Article Type : Other Papers

Abstract :NMDA receptor insert ignore into journalissuearticles values(NMDAR); overstimulation by glutamate promotes massive calcium insert ignore into journalissuearticles values(Ca2+); entry and initiates a cascade of events leading to the overproduction of Reactive Oxygen Species insert ignore into journalissuearticles values(ROS);, mitochondrial dysfunction, intraneuronal zinc insert ignore into journalissuearticles values(Zn2+); mobilization, and, ultimately, neuronal demise insert ignore into journalissuearticles values(Choi 1992);.  This glutamate-driven form of neuronal death has been described as excitotoxicity insert ignore into journalissuearticles values(Olney 1969);.  NADPH-diaphorase neurons [nNOS insert ignore into journalissuearticles values(+); neurons] are a subpopulation of nitric-oxide synthase-overexpressing interneurons that is spared from the NMDAR-mediated neuronal death insert ignore into journalissuearticles values(Koh and Choi, 1988);.  The mechanisms underlying the reduced vulnerability of nNOS insert ignore into journalissuearticles values(+); 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 insert ignore into journalissuearticles values(+); neurons.  Differences between nNOS insert ignore into journalissuearticles values(+); and nNOS insert ignore into journalissuearticles values(-); 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 insert ignore into journalissuearticles values(+); neurons differ from nNOS insert ignore into journalissuearticles values(-); 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 insert ignore into journalissuearticles values(+); neurons abolished the neurotoxic accumulation of Zn2+.  Exposure of nNOS insert ignore into journalissuearticles values(-); neurons to NMDA in the presence of TPEN insert ignore into journalissuearticles values(a Zn2+ chelator); mimicked the behavior of the nNOS insert ignore into journalissuearticles values(+); subpopulation and preserved the nNOS insert ignore into journalissuearticles values(-); 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