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

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.&nbsp