Zinc Dyshomeostasis in Neuronal Injury

Concluding Remarks: New Paradigms in Excitotoxicity

Given the emerging pathogenic role played by intracellular Zn²⁺ accumulation in neuronal death and the fact that the ion seems to promote injury with greater potency compared to Ca²⁺, Zn²⁺ may be an underappreciated mediator of excitotoxicity, which has for the most part been thought of as a purely Ca²⁺-dependent phenomenon. Moreover, the deleterious effects of cytosolic [Ca²⁺]_i increases in ischemia should perhaps be reevaluated in light of emerging data regarding the Ca²⁺ dependence of intracellular mobilization of Zn²⁺. The observation that intracellular Zn²⁺ release from mitochondria is particularly prominent in the case of large, glutamate-evoked [Ca²⁺]_i rises, coupled with the likely probability that Ca²⁺-induced mitochondrial ROS generation would also promote Zn²⁺ release from MTs, offers the possibility of a more complex injury paradigm than previously imagined. In such a model, glutamate-driven [Ca²⁺]_i rises might actually serve as an “accomplice” to spark the release of the true ionic mediator of neuronal damage: Zn²⁺.