The Zinc Ion Chelating Agent TPEN Attenuates Neuronal Death/apoptosis Caused by Hypoxia/ischemia Via Mediating the Pathophysiological Cascade Including Excitotoxicity, Oxidative Stress, and Inflammation

摘要

Summary Aims We aim to determine the significant effect of TPEN , a Zn2+ chelator, in mediating the pathophysiological cascade in neuron death/apoptosis induced by hypoxia/ischemia. Methods We conducted both in vivo and in vitro experiments in this study. PC 12 cells were used to establish hypoxia/ischemia model by applying oxygen–glucose deprivation ( OGD ). SHR ‐ SP rats were used to establish an acute ischemic model by electrocoagulating middle cerebral artery occlusion. The effect of TPEN on neuron death/apoptosis was evaluated. In addition, the relative biomarks of excitotoxicity, oxidative stress, and inflammation reactions in hypoxia/ischemia PC 12 cell model as well as in SHR ‐ SP rat hypoxia/ischemia model were also assessed. Results TPEN significantly attenuates the neurological deficit, reduced the cerebral infarction area and the ratio of apoptotic neurons, and increased the expression of GluR2 in the rat hypoxia/ischemia brain. TPEN also increased blood SOD activity, decreased blood NOS activity and blood MDA and IL ‐6 contents in rats under hypoxia/ischemia. In addition, TPEN significantly inhibited the death and apoptosis of cells and attenuated the alteration of GluR2 and NR 2 expression caused by OGD or OGD plus high Zn2+ treatments. Conclusions Zn2+ is involved in neural cell apoptosis and/or death caused by hypoxia/ischemia via mediating excitotoxicity, oxidative stress, and inflammation.