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.

Abstract

AIMS:

We aim to determine the significant effect of TPEN, a Zn(2+) 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. PC12 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 PC12 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 NR2 expression caused by OGD or OGD plus high Zn(2+) treatments.

CONCLUSIONS:

Zn(2+) is involved in neural cell apoptosis and/or death caused by hypoxia/ischemia via mediating excitotoxicity, oxidative stress, and inflammation.

• Authors: Wei-Ming Wang, Zhao Liu, Ai-Jun Liu, Yu-Xiang Wang, Hong-Gang Wang, Di An, Bin Heng, Lai-Hua Xie, Jun-Li Duan, Yan-Qiang Liu
• Journal: CNS neuroscience & therapeutics (CNS Neurosci Ther) Vol. 21 Issue 9 Pg. 708-17 (Sep 2015) ISSN: 1755-5949 [Electronic] England
• PMID: 26190227 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 John Wiley & Sons Ltd.

Chemical References

• Chelating Agents
• Ethylenediamines
• Neuroprotective Agents
• Receptors, AMPA
• Receptors, N-Methyl-D-Aspartate
• Glucose
• Zinc
• glutamate receptor ionotropic, AMPA 2
• N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine

Topics

• Animals
• Apoptosis (drug effects, physiology)
• Brain (drug effects, pathology, physiopathology)
• Brain Ischemia (drug therapy, pathology, physiopathology)
• Cell Hypoxia (drug effects, physiology)
• Chelating Agents (pharmacology)
• Disease Models, Animal
• Ethylenediamines (pharmacology)
• Female
• Glucose (deficiency)
• Infarction, Middle Cerebral Artery
• Ischemia (drug therapy, pathology, physiopathology)
• Neuroimmunomodulation (drug effects, physiology)
• Neurons (drug effects, pathology, physiology)
• Neuroprotective Agents (pharmacology)
• Oxidative Stress (drug effects, physiology)
• PC12 Cells
• Rats
• Rats, Inbred SHR
• Receptors, AMPA (metabolism)
• Receptors, N-Methyl-D-Aspartate (metabolism)
• Zinc (metabolism)