Hypothermia protects against oxygen-glucose deprivation-induced neuronal injury by down-regulating the reverse transport of glutamate by astrocytes as mediated by neurons.

Abstract

Glutamate is the major mediator of excitotoxic neuronal death following cerebral ischemia. Under severe ischemic conditions, glutamate transporters can functionally reverse to release glutamate, thereby inducing further neuronal injury. Hypothermia has been shown to protect neurons from brain ischemia. However, the mechanism(s) involved remain unclear. Therefore, the aim of this study was to investigate the mechanism(s) mediating glutamate release during brain ischemia-reperfusion injury under hypothermic conditions. Neuron/astrocyte co-cultures were exposed to oxygen-glucose deprivation (OGD) at various temperatures for 2h, and cell viability was assayed 12h after reoxygenation. PI and MAP-2 staining demonstrated that hypothermia significantly decreased neuronal injury. Furthermore, [(3)H]-glutamate uptake assays showed that hypothermia protected rat primary cortical cultures against OGD reoxygenation-induced injury. Protein levels of the astrocytic glutamate transporter, GLT-1, which is primarily responsible for the clearance of extracellular glutamate, were also found to be reduced in a temperature-dependent manner. In contrast, expression of GLT-1 in astrocyte-enriched cultures was found to significantly increase following the addition of neuron-conditioned medium maintained at 37 °C, and to a lesser extent with neuron-conditioned medium at 33 °C. In conclusion, the neuroprotective effects of hypothermia against brain ischemia-reperfusion injury involve down-regulation of astrocytic GLT-1, which mediates the reverse transport of glutamate. Moreover, this process may be regulated by molecules secreted by stressed neurons.

• Authors: D Wang, Y Zhao, Y Zhang, T Zhang, X Shang, J Wang, Y Liu, Q Kong, B Sun, L Mu, X Liu, G Wang, H Li
• Journal: Neuroscience (Neuroscience) Vol. 237 Pg. 130-8 (May 01 2013) ISSN: 1873-7544 [Electronic] United States
• PMID: 23402854 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.

Chemical References

• Culture Media, Conditioned
• Nerve Tissue Proteins
• Tritium
• Glutamic Acid
• Glucose

Topics

• Analysis of Variance
• Animals
• Astrocytes (drug effects)
• Cell Survival (drug effects)
• Cells, Cultured
• Cerebral Cortex (cytology)
• Coculture Techniques
• Culture Media, Conditioned (pharmacology)
• Down-Regulation (drug effects, physiology)
• Embryo, Mammalian
• Glucose (deficiency, metabolism)
• Glutamic Acid (metabolism, pharmacology)
• Hyperbaric Oxygenation (methods)
• Hypothermia, Induced (methods)
• Hypoxia (prevention & control)
• Nerve Tissue Proteins (metabolism)
• Neurons (drug effects)
• Rats
• Tritium (pharmacokinetics)