HYPOXIC PRECONDITIONING ATTENUATES GLOBAL CEREBRAL ISCHEMIC INJURY FOLLOWING ASPHYXIAL CARDIAC ARREST THROUGH REGULATION OF DELTA OPIOID RECEPTOR SYSTEM

This study was designed to investigate whether delta opioid receptor (DOR) is involved in the neuroprotective effect induced by hypoxic preconditioning (HPC) in the asphyxial cardiac arrest (CA) rat model. Twenty-four hours after the end of 7-day HPC, the rats were subjected to 8-min asphyxiation and resuscitated with a standardized method. In the asphyxial CA rat model, HPC improved the neurological deficit score (NDS), inhibited neuronal apoptosis, and increased the number of viable hippocampal CA1 neurons at 24 h, 72 h, or 7 days after restoration of spontaneous circulation (ROSC); however, the above-mentioned neuroprotection of HPC was attenuated by naltrindole (a selective DOR antagonist). The expression of hypoxia-inducible factor-1 alpha (HIF-1 alpha) and DOR, and the content of leucine enkephalin (L-ENK) in the brain were also investigated after the end of 7-day HPC. HPC upregulated the neuronal expression of HIF-1 alpha and DOR, and synchronously elevated the content of L-ENK in the rat brain. HIF-1 alpha siRNA was used to further elucidate the relationship between HIF-1 alpha and DOR in the HPC-treated brain. Knockdown of HIF-1 alpha by siRNA markedly abrogated the HPC induced upregulation of HIF-1 alpha and DOR. The present study demonstrates that the expression of DOR in the rat brain is upregulated by HIF-1 alpha following exposure to 7-day HPC, at the same time, HPC also increases the production of endogenous DOR ligand L-ENK in the brain. DOR activation after HPC results in prolonged neuroprotection against subsequent global cerebral ischemic injury, suggesting a new mechanism of HPC-induced neuroprotection on global cerebral ischemia following CA and resuscitation. (C) 2011 IBRO. Published by Elsevier Ltd. All rights reserved.