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-1α (HIF-1α) 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-1α and DOR, and synchronously elevated the content of L-ENK in the rat brain. HIF-1α siRNA was used to further elucidate the relationship between HIF-1α and DOR in the HPC-treated brain. Knockdown of HIF-1α by siRNA markedly abrogated the HPC induced upregulation of HIF-1α and DOR. The present study demonstrates that the expression of DOR in the rat brain is upregulated by HIF-1α 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.
Department of Anesthesiology, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province 710038, China.
C-J
CJ
Gao
L
L
Niu
P-C
PC
Ren
W
W
Wang
C
C
Zhu
Y-Q
YQ
Li
W
W
Chai
X-D
XD
Sun
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001143:Arousal; D001237:Asphyxia / Q000473:pathology*; D001522:Behavior, Animal / Q000502:physiology; D015153:Blotting, Western; D002545:Brain Ischemia / Q000473:pathology*; D001933:Brain Stem / Q000502:physiology; D004743:Enkephalin, Leucine / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D006323:Heart Arrest / Q000473:pathology*; D002534:Hypoxia, Brain / Q000473:pathology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000502:physiology; D020287:In Situ Nick-End Labeling; D019194:Ischemic Preconditioning; D008297:Male; D009043:Motor Activity / Q000502:physiology; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D004856:Postural Balance / Q000502:physiology; D034741:RNA, Small Interfering / Q000502:physiology; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D017465:Receptors, Opioid, delta / Q000502:physiology*; D012640:Seizures / Q000503:physiopathology; D016019:Survival Analysis
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009292:Narcotic Antagonists; D034741:RNA, Small Interfering; D017465:Receptors, Opioid, delta; D004743:Enkephalin, Leucine; D009271:Naltrexone; C055382:naltrindole