Remote ischemic postconditioning protects the brain from global cerebral ischemia/reperfusion injury by up-regulating endothelial nitric oxide synthase through the PI3K/Akt pathway.
Remote ischemic postconditioning (RIPoC) attenuates ischemia/reperfusion (I/R) injury in the heart, lung and hind limb. RIPoC performed in the hind limb reduces brain injury following focal cerebral ischemia in rats. Whether RIPoC has a neuroprotective effect with respect to global cerebral I/R injury is, however, unknown, and the mechanism of neuroprotection needs further elucidation. Here we investigated whether RIPoC could reduce global cerebral I/R injury in rats and whether this neuroprotective effect was induced by up-regulating endothelial nitric oxide synthase (eNOS) through the phosphatidylinositol-3 kinase/Akt (PI3K/Akt) pathway. Global cerebral ischemia was performed via 8min of four-vessel occlusion. Neuronal density, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive cells and expression of Bcl-2 and Bax in the hippocampal CA1 region were assessed after reperfusion. Morris water maze task was used to quantify spatial learning and memory deficits after reperfusion. The expression of eNOS, phosphorylated eNOS (Ser1177), Akt and phosphorylated Akt (Ser473) in the CA1 region was measured after reperfusion. RIPoC significantly attenuated delayed neuronal death and reduced the spatial learning and memory deficits associated with global cerebral ischemia. Pre-administration of N(ω)-nitro-l-arginine methyl ester (a nonselective NOS inhibitor) significantly abolished the neuroprotective effect of RIPoC. Moreover, pre-administration of LY294002 (a highly selective inhibitor of PI3K) not only significantly reversed the neuroprotective effect of RIPoC, but also obviously inhibited the up-regulation of eNOS induced by RIPoC. Our findings suggest that RIPoC protects the brain against global cerebral I/R injury and that this neuroprotection is mediated by up-regulating eNOS through the PI3K/Akt pathway.
Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, PR China.
Bei
B
Peng
Qu-Lian
QL
Guo
Zhi-Jing
ZJ
He
Zhi
Z
Ye
Ya-Jing
YJ
Yuan
Na
N
Wang
Jun
J
Zhou
D000704:Analysis of Variance; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D001921:Brain / Q000098:blood supply* / Q000201:enzymology; D020520:Brain Infarction / Q000517:prevention & control; D002545:Brain Ischemia / Q000473:pathology / Q000503:physiopathology / Q000628:therapy; D016923:Cell Death / Q000502:physiology; D002867:Chromones / Q000494:pharmacology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000502:physiology; D020287:In Situ Nick-End Labeling; D057775:Ischemic Postconditioning / Q000379:methods*; D008297:Male; D018782:Maze Learning / Q000502:physiology; D009025:Morpholines / Q000494:pharmacology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D019335:Nitroarginine / Q000494:pharmacology; D051058:Oncogene Protein v-akt / Q000378:metabolism; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D015427:Reperfusion Injury / Q000473:pathology* / Q000628:therapy*
D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; D019335:Nitroarginine; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D052250:Nitric Oxide Synthase Type III; D058539:Phosphatidylinositol 3-Kinase; D051058:Oncogene Protein v-akt; D019331:NG-Nitroarginine Methyl Ester