Neuroprotective effect of nicorandil through inhibition of apoptosis by the PI3K/Akt1 pathway in a mouse model of deep hypothermic low flow.
OBJECTIVE
Nicorandil exerts a protective effect on ischemia-reperfusion (I/R) injury in the brain and kidney through anti-apoptotic mechanisms. However, the mechanism by which nicorandil protects against I/R injury induced by deep hypothermic low flow (DHLF) remains unclear.


METHODS
We used a cerebral I/R model induced by DHLF to determine the neuroprotective effects and possible mechanisms of nicorandil.


RESULTS
Hematoxylin-eosin (HE) staining and in situ terminal deoxynucleotidyl transferase UTP nick end labeling (TUNEL) assay were used to detect changes in cell morphology and the number of apoptotic cells in hippocampus, respectively. The apoptotic regulators including Bcl-2, Bax, Akt, and p-Akt (the active, phosphorylated form of Akt) were examined by Western blot (WB). Histopathological findings showed that nicorandil significantly alleviated morphological damage in hippocampal and reduced the number of TUNEL-positive nuclei induced by DHLF. Nicorandil also increased the expression of Bcl-2 and decreased the expression of Bax, while increasing p-Akt level. Consistent with these results, nicorandil-mediated neuroprotection was reduced in the Akt1+/- mutant mice and inhibited by LY294002, a PI3K inhibitor.


CONCLUSIONS
These findings showed that nicorandil provides a neuroprotective role in DHLF-induced I/R injury by inhibiting apoptosis via activation of the PI3K/Akt1 signaling pathway.
Department of Cardiothoracic Surgery, Nanjing Children's Hospital, Nanjing Medical University, Nanjing 210008, China.
Di
D
Yu
Department of Cardiothoracic Surgery, Nanjing Children's Hospital, Nanjing Medical University, Nanjing 210008, China.
Changfeng
C
Fan
Department of Cardiothoracic Surgery, Nanjing Children's Hospital, Nanjing Medical University, Nanjing 210008, China.
Weiyan
W
Zhang
Department of Cardiothoracic Surgery, Nanjing Children's Hospital, Nanjing Medical University, Nanjing 210008, China.
Zhongyuan
Z
Wen
Department of Cardiothoracic Surgery, Nanjing Children's Hospital, Nanjing Medical University, Nanjing 210008, China.
Liang
L
Hu
Department of Cardiothoracic Surgery, Nanjing Children's Hospital, Nanjing Medical University, Nanjing 210008, China.
Lei
L
Yang
Department of Cardiothoracic Surgery, Nanjing Children's Hospital, Nanjing Medical University, Nanjing 210008, China.
Yu
Y
Feng
Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI 48109, USA.
Ke-Jie
KJ
Yin
Department of Cardiothoracic Surgery, Nanjing Children's Hospital, Nanjing Medical University, Nanjing 210008, China. Electronic address: mohsuming15@sina.com.
Xuming
X
Mo
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002867:Chromones / Q000494:pharmacology; D050792:Circulatory Arrest, Deep Hypothermia Induced / Q000009:adverse effects*; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D018696:Neuroprotective Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D020108:Nicorandil / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D015427:Reperfusion Injury / Q000188:drug therapy; D015398:Signal Transduction / Q000187:drug effects*; D015854:Up-Regulation / Q000187:drug effects; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis
D002867:Chromones; D009025:Morpholines; D018696:Neuroprotective Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D020108:Nicorandil; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt
Apoptosis; Deep hypothermic low flow; Neuroprotection; Nicorandil; PI3K/Akt