Neuroprotective effect of orexin-A is mediated by an increase of hypoxia-inducible factor-1 activity in rat.
BACKGROUND
Recent studies suggest that the novel neuropeptide orexin-A may play an essential role during neuronal damage. However, the function of orexin-A during brain ischemia remains unclear. Recently, hypoxia-inducible factor-1α (HIF-1α) was shown to be activated by orexin-A. The aim of the current study is to test the hypothesis that administration of exogenous orexin-A can attenuate ischemia-reperfusion injury through the facilitation of HIF-1α expression.


METHODS
Sprague-Dawley rats were subjected to transient middle cerebral artery occlusion for 120 min. Rats were treated with different doses of orexin-A or vehicle before the ischemia and at the onset of reperfusion. To investigate the action of HIF-1α in the neuroprotective effects of orexin-A, the HIF-1α inhibitor YC-1 was used alone or combined with orexin-A. Neurologic deficit scores and infarct volume were assessed. Brains were harvested for immunohistochemical staining and western blot analysis.


RESULTS
Orexin-A significantly ameliorated neurologic deficit scores and reduced infarct volume after cerebral ischemia reperfusion. Administration of 30 μg/kg orexin-A showed optimal neuroprotective effects. This effect was still present 7 days after reperfusion. Furthermore, orexin-A decreased the number of apoptotic cells and significantly enhanced HIF-1α expression after cerebral ischemia reperfusion. Moreover, the facilitation of HIF-1α expression was accompanied with inhibition of von Hippel-Lindau expression. Administration of HIF-1α inhibitor suppressed the increase of HIF-1α and reversed the neuroprotective effects of orexin-A.


CONCLUSIONS
Orexin-A has a neuroprotective effect against cerebral ischemia-reperfusion injury. These effects may be mediated through the HIF-1α pathway.
Department of Anesthesiology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
Li-Bang
LB
Yuan
Hai-Long
HL
Dong
Hao-Peng
HP
Zhang
Rui-Ni
RN
Zhao
Gu
G
Gong
Xiao-Mei
XM
Chen
Li-Na
LN
Zhang
Lize
L
Xiong
D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D002545:Brain Ischemia / Q000378:metabolism / Q000517:prevention & control; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000187:drug effects / Q000378:metabolism*; D020287:In Situ Nick-End Labeling; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D009479:Neuropeptides / Q000378:metabolism / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000378:metabolism / Q000494:pharmacology*; D018377:Neurotransmitter Agents / Q000378:metabolism / Q000494:pharmacology; D000068797:Orexins; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000378:metabolism / Q000517:prevention & control*
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D018696:Neuroprotective Agents; D018377:Neurotransmitter Agents; D000068797:Orexins