Abstract
Orexin-A is a neuropeptide with potent neuroprotective activity towards cerebral ischemia-reperfusion (I/R) injury, but few studies have attempted to elucidate the mechanism. Herein, we performed global gene expression profiling of the hippocampus following reperfusion with Orexin-A using RNA sequencing (RNA-seq). RNA-seq identified 649 differentially expressed genes (DEGs) in the Orexin-A group compared with saline controls (I/R group), of which 149 were up-regulated and 500 were down-regulated. DEGs were confirmed using qRT-PCR, their molecular functions, biological processes and molecular components were explored using Gene Ontology (GO) analysis and 206 KEGG pathways were associated with Orexin-A treatment. MAPK, chemokine and calcium signalling pathways were mainly responsible for the neuroprotective effects of Orexin-A. Hspb1, Igf2 and Ptk2b were selected for functional interaction analysis by GeneMANIA. The results suggest that Orexin-A modifies gene expression in the hippocampus, leading to neuroprotection from I/R injury. The study provides a basis for future elucidation of the molecular mechanisms underlying Orexin-A.
Highlights
Orexin-A is a novel neuropeptide involved in the regulation of feeding behaviour [1, 2], energy metabolism [3], hormone secretion [4], the sleep-wake cycle [5] and anaesthesia [6]
Orexin-A levels change during hepatic reperfusion, indicating involvement in the regulation of liver injury induced by this process [15]
The Orexin-A group displayed a rate of infarction that was 12.497% ± 1.912% lower than that displayed by the I/R group (**p < 0.01), indicating that pre-treatment with Orexin-A significantly decreased the infarction area, and Orexin-A exhibited a clear neuroprotective effect on I/R injury
Summary
Orexin-A is a novel neuropeptide involved in the regulation of feeding behaviour [1, 2], energy metabolism [3], hormone secretion [4], the sleep-wake cycle [5] and anaesthesia [6]. Orexin-A protects against ischemia-reperfusion (I/R) injury by reducing gastric lesions through increasing HO-2 expression and decreasing HO-1 expression [13]. Orexin-A levels change during hepatic reperfusion, indicating involvement in the regulation of liver injury induced by this process [15]. Kitamura et al found that the number of neurons expressing Orexin-A was significantly lower in the non-ischemic side than the ischemic side [16]. They found Orexin-A pre-treatment significantly reduced the brain infarction volume induced by reperfusion injury, ameliorated neurologic deficit scores and reduced the infarction volume after rat cerebral I/R injury. The neuroprotective effect of Orexin-A was shown to be mediated by an increase in hypoxia-inducible factor-1 (HIF-1α) activity [17], and our lab demonstrated that Orexin-A protects SHY-5Y cells against oxidative stress by activating the PI3K/AKT signalling pathway
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