Neuroprotective Effect of Orexin-A Is Mediated by an Increase of Hypoxia-inducible Factor-1 Activity in Rat

Abstract

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-1␣ (HIF-1␣) 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-1␣ 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-1␣ in the neuroprotective effects of orexin-A, the HIF-1␣ 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 g/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-1␣

Orexin-A Suppresses Postischemic Glucose Intolerance and Neuronal Damage through Hypothalamic Brain-Derived Neurotrophic Factor

“…In addition, the level of orexin-A in cerebrospinal fluid was found to be reduced in subsets of patients with vascular diseases (Ripley et al, 2001). The mechanisms of the neuroprotective effects of orexin-A have been proven to be related with some intracellular signal transduction pathway, such as hypoxia-inducible factor-1a (Yuan et al, 2011). Therefore, it was hypothesized that hypothalamic orexin-A might be involved in the development of postischemic glucose intolerance and neuronal damage.…”

Acute cerebral ischaemia: Relationship between serum and cerebrospinal fluid orexin-A concentration and infarct volume

“…18,19 Examining the relationship between traditional risk factors for cardiovascular disease and stroke might clarify the associations between CSF orexin-A concentrations and cerebrovascular infarction. Yuan et al 20 showed that orexin-A treatment can induce prominent neuroprotective effects on transient cerebral ischaemia in rats by improving neurological function and decreasing infarct size. In the authors' opinion, serum orexin-A is not a useful indicator for the prediction of symptomatic brain ischaemic infarction, but lower orexin-A concentrations in the CSF may be related to ischaemic injury.…”

Orexin/Hypocretin Activates mTOR Complex 1 (mTORC1) via an Erk/Akt-independent and Calcium-stimulated Lysosome v-ATPase Pathway

“…For example, mTORC1 positively regulates the activities of SREBP1 and PPAR␥, the two transcription factors that control expression of proteins involved in lipid and cholesterol homeostasis (65,66). Moreover, mTORC1 activates the transcription factor HIF1␣ to stimulate specific metabolic pathways, including glycolysis and the oxidative arm of the pentose phosphate pathway (65,(67)(68)(69). Therefore, the orexin-mTORC1 signaling axis may provide a plausible explanation for the metabolic phenotypes resulting from chronic gain or loss-of-function of orexin/GPCR signaling.…”