Effect of orexin-A on post-ischemic glucose intolerance and neuronal damage

Orexin-a is a newly identified neuropeptide expressed in the lateral areas of the hypothalamus that plays a role in various physiological functions,including regulation of glucose metabolism. we have previously reported that the development of post-ischemic glucose intolerance is one of the triggers of ischemic neuronal damage. therefore,the aim of this study was to determine the effects of orexin-a on the development of post-ischemic glucose intolerance and ischemic neuronal damage. male ddy mice were subjected to middle cerebral artery occlusion (mcao) for 2 h. neuronal damage was estimated by histological and behavioral analysis after mcao. intracerebroventricular administration of orexin-a (2.5,25,or 250 pmol/mouse) significantly and dose-dependently suppressed the development of post-ischemic glucose intolerance on day 1 after mcao and neuronal damage on day 3 after mcao. in the liver and skeletal muscle,the expression levels of insulin receptor were decreased,whereas those of gluconeogenic enzymes were increased on day 1 after mcao. furthermore,these expressions were completely recovered to normal levels by orexin-a and were reversed by the administration of sb334867,a specific orexin-1 receptor antagonist. these results suggest that regulation of post-ischemic glucose intolerance by orexin-a suppressed cerebral ischemic neuronal damage. © the japanese pharmacological society.