Effect of Orexin-A on Post-ischemic Glucose Intolerance and Neuronal Damage

Abstract

Abstract. 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.

Ameliorating Effect of Hypothalamic Brain-Derived Neurotrophic Factor Against Impaired Glucose Metabolism After Cerebral Ischemic Stress in Mice

“…These results suggest that BDNF in the central nervous system is an important regulator of glucose metabolism in peripheral organs via "inter-tissue communication", and the hypothalamus is an essential brain region that directs this system (24). Furthermore, our previous observation showed that hyperglycemia or a decrease in whole-body insulin sensitivity after cerebral ischemia was due to decreased hepatic InsR expression and activity and to the induction of PEPCK and G6Pase (16). Therefore, it is possible that post-ischemic glucose intolerance can be improved through suppression of hypothalamic BDNF loss caused by cerebral ischemic stress.…”

Ischemic Stroke and Glucose Intolerance: a Review of the Evidence and Exploration of Novel Therapeutic Targets

“…We found that hepatic InsR and p-InsR protein expression levels were significantly lower in animals from the MCAO group than in the sham group on day 1 after MCAO ( Fig. 2: D and E) (50). In addition, in skeletal muscle, the InsR and p-InsR levels tended to be lower in the MCAO group than in the sham group (50).…”

“…After ischemic stroke, we have demonstrated that hepatic PEPCK and G6Pase levels are significantly higher in the MCAO group than in the sham group (Fig. 2: F and G) (50). Hence, postischemic hyperglycemia or decrease in whole-body insulin sensitivity after ischemic stroke may be due to decreased hepatic InsR expression and to upregulation of gluconeogenesis (42).…”

“…2: D and E) (50). In addition, in skeletal muscle, the InsR and p-InsR levels tended to be lower in the MCAO group than in the sham group (50). This decrease in p-InsR was due to a decrease in total InsR because p-InsR/InsR was not altered between the sham and MCAO group.…”

“…administration of orexin-A (2.5, 25, 250 pmol/mouse) significantly suppressed the development of neuronal damage (infarction, behavioral abnormality, and memory disturbance) on day 3 after ischemic stroke, in a dose-dependent manner ( Fig. 5) (50). Furthermore, the development of postischemic glucose intolerance on day 1 after the MCAO was significantly suppressed by orexin-A (50).…”