title: Orexin-A suppresses postischemic glucose intolerance and neuronal damage through hypothalamic brain-derived neurotrophic factor.
abstract: Orexin-A (a glucose-sensing neuropeptide in the hypothalamus) and brain-derived neurotrophic factor (BDNF; a member of the neurotrophin family) play roles in many physiologic functions, including regulation of glucose metabolism. We previously showed that the development of postischemic glucose intolerance is one of the triggers of ischemic neuronal damage. The aim of this study was to determine whether there was an interaction between orexin-A and BDNF functions in the hypothalamus after cerebral ischemic stress. Male ddY mice were subjected to 2 hours of middle cerebral artery occlusion (MCAO). Neuronal damage was estimated by histologic and behavioral analyses. Expression of protein levels was analyzed by Western blot. Small interfering RNA directed BDNF, orexin-A, and SB334867 [N-(2-methyl-6-benzoxazolyl)-N'-1,5-naphthyridin-4-yl urea; a specific orexin-1 receptor antagonist] were administered directly into the hypothalamus. The level of hypothalamic orexin-A, detected by immunohistochemistry, was decreased on day 1 after MCAO. Intrahypothalamic administration of orexin-A (1 or 5 pmol/mouse) significantly and dose-dependently suppressed the development of postischemic glucose intolerance on day 1 and development of neuronal damage on day 3. The MCAO-induced decrease in insulin receptor levels in the liver and skeletal muscle on day 1 was recovered to control levels by orexin-A, and this effect of orexin-A was reversed by the administration of SB334867 as well as by hypothalamic BDNF knockdown. These results suggest that suppression of postischemic glucose intolerance by orexin-A assists in the prevention of cerebral ischemic neuronal damage. In addition, hypothalamic BDNF may play an important role in this effect of orexin-A.
authors.affiliation: Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Kobe Gakuin University, 1-1-3 Minatojima, Chuo-ku, Kobe 650-8586, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Harada
authors.forename: Yui
authors.initials: Y
authors.lastname: Yamazaki
authors.forename: Shogo
authors.initials: S
authors.lastname: Tokuyama
mesh_terms: D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D002545:Brain Ischemia / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D002544:Cerebral Infarction / Q000473:pathology; D018149:Glucose Intolerance / Q000188:drug therapy* / Q000209:etiology; D005954:Glucosephosphate Dehydrogenase / Q000378:metabolism; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism*; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D008568:Memory / Q000187:drug effects; D051379:Mice; D008845:Microinjections; D009460:Neurologic Examination; D009474:Neurons / Q000473:pathology*; D009479:Neuropeptides / Q000008:administration & dosage / Q000494:pharmacology*; D000068797:Orexins; D019764:Phosphoenolpyruvate Carboxykinase (ATP) / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000494:pharmacology; D011972:Receptor, Insulin / Q000096:biosynthesis
chemical_list: D001786:Blood Glucose; D019208:Brain-Derived Neurotrophic Factor; D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D000068797:Orexins; D016760:Proto-Oncogene Proteins c-fos; D034741:RNA, Small Interfering; D005954:Glucosephosphate Dehydrogenase; D011972:Receptor, Insulin; D019764:Phosphoenolpyruvate Carboxykinase (ATP)