title: Severe instead of mild hyperglycemia inhibits neurogenesis in the subventricular zone of adult rats after transient focal cerebral ischemia.
abstract: Accumulated evidence suggests that enhanced neurogenesis stimulated by ischemic injury contributes to stroke outcome. However, it is unclear whether hyperglycemia, which is frequently tested positive in patients with acute ischemic stroke, influences stroke-induced neurogenesis. The aim of the present study is to examine the effect of hyperglycemia on stroke-induced neurogenesis in a rat model of transient focal cerebral ischemia. For this purpose, adult male Sprague-Dawley rats (220-250 g) were subjected to 90 min of middle cerebral artery occlusion (MCAO). Glucose was administered during ischemia to produce target blood levels ranging from 4.83 ± 0.94 mM (normoglycemia) to 20.76 ± 1.56 mM. To label proliferating cells in ischemic ipsilateral subventricular zone (SVZ) of lateral ventricles, 5'-bromo-2'-deoxyuridine (BrdU) was injected 24h after MCAO. Brains were harvested 2h post-BrdU to evaluate the effects of hyperglycemia on infarct volume and SVZ cell proliferation. Rats that were severely hyperglycemic (19.26 ± 1.48 mM to 20.76 ± 1.56 mM) during ischemia had 24.26% increase in infarct volume (P<0.05) and more serious neurological function deficits (P<0.05). The severe hyperglycemic rats also showed dramatically decreased proliferation of neural stem/progenitor cells (NSPCs) (P<0.05) and down-regulation of the phosphorylation of cyclic-AMP response element-binding protein (pCREB) (P<0.05)and brain-derived neurotrophic factor (BDNF) (P<0.05) in ipsilateral SVZ. But the above-mentioned detrimental effects were not observed in rats that were rendered with mild hyperglycemia (9.43 ± 1.39-10.13 ± 1.24 mM). Our findings indicate that severe instead of mild hyperglycemia exacerbates ischemic injury and inhibits stroke-induced SVZ neurogenesis by a mechanism involving suppression of CREB and BDNF signaling.
authors.affiliation: Department of Neurology, Zhujiang Hospital of Southern Medical University, Guangzhou 510282, Guangdong Province, China.
authors.forename: S
authors.initials: S
authors.lastname: Tan
authors.affiliation: Department of Oncology, The First Affiliated Hospital Of Henan University Of Science and Technology, Luoyang 471000, Henan Province, China.
authors.forename: P K
authors.initials: PK
authors.lastname: Zhi
authors.affiliation: Department of Neurology,The First People's Hospital of Yibin, Yibin 644000, Sichuan Province, China.
authors.forename: Z K
authors.initials: ZK
authors.lastname: Luo
authors.affiliation: Department of Neurology, The First Affiliated Hospital Of Henan University Of Science and Technology, Luoyang 471000, Henan Province, China. Electronic address: s_j2008@163.com.
authors.forename: J
authors.initials: J
authors.lastname: Shi
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006943:Hyperglycemia / Q000150:complications / Q000378:metabolism / Q000503:physiopathology*; D002546:Ischemic Attack, Transient / Q000150:complications / Q000378:metabolism / Q000503:physiopathology*; D020547:Lateral Ventricles / Q000503:physiopathology*; D008297:Male; D055495:Neurogenesis; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D020521:Stroke / Q000150:complications / Q000378:metabolism / Q000503:physiopathology*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D017362:Cyclic AMP Response Element-Binding Protein; D005904:Glial Fibrillary Acidic Protein
keywords: brain-derived neurotrophic factor; cAMP-responsive element-binding protein; cerebral ischemia; hyperglycemia; neurogenesis; subventricular zone