title: Augmentation of endoplasmic reticulum stress in cerebral ischemia/reperfusion injury associated with comorbid type 2 diabetes.
abstract: OBJECTIVE
  Diabetes is one of the major risk factors for ischemic stroke and is reported to aggravate the ischemic brain damage in different experimental models as well as clinical situations. However, the mechanisms underlying the exacerbated ischemia/reperfusion  (I/R) brain injury associated with comorbid diabetes are still not clear. This study investigated the role of endoplasmic reticulum (ER) stress in pathophysiology of aggravated I/R brain injury associated with diabetes.
  
  
  METHODS
  Focal cerebral ischemia was induced by middle cerebral  artery occlusion for 2 hours followed by 22 hours of reperfusion in high-fat diet-fed and low-dose streptozotocin-treated type 2 diabetic rats. Immunohistochemistry and western blotting analysis were performed to detect the changes in expression of various ER stress and apoptotic markers such  as 78 kDa glucose-regulated protein (GRP78), CCAAT/enhancer binding protein homologous protein or growth arrest DNA damage-inducible gene 153 (CHOP/GADD153), and caspase-12. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay was performed to detect the extent  of DNA fragmentation and cell death.
  
  
  RESULTS
  The diabetic rats subjected to I/R manifested significantly larger brain infarct volume and severe deterioration in neurological deficits than their normal, non-diabetic counterparts. There was a marked upregulation of GRP78 observed  in brains of diabetic rats after 22 hours of reperfusion. Furthermore, augmentation of CHOP/GADD153 expression and activation of caspase-12 (ER stress-induced apoptotic factors) were observed in parallel with enhanced TUNEL-positive cells or DNA fragmentation in diabetic rats compared to normal  rats following cerebral I/R.
  
  
  CONCLUSIONS
  Taken together, the current experimental findings demonstrate that diabetes exacerbates brain I/R injury which may be mediated through enhanced ER stress and cell death involving CHOP/GADD153 and caspase-12 activation.
authors: Molecular Neuropharmacology Laboratory, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar, Punjab, India.
authors: Krishnamoorthy
authors: K
authors: Srinivasan
authors: Shyam S
authors: SS
authors: Sharma
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002545:Brain Ischemia / Q000150:complications / Q000378:metabolism*; D016923:Cell Death / Q000502:physiology; D053938:DNA Fragmentation; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000378:metabolism*; D059305:Diet, High-Fat; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000378:metabolism / Q000473:pathology; D008297:Male; D051381:Rats; D015427:Reperfusion Injury / Q000150:complications / Q000378:metabolism* / Q000473:pathology