title: 3-Bromo-7-nitroindazole attenuates brain ischemic injury in diabetic stroke via inhibition of endoplasmic reticulum stress pathway involving CHOP.
abstract: OBJECTIVE
  The role of nitric oxide (NO) and endoplasmic reticulum (ER) stress has been implicated in the pathogenesis of cerebral ischemic/reperfusion (I/R) injury and diabetes. The aim of the study was to investigate the neuroprotective potential of 3-bromo-7-nitroindazole (3-BNI), a potent and selective neuronal nitric oxide synthase (nNOS) inhibitor against ER stress and focal cerebral I/R injury associated with comorbid type 2 diabetes in-vivo.
  
  
  METHODS
  Type 2 diabetes was induced by feeding high-fat diet and streptozotocin (35 mg/kg) treatment in rats. Focal cerebral ischemia was induced by 2h middle cerebral artery occlusion (MCAO) followed by 22 h of reperfusion. Immunohistochemistry and western blotting methods were employed for the detection and expression of ER stress/apoptosis markers [78 kDa glucose regulated protein (GRP78) and CCAAT/enhancer binding protein homologous protein (CHOP)]. TUNEL assay for DNA fragmentation was also performed.
  
  
  RESULTS
  The diabetic rats subjected to cerebral I/R had prominent neurological damage and functional deficits compared with sham-operated rats. Massive DNA fragmentation was observed in ischemic penumbral region of diabetic brains. Concomitantly, the enhanced immunoreactivity and expression of ER stress/apoptosis markers were noticed. 3-BNI (30 mg/kg, i.p.) treatment significantly inhibited the cerebral infarct, edema volume and improved functional recovery of neurological deficits. The neuroprotection was further evident by lesser DNA fragmentation with a concomitant reduction of GRP78 and CHOP.
  
  
  CONCLUSIONS
  The study demonstrates the neuroprotective potential of 3-BNI in diabetic stroke model which may be partly due to inhibition of ER stress pathway involving CHOP.
authors.affiliation: Molecular Neuropharmacology Laboratory, Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education & Research (NIPER), Sector 67, S.A.S. Nagar, Punjab-160062, India.
authors.forename: Krishnamoorthy
authors.initials: K
authors.lastname: Srinivasan
authors.forename: Shyam S
authors.initials: SS
authors.lastname: Sharma
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000150:complications / Q000378:metabolism / Q000517:prevention & control*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000378:metabolism / Q000517:prevention & control*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000502:physiology*; D007191:Indazoles / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D020521:Stroke / Q000150:complications / Q000378:metabolism / Q000517:prevention & control*; D051742:Transcription Factor CHOP / Q000096:biosynthesis / Q000502:physiology*
chemical_list: C106731:3-bromo-7-nitroindazole; D007191:Indazoles; D051742:Transcription Factor CHOP; D019001:Nitric Oxide Synthase