3-Bromo-7-nitroindazole attenuates brain ischemic injury in diabetic stroke via inhibition of endoplasmic reticulum stress pathway involving CHOP

• Published in: Life sciences (1973) 2012-01, Vol.90 (3), p.154-160
• Main Authors: Srinivasan, Krishnamoorthy, Sharma, Shyam S.
• Format: Article
• Language: English
• Subjects: 3-Bromo-7-nitroindazole; Animals; Apoptosis; binding proteins; brain; Brain injury; Brain Ischemia - complications; Brain Ischemia - metabolism; Brain Ischemia - prevention & control; Cerebral blood flow; Cerebral infarction; CHOP; Diabetes mellitus; Diabetes Mellitus, Type 2 - complications; Diabetes Mellitus, Type 2 - metabolism; Diabetes Mellitus, Type 2 - prevention & control; DNA fragmentation; Edema; Endoplasmic reticulum; Endoplasmic Reticulum Stress - drug effects; Endoplasmic Reticulum Stress - physiology; ER stress; Focal cerebral ischemia; glucose; GRP78; high fat diet; immunohistochemistry; Indazoles - pharmacology; Indazoles - therapeutic use; infarction; Injuries; Ischemia; Male; Neurological diseases; neuronal nitric oxide synthase; Neuroprotection; neuroprotective effect; Nitric oxide; Nitric Oxide Synthase - antagonists & inhibitors; noninsulin-dependent diabetes mellitus; pathogenesis; Rats; Rats, Sprague-Dawley; Recovery of function; Reperfusion; Signal Transduction - drug effects; Signal Transduction - physiology; Streptozocin; streptozotocin; Stress; Stroke; Stroke - complications; Stroke - metabolism; Stroke - prevention & control; Transcription Factor CHOP - biosynthesis; Transcription Factor CHOP - physiology; Type 2 diabetes; Western blotting
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/j.lfs.2011.10.017

Aims 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. Main 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 2 h 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. Key findings 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. Significance 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.