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

Abstract

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 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.

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.

• Authors: Krishnamoorthy Srinivasan, Shyam S Sharma
• Journal: Life sciences (Life Sci) Vol. 90 Issue 3-4 Pg. 154-60 (Jan 16 2012) ISSN: 1879-0631 [Electronic] Netherlands
• PMID: 22075494 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Inc. All rights reserved.

Chemical References

• 3-bromo-7-nitroindazole
• Indazoles
• Transcription Factor CHOP
• Nitric Oxide Synthase

Topics

• Animals
• Brain Ischemia (complications, metabolism, prevention & control)
• Diabetes Mellitus, Type 2 (complications, metabolism, prevention & control)
• Endoplasmic Reticulum Stress (drug effects, physiology)
• Indazoles (pharmacology, therapeutic use)
• Male
• Nitric Oxide Synthase (antagonists & inhibitors)
• Rats
• Rats, Sprague-Dawley
• Signal Transduction (drug effects, physiology)
• Stroke (complications, metabolism, prevention & control)
• Transcription Factor CHOP (biosynthesis, physiology)