PMID- 21767572 OWN - NLM STAT- MEDLINE DCOM- 20120118 LR - 20210309 IS - 1872-7549 (Electronic) IS - 0166-4328 (Linking) VI - 225 IP - 1 DP - 2011 Nov 20 TI - Sodium phenylbutyrate ameliorates focal cerebral ischemic/reperfusion injury associated with comorbid type 2 diabetes by reducing endoplasmic reticulum stress and DNA fragmentation. PG - 110-6 LID - 10.1016/j.bbr.2011.07.004 [doi] AB - Endoplasmic reticulum (ER) stress has been postulated to play a crucial role in the pathophysiology of cerebral ischemic/reperfusion (I/R) injury and diabetes. Diabetes is a major risk factor and also common amongst the people who suffer from stroke. In this study, we have investigated the neuroprotective potential of sodium 4-phenylbutyrate (SPB; 30-300mg/kg), a chemical chaperone by targeting ER stress in a rat model of transient focal cerebral ischemia associated with comorbid type 2 diabetes. Intraperitoneal treatment with SPB (100 and 300mg/kg) significantly ameliorated brain I/R damage as evidenced by reduction in cerebral infarct and edema volume. It also significantly improved the functional recovery of various neurobehavioral impairments (neurological deficit score, grip strength and rota rod) evoked by I/R compared with vehicle-treatment. Further, SPB (100mg/kg) significantly reduced the DNA fragmentation as shown by prominent reduction in terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)-positive cells. This effect was observed concomitantly with significant attenuation in upregulation of 78kDa glucose regulated protein (GRP78), CCAAT/enhancer binding protein homologous protein or growth arrest DNA damage-inducible gene 153 (CHOP/GADD153) and activation of caspase-12, specific markers of ER stress/apoptosis. The neuroprotection observed with SPB was independent of its effect on cerebral blood flow and blood glucose. In conclusion, this study demonstrates the neuroprotective effect of SPB owing to amelioration of ER stress and DNA fragmentation. It also suggest that targeting ER stress might offer a promising therapeutic approach and benefits against ischemic stroke associated with comorbid type 2 diabetes. CI - Copyright (c) 2011 Elsevier B.V. All rights reserved. FAU - Srinivasan, Krishnamoorthy AU - Srinivasan K AD - Molecular Neuropharmacology Laboratory, Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education & Research (NIPER), Sector 67, S.A.S. Nagar, Punjab 160062, India. FAU - Sharma, Shyam S AU - Sharma SS LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20110708 PL - Netherlands TA - Behav Brain Res JT - Behavioural brain research JID - 8004872 RN - 0 (Ddit3 protein, rat) RN - 0 (GRP78 protein, rat) RN - 0 (Heat-Shock Proteins) RN - 0 (Phenylbutyrates) RN - 147336-12-7 (Transcription Factor CHOP) SB - IM MH - Analysis of Variance MH - Animals MH - Body Weight/drug effects MH - Brain Edema/drug therapy/etiology MH - Brain Infarction/etiology/prevention & control MH - Brain Ischemia/complications/*drug therapy MH - DNA Fragmentation/*radiation effects MH - Diabetes Mellitus, Experimental/chemically induced/*complications MH - Disease Models, Animal MH - Endoplasmic Reticulum Stress/*drug effects MH - Hand Strength/physiology MH - Heat-Shock Proteins/metabolism MH - Male MH - Motor Activity/drug effects MH - Nervous System Diseases/etiology MH - Phenylbutyrates/pharmacology/*therapeutic use MH - Rats MH - Rats, Sprague-Dawley MH - Regional Blood Flow/drug effects MH - Reperfusion Injury/complications/*drug therapy MH - Transcription Factor CHOP/metabolism MH - Treatment Outcome EDAT- 2011/07/20 06:00 MHDA- 2012/01/19 06:00 CRDT- 2011/07/20 06:00 PHST- 2011/05/04 00:00 [received] PHST- 2011/06/29 00:00 [revised] PHST- 2011/07/04 00:00 [accepted] PHST- 2011/07/20 06:00 [entrez] PHST- 2011/07/20 06:00 [pubmed] PHST- 2012/01/19 06:00 [medline] AID - S0166-4328(11)00514-6 [pii] AID - 10.1016/j.bbr.2011.07.004 [doi] PST - ppublish SO - Behav Brain Res. 2011 Nov 20;225(1):110-6. doi: 10.1016/j.bbr.2011.07.004. Epub 2011 Jul 8.