title: Endoplasmic reticulum stress plays critical role in brain damage after cerebral ischemia/reperfusion in rats.
abstract: The endoplasmic reticulum(ER) stress plays a vital role in mediating ischemic neuronal cell death. However, very little is known about the role of ER stress in mediating pathophysiological reactions to acute brain injuries. An attempt was therefore made to assess the role of cerebral ischemia/reperfusion (I/R) induced ER stress and its modulation on outcome of ischemic insult. Focal cerebral ischemia was induced in rats by middle cerebral artery occlusion (MCAO) for 2 h followed by varying time points of reperfusion. The brain loci specific and time-dependent alterations were seen in the expression pattern of molecular markers, i.e., heat-shock protein 70 (HSP70) for cytoplasmic dysfunction, glucose-regulated protein 78 (GRP78), Caspase-12, C/EBP homologous protein/growth arrest and DNA damage-inducible gene 153 (CHOP/GADD153), activating transcription factor 4 (ATF-4), and Processed X-box protein 1 (xbp1) mRNA for ER dysfunction. Further, histological examinations indicated pronounced brain damage, massive neuronal loss, and DNA fragmentation predominantly in the striatum and cortex. The enhanced expression of GRP78, Caspase-12, CHOP/GADD153, ATF4 and processing of xbp1 mRNA in the affected brain regions clearly indicate the critical involvement of ER-mediated cell death/survival mechanisms and also collectively demonstrated the activation of unfolded protein response (UPR). Moreover, Salubrinal, a selective inhibitor of eIF2alpha dephosphorylation was used to counteract ER stress, which significantly increased the phosphorylation of eukaryotic translation initiation factor 2 subunit alpha (eIF2alpha), leading to reduced brain damage after I/R injury. Therefore, inhibition of ER stress following I/R injury may be used as key therapeutic target for neuroprotection.
authors.affiliation: Division of Pharmacology, Central Drug Research Institute, Lucknow, India.
authors.forename: Venkata Prasuja
authors.initials: VP
authors.lastname: Nakka
authors.forename: Anchal
authors.initials: A
authors.lastname: Gusain
authors.forename: Ram
authors.initials: R
authors.lastname: Raghubir
mesh_terms: D051701:Activating Transcription Factor 4 / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000473:pathology* / Q000648:ultrastructure; D053454:Caspase 12 / Q000378:metabolism; D002934:Cinnamates / Q000627:therapeutic use; D004268:DNA-Binding Proteins / Q000235:genetics; D004195:Disease Models, Animal; D018450:Disease Progression; D004721:Endoplasmic Reticulum / Q000473:pathology* / Q000648:ultrastructure*; D007839:Functional Laterality; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000502:physiology; D050884:HSP72 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D020287:In Situ Nick-End Labeling / Q000379:methods; D007211:Indoles; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology* / Q000517:prevention & control; D008297:Male; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D000071701:Regulatory Factor X Transcription Factors; D015427:Reperfusion Injury / Q000188:drug therapy / Q000473:pathology*; D018709:Statistics, Nonparametric; D013890:Thiourea / Q000031:analogs & derivatives / Q000627:therapeutic use; D013997:Time Factors; D051742:Transcription Factor CHOP / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics; D000071717:X-Box Binding Protein 1; D000091342:Endoplasmic Reticulum Chaperone BiP
chemical_list: D051701:Activating Transcription Factor 4; D053454:Caspase 12; D002934:Cinnamates; D004268:DNA-Binding Proteins; D050884:HSP72 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D007211:Indoles; D010751:Phosphopyruvate Hydratase; D012333:RNA, Messenger; D000071701:Regulatory Factor X Transcription Factors; D013890:Thiourea; D051742:Transcription Factor CHOP; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C497110:Atf4 protein, rat; C051684:GRP78 protein, rat; D000091342:Endoplasmic Reticulum Chaperone BiP; C000605545:Xbp1 protein, rat; C496827:salubrinal; C007293:DAPI