title: Edaravone offers neuroprotection in a diabetic stroke model via inhibition of endoplasmic reticulum stress.
abstract: Recent investigations have postulated a link between oxidative stress and endoplasmic reticulum (ER) dysfunction in cerebral ischaemic/reperfusion (I/R) injury. Diabetes is common amongst elderly patients with stroke and has been postulated to aggravate brain I/R damage by triggering oxidative as well as ER stress. We investigated whether treatment with edaravone (1-10 mg/kg), a potent free radical scavenger protects against cerebral I/R injury in rats associated with comorbid type 2 diabetes. Diabetic rats exposed to 2-hr middle cerebral artery occlusion (MCAO) and 22 hr of reperfusion significantly had increased infarct, oedema volume and functional neurological deficits as compared to sham-operated rats. Also, the massive DNA fragmentation accompanied by significant increase in terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL) positive cells was noticed in the ipsilateral penumbral brain region of diabetic I/R rats. The effects of I/R injury were associated with significant up-regulation of 78 kDa-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, markers of ER stress/apoptosis. Treatment with edaravone (3 and 10 mg/kg) significantly diminished the cerebral infarct, oedema volume and improved functional recovery of neurological deficits. In addition, edaravone treatment ameliorated the DNA fragmentation concomitantly with a significant decrease in induction of GRP78, CHOP/GADD153 immunoreactivity/expression and activation of caspase-12 in the ischaemic brain hemispheres. Overall, the present data indicate that edaravone offers good neuroprotection against diabetic stroke by interrupting the ER stress-mediated apoptotic pathways involving CHOP/GADD153 and caspase-12.
authors.affiliation: Molecular Neuropharmacology Laboratory, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education & Research (NIPER), Punjab, India.
authors.forename: Krishnamoorthy
authors.initials: K
authors.lastname: Srinivasan
authors.forename: Shyam S
authors.initials: SS
authors.lastname: Sharma
mesh_terms: D000818:Animals; D000983:Antipyrine / Q000031:analogs & derivatives* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D053454:Caspase 12 / Q000235:genetics / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D000077553:Edaravone; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D020287:In Situ Nick-End Labeling; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D020521:Stroke / Q000517:prevention & control*; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D000091342:Endoplasmic Reticulum Chaperone BiP
chemical_list: D000983:Antipyrine; D053454:Caspase 12; D000077553:Edaravone; D006360:Heat-Shock Proteins; D018696:Neuroprotective Agents; D051742:Transcription Factor CHOP; C497251:Ddit3 protein, rat; C051684:GRP78 protein, rat; D000091342:Endoplasmic Reticulum Chaperone BiP; C506443:Casp12 protein, rat