Premium
Edaravone Offers Neuroprotection in a Diabetic Stroke Model via Inhibition of Endoplasmic Reticulum Stress
Author(s) -
Srinivasan Krishnamoorthy,
Sharma Shyam S.
Publication year - 2012
Publication title -
basic and clinical pharmacology and toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.805
H-Index - 90
eISSN - 1742-7843
pISSN - 1742-7835
DOI - 10.1111/j.1742-7843.2011.00763.x
Subject(s) - edaravone , neuroprotection , tunel assay , medicine , free radical scavenger , oxidative stress , chop , pharmacology , brain damage , endoplasmic reticulum , dna fragmentation , stroke (engine) , endocrinology , anesthesia , apoptosis , chemistry , programmed cell death , biochemistry , chemotherapy , immunohistochemistry , mechanical engineering , engineering
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.