Abstract
Endothelin-B receptor agonist, IRL-1620, provides significant neuroprotection following cerebral ischemia in rats. Whether this neuroprotection is due to inhibition of apoptosis is unknown. IRL-1620-treated rats following permanent middle cerebral artery occlusion (MCAO) showed significant improvement in neurological and motor functions along with a decrease in infarct volume at 24 h (−81.3%) and day 7 (−73.0%) compared to vehicle group. Cerebral blood flow (CBF) significantly improved in IRL-1620-treated animals compared to vehicle by day 7 post MCAO. IRL-1620-treated rats showed an increase in phospho-Akt and decrease in Bad level 7 h post-occlusion compared to vehicle, while Akt and Bad expression was similar in cerebral hemispheres at 24 h post-MCAO. The phospho-Bad level was lower in vehicle- but not in IRL-1620-treated rats at 24 h. Anti-apoptotic Bcl-2 expression decreased, while pro-apoptotic Bax expression increased in vehicle-treated MCAO rats, these changes were attenuated (P < 0.01) by IRL-1620. Mitochondrial membrane-bound Bax intensity significantly decreased in IRL-1620 compared to vehicle-treated MCAO rats. IRL-1620 treatment reduced (P < 0.001) the number of TUNEL-positive cells compared to vehicle at 24 h and day 7 post MCAO. The results demonstrate that IRL-1620 is neuroprotective and attenuates neural damage following cerebral ischemia in rats by increasing CBF and reducing apoptosis.
Highlights
Endothelin-B receptor agonist, IRL-1620, provides significant neuroprotection following cerebral ischemia in rats
We observed a significant increase in the phosphorylation of Ser[473] of Akt in right hemisphere of IRL-1620 treated rats compared to the sham (P < 0.01) and vehicle-treated (P < 0.05) rats 7 h post middle cerebral artery occlusion (MCAO); no significant difference in phosphorylation of Ser473 of Akt (pAkt) level was seen among the groups at 24 h post MCAO
We have demonstrated that selective stimulation of the endothelin B (ETB) receptors enhances neurovascular repair with significant reductions in neurological deficit, infarct volume and oxidative stress in rat models of cerebral ischemia[20,21,22]
Summary
Endothelin-B receptor agonist, IRL-1620, provides significant neuroprotection following cerebral ischemia in rats. IRL1620-treated rats following permanent middle cerebral artery occlusion (MCAO) showed significant improvement in neurological and motor functions along with a decrease in infarct volume at 24 h (−81.3%) and day 7 (−73.0%) compared to vehicle group. Cerebral blood flow (CBF) significantly improved in IRL-1620-treated animals compared to vehicle by day 7 post MCAO. The results demonstrate that IRL-1620 is neuroprotective and attenuates neural damage following cerebral ischemia in rats by increasing CBF and reducing apoptosis. Previous studies from our laboratory have demonstrated that selective stimulation of ETB receptors by agonist, IRL-1620, could significantly improve neurological and motor functions, with concurrent decrease in infarct volume and oxidative stress damage following permanent middle cerebral artery occlusion (MCAO) in rats[20,21]. A randomized, double blind, controlled, multicenter phase II trial is in progress in patients with cerebral ischemic stroke (CTRI/2017/11/010654)
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