Tideglusib Ameliorates Ischemia/Reperfusion Damage by Inhibiting GSK-3β and Apoptosis in Rat Model of Ischemic Stroke

• Published in: Journal of stroke and cerebrovascular diseases Vol. 31; no. 4; p. 106349
• Main Authors: Joshi, Balu, Singh, Devendra, Wasan, Himika, Sharma, Uma, Reeta, KH
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.04.2022
• Subjects: Animals; Apoptosis; Glycogen Synthase Kinase 3 beta; GSK-3β; Humans; Infarction, Middle Cerebral Artery - diagnostic imaging; Infarction, Middle Cerebral Artery - drug therapy; Ischemia; Ischemic Stroke; Male; MCAo; Rats; Rats, Wistar; Reperfusion; Reperfusion Injury - drug therapy; Reperfusion Injury - metabolism; Reperfusion Injury - prevention & control; Thiadiazoles; Tideglusib; MCAo; GSK-3β; Tideglusib; Reperfusion; Ischemia
• ISSN: 1052-3057; 1532-8511
• DOI: 10.1016/j.jstrokecerebrovasdis.2022.106349

Glycogen synthase kinase-3β (GSK-3β), a serine/threonine protein kinase, gets activated and worsen stroke outcome after ischemia/reperfusion (I/R) injury by inducing inflammation and apoptosis. In this study, tideglusib, a selective irreversible and non-ATP competitive inhibitor of GSK-3β, was explored in cerebral I/R damage using middle cerebral artery occlusion (MCAo) model in rats. MCAo was done for 90 min in male Wistar rats (250-280 g) using doccol suture. In pre-treatment group, tideglusib (50 mg/kg) was administered once daily for 2 days and on the day of surgery, 30 min before MCAo. Next day, rats were examined for neurobehavioral parameters and MRI was performed to assess brain damage. In post-treatment group, tideglusib was started at 30 min after MCAo and continued for the next 2 days. After 72 h of MCAo, behavioral parameters and brain damage by MRI were assessed. Further, oxidative stress markers (MDA and GSH), inflammatory cytokines (TNF-α, IL-1β and IL-10) and expression levels of pGSK-3β S9, Bcl-2 and Bax were estimated in pre-treatment group. Tideglusib pre-treatment but not post-treatment significantly improved neurobehavioral parameters (p < 0.05) and reduced brain damage (p < 0.01) when compared with MCAo group. I/R induced changes in MDA (p < 0.01), TNF-α and IL-1β (p < 0.05) were significantly attenuated by pre-treatment. Further, tideglusib pre-treatment ameliorated MCAo induced altered expressions of pGSK-3β S9, Bcl-2 and Bax. The results of our exploratory study indicated prophylactic potential of tideglusib in I/R injury by modulating pGSK-3β S9, apoptosis and neuro-inflammation.