Dexmedetomidine alleviates cerebral ischemia-reperfusion injury via inhibiting autophagy through PI3K/Akt/mTOR pathway.

Abstract

Dexmedetomidine has been shown to protect against cerebral ischemia-reperfusion injury (CIRI). Nevertheless, the precise mechanism is obscure. In order to explore the effect of dexmedetomidine pre-conditioning on autophagy against CIRI in rats, middle cerebral artery occlusion (MCAO) was conducted to establish cerebral ischemia-reperfusion (I/R) model in male SD rats with 2 h ischemia and 24 h reperfusion. Dexmedetomidine was delivered to rats at 10, 50 and 100 µg/kg doses respectively, and LY294002, a PI3K/Akt/mTOR pathway inhibitor, was administered at 10 mg/kg intraperitoneally 30 min before MCAO. Neurological deficit score was assessed and cerebral infarct size was detected by TTC staining. Morris water maze (MWM) was performed to estimate spatial learning and memory ability. Furthermore, to detect activity of PI3K/Akt/mTOR pathway and autophagy, p-Akt, p-mTOR, Beclin-1 and LC3 were measured by western blot. Our findings revealed that 50 and 100 µg/kg of dexmedetomidine pretreatment could improve the neurological deficit score and reduce cerebral infarct size after CIRI, while these effects were markedly suppressed by LY294002. In MWM test, dexmedetomidine was confirmed to shorten escape latency and increase times across platform after CIRI. Nevertheless, LY294002 pretreatment eliminated the improvement of dexmedetomidine on spatial learning and memory ability. Furthermore, dexmedetomidine pretreatment reduced ratios of Beclin-1 and LC3II/LC3I and elevated p-Akt/Akt and p-mTOR/mTOR after CIRI. However, above effects of dexmedetomidine were partly reversed by LY294002. Overall, dexmedetomidine pretreatment exerted neuroprotection against CIRI in rats by attenuating autophagy via the PI3K/Akt/mTOR pathway.

• Authors: Jianli Li, Keyan Wang, Meinv Liu, Jinhua He, Huanhuan Zhang, Huan Liu
• Journal: Journal of molecular histology (J Mol Histol) Vol. 54 Issue 3 Pg. 173-181 (Jun 2023) ISSN: 1567-2387 [Electronic] Netherlands
• PMID: 37186301 (Publication Type: Journal Article)
• Copyright: © 2023. The Author(s), under exclusive licence to Springer Nature B.V.

Chemical References

• Proto-Oncogene Proteins c-akt
• Phosphatidylinositol 3-Kinases
• Dexmedetomidine
• Beclin-1
• Neuroprotective Agents
• TOR Serine-Threonine Kinases
• mTOR protein, rat

Topics

• Rats
• Male
• Animals
• Signal Transduction
• Proto-Oncogene Proteins c-akt (metabolism)
• Phosphatidylinositol 3-Kinases (metabolism)
• Dexmedetomidine (pharmacology, therapeutic use)
• Rats, Sprague-Dawley
• Beclin-1
• Neuroprotective Agents (pharmacology, therapeutic use)
• TOR Serine-Threonine Kinases (metabolism)
• Reperfusion Injury (drug therapy, metabolism)
• Cerebral Infarction (drug therapy)
• Autophagy
• Infarction, Middle Cerebral Artery (drug therapy, metabolism)