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.
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The datasets used during the current study are available from the corresponding author on reasonable request.
References
Balduini W, Carloni S, Buonocore G (2012) Autophagy in hypoxia-ischemia induced brain injury. J Matern Fetal Neonatal Med 25:30–34. https://doi.org/10.3109/14767058.2012.663176
Bozorgi H, Zamani M, Motaghi E, Eslami M (2021) Dexmedetomidine as an Analgesic Agent with Neuroprotective Properties: experimental and clinical aspects. J Pain Palliat Care Pharmacother 35:215–225. https://doi.org/10.1080/15360288.2021.1914280
Bunte S, Behmenburg F, Majewski N, Stroethoff M, Raupach A, Mathes A et al (2020) Characteristics of Dexmedetomidine Postconditioning in the Field of Myocardial Ischemia-Reperfusion Injury. Anesth Analg 130:90–98. https://doi.org/10.1213/ANE.0000000000004417
Cai Y, Xu H, Yan J, Zhang L, Lu Y (2014) Molecular targets and mechanism of action of dexmedetomidine in treatment of ischemia/reperfusion injury. Mol Med Rep 9:1542–1550. https://doi.org/10.3892/mmr.2014.2034
El-Marasy SA, Abdel-Rahman RF, Abd-Elsalam RM (2018) Neuroprotective effect of vildagliptin against cerebral ischemia in rats. Naunyn Schmiedebergs Arch Pharmacol 391:1133–1145. https://doi.org/10.1007/s00210-018-1537-x
Ersahin T, Tuncbag N, Cetin-Atalay R (2015) The PI3K/AKT/mTOR interactive pathway. Mol Biosyst 11:1946–1954. https://doi.org/10.1039/c5mb00101c
Farag E, Argalious M, Abd-Elsayed A, Ebrahim Z, Doyle DJ (2012) The Use of Dexmedetomidine in Anesthesia and Intensive Care: a review. Curr Pharm Des 18:6257–6265. https://doi.org/10.2174/138161212803832272
Gorelick PB (2019) The global burden of stroke: persistent and disabling. Lancet Neurol 18:417–418. https://doi.org/10.1016/S1474-4422(19)30030-4
Jin L, Mo Y, Yue EL, Liu Y, Liu KY (2021) Ibrutinib ameliorates cerebral ischemia/reperfusion injury through autophagy activation and PI3K/Akt/mTOR signaling pathway in diabetic mice. Bioengineered 12:7432–7445. https://doi.org/10.1080/21655979.2021.1974810
Kim E, Kim HC, Lee S, Ryu HG, Park YH, Kim JH et al (2017) Dexmedetomidine confers neuroprotection against transient global cerebral ischemia/reperfusion injury in rats by inhibiting inflammation through inactivation of the TLR-4/NF-κB pathway. Neurosci Lett 649:20–27. https://doi.org/10.1016/j.neulet.2017.04.011
Lempiäinen J, Finckenberg P, Mervaala EE, Storvik M, Kaivola J, Lindstedt K et al (2014) Dexmedetomidine preconditioning ameliorates kidney ischemia-reperfusion injury. Pharmacol Res Perspect 2:1–15. https://doi.org/10.1002/prp2.45
Li P, Zhang Y, Liu H (2019) The role of Wnt/β-catenin pathway in the protection process by dexmedetomidine against cerebral ischemia/reperfusion injury in rats. Life Sci 236:116921. https://doi.org/10.1016/j.lfs.2019.116921
Liaquat Z, Xu X, Zilundu PLM, Fu R, Zhou L (2021) The current role of dexmedetomidine as neuroprotective agent: an updated review. Brain Sci 11:846. https://doi.org/10.3390/brainsci11070846
Liang TY, Peng SY, Ma M, Li HY, Wang Z, Chen G (2021) Protective effects of sevoflurane in cerebral ischemia reperfusion injury: a narrative review. Med Gas Res 11:152–154. https://doi.org/10.4103/2045-9912.318860
Longa EZ, Weinstein PR, Carlson S, Cummins R (1989) Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke 20:84–91. https://doi.org/10.1161/01.STR.20.1.84
Lu LY, Liu Y, Gong YF, Zheng XY (2019) A preliminary report: Genistein attenuates cerebral ischemia injury in ovariectomized rats via regulation of the PI3K-Akt-mTOR pathway. Gen Physiol Biophys 38:389–397. https://doi.org/10.4149/gpb_2019024
Luo C, Ouyang MW, Fang YY, Li SJ, Zhou Q, Fan J et al (2017) Dexmedetomidine protects mouse brain from ischemia-reperfusion injury via inhibiting neuronal autophagy through up-regulating HIF-1α. Front Cell Neurosci 11:1–13. https://doi.org/10.3389/fncel.2017.00197
Meng J, Ma H, Zhu Y, Zhao Q (2021) Dehydrocostuslactone attenuated oxygen and glucose deprivation/reperfusion-induced PC12 cell injury through inhibition of apoptosis and autophagy by activating the PI3K/AKT/mTOR pathway. Eur J Pharmacol 911:174554. https://doi.org/10.1016/j.ejphar.2021.174554
Nakka VP, Gusain A, Mehta SL, Raghubir R (2008) Molecular mechanisms of apoptosis in cerebral ischemia: multiple neuroprotective opportunities. Mol Neurobiol 37:7–38. https://doi.org/10.1007/s12035-007-8013-9
Nazarinia D, Aboutaleb N, Gholamzadeh R, Nasseri Maleki S, Mokhtari B, Nikougoftar M (2019) Conditioned medium obtained from human amniotic mesenchymal stem cells attenuates focal cerebral ischemia/reperfusion injury in rats by targeting mTOR pathway. J Chem Neuroanat 102:101707. https://doi.org/10.1016/j.jchemneu.2019.101707
Nunes RR, Duval Neto GF, de Alencar JC, Franco SB, de Andrade NQ, Dumaresq DM et al (2013) Anesthetics, Cerebral Protection and Preconditioning. Braz J Anesthesiol 63:119–128. https://doi.org/10.1016/j.bjane.2012.06.003
Ryan F, Khodagholi F, Dargahi L, Minai-Tehrani D, Ahmadiani A (2018) Temporal pattern and crosstalk of necroptosis markers with autophagy and apoptosis Associated Proteins in ischemic Hippocampus. Neurotox Res 34:79–92. https://doi.org/10.1007/s12640-017-9861-3
Shao ZQ, Dou SS, Zhu JG, Wang HQ, Wang CM, Cheng BH et al (2021) Apelin-13 inhibits apoptosis and excessive autophagy in cerebral ischemia/reperfusion injury. Neural Regen Res 16:1044–1051. https://doi.org/10.4103/1673-5374.300725
Shen M, Wang S, Wen X, Han XR, Wang YJ, Zhou XM et al (2017) Dexmedetomidine exerts neuroprotective effect via the activation of the PI3K/Akt/mTOR signaling pathway in rats with traumatic brain injury. Biomed Pharmacother 95:885–893. https://doi.org/10.1016/j.biopha.2017.08.125
Tuo QZ, Zhang ST, Lei P (2022) Mechanisms of neuronal cell death in ischemic stroke and their therapeutic implications. Med Res Rev 42:259–305. https://doi.org/10.1002/med.21817
Unchiti K, Leurcharusmee P, Samerchua A, Pipanmekaporn T, Chattipakorn N, Chattipakorn SC (2021) The potential role of dexmedetomidine on neuroprotection and its possible mechanisms: evidence from in vitro and in vivo studies. Eur J Neurosci 54:7006–7047. https://doi.org/10.1111/ejn.15474
Wasan H, Singh S, Joshi B, Sharma U, Dinda AK, Reeta KH (2021) Post Stroke Safinamide Treatment attenuates neurological damage by modulating autophagy and apoptosis in experimental model of stroke in rats. Mol Neurobiol 58:6121–6135. https://doi.org/10.1007/s12035-021-02523-6
Zhang MH, Zhou XM, Gao JL, Wang KJ, Cui JZ (2014) PI3K/Akt/mTOR pathway participates in neuroprotection by dexmedetomidine inhibits neuronic autophagy following traumatic brain injury in rats. Int J Res Med Sci 2:1569–1575. https://doi.org/10.5455/2320-6012.ijrms20141161
Zhang Y, Zhang Y, Jin XF, Zhou XH, Dong XH, Yu WT et al (2019a) The role of Astragaloside IV against Cerebral Ischemia/Reperfusion Injury: suppression of apoptosis via Promotion of P62-LC3-Autophagy. Molecules 24:1838. https://doi.org/10.3390/molecules24091838
Zhang J, Jiang H, Liu DH, Wang GN (2019b) Effects of dexmedetomidine on myocardial ischemia-reperfusion injury through PI3K-Akt-mTOR signaling pathway. Eur Rev Med Pharmacol Sci 23:6736–6743. https://doi.org/10.26355/eurrev_2019b08_18565
Zhu Y, Li S, Liu J, Wen Q, Yu J, Yu L et al (2019) Role of JNK Signaling Pathway in Dexmedetomidine Post-Conditioning-Induced reduction of the inflammatory response and Autophagy Effect of Focal Cerebral Ischemia Reperfusion Injury in rats. Inflammation 42:2181–2191. https://doi.org/10.1007/s10753-019-01082-2
Zhu YM, Wang CC, Chen L, Qian LB, Ma LL, Yu J et al (2013) Both PI3K/Akt and ERK1/2 pathways participate in the protection by dexmedetomidine against transient focal cerebral ischemia/reperfusion injury in rats. Brain Res 1494:1–8. https://doi.org/10.1016/j.brainres.2012.11.047
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This work was supported by the 333 talent project of Hebei Province [Grant number A202005012].
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Li, J., Wang, K., Liu, M. et al. Dexmedetomidine alleviates cerebral ischemia-reperfusion injury via inhibiting autophagy through PI3K/Akt/mTOR pathway. J Mol Histol 54, 173–181 (2023). https://doi.org/10.1007/s10735-023-10120-1
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DOI: https://doi.org/10.1007/s10735-023-10120-1