Department of Anesthesiology, Hebei General Hospital, Shijiazhuang, 050051, China.
J Mol Histol. 2023 Jun;54(3):173-181. doi: 10.1007/s10735-023-10120-1. Epub 2023 Apr 26.
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.
右美托咪定已被证明可预防脑缺血再灌注损伤（CIRI）。然而，确切的机制尚不清楚。为了探讨右美托咪定预处理对大鼠脑缺血再灌注（I/R）模型自噬的影响，采用大脑中动脉闭塞（MCAO）法建立雄性 SD 大鼠 2 h 缺血和 24 h 再灌注的脑 I/R 模型。分别给予大鼠 10、50 和 100μg/kg 剂量的右美托咪定，在 MCAO 前 30 min 腹腔内给予 10mg/kg 的 LY294002，一种 PI3K/Akt/mTOR 通路抑制剂。通过 TTC 染色检测神经功能缺损评分和脑梗死面积。通过 Morris 水迷宫（MWM）评估空间学习和记忆能力。此外，通过 Western blot 检测 PI3K/Akt/mTOR 通路和自噬活性，测量 p-Akt、p-mTOR、Beclin-1 和 LC3。我们的研究结果表明，50 和 100μg/kg 的右美托咪定预处理可改善 CIRI 后的神经功能缺损评分和减少脑梗死面积，而 LY294002 可显著抑制这些作用。在 MWM 测试中，右美托咪定被证实可缩短 CIRI 后的逃避潜伏期并增加穿越平台的次数。然而，LY294002 预处理消除了右美托咪定对空间学习和记忆能力的改善。此外，右美托咪定预处理可降低 CIRI 后 Beclin-1 和 LC3II/LC3I 的比值，并升高 p-Akt/Akt 和 p-mTOR/mTOR。然而，LY294002 部分逆转了右美托咪定的上述作用。总之，右美托咪定预处理通过抑制 PI3K/Akt/mTOR 通路减轻自噬对大鼠 CIRI 发挥神经保护作用。
