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

Li, Jianli; Wang, Keyan; Liu, Meinv; He, Jinhua; Zhang, Huanhuan; Liu, Huan

doi:10.1007/s10735-023-10120-1

Cited by 9 publications

(3 citation statements)

References 32 publications

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“…Given this robust increase in the S6 and Akt phosphorylation, it is possible that mTOR signaling was maximal after ischemia-reperfusion and was not increased further by the leucine injection. In contrast, other investigators have reported that the phosphorylation of mTOR and Akt significantly decreases after 24 h of reperfusion, which differs from the findings of this study [40]. This suggests that mTOR signaling may be affected by the duration of the reperfusion.…”

Section: Discussioncontrasting

confidence: 99%

Leucine Reduced Blood–Brain Barrier Disruption and Infarct Size in Early Cerebral Ischemia-Reperfusion

Chi,

Liu,

Magsino

et al. 2023

Brain Sciences

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A disruption of the blood–brain barrier (BBB) is a crucial pathophysiological change that can impact the outcome of a stroke. Ribosomal protein S6 (S6) and protein kinase B (Akt) play significant roles in early cerebral ischemia-reperfusion injury. Studies have suggested that branched-chain amino acids (BCAAs) may have neuroprotective properties for spinal cord or brain injuries. Therefore, we conducted research to investigate if leucine, one of the BCAAs, could offer neuroprotection and alter BBB disruption, along with its effects on the phosphorylation of S6 and Akt during the early phase of cerebral ischemia-reperfusion, specifically within the thrombolytic therapy time window. In rats, ten min after left middle cerebral artery occlusion (MCAO), 5 µL of 20 mM L-leucine or normal saline was injected into the left lateral ventricle. After two hours of reperfusion following one hour of MCAO, we determined the transfer coefficient (Ki) of 14C-α-aminoisobutyric acid to assess the BBB disruption, infarct size, and phosphorylation of S6 and Akt. Ischemia-reperfusion increased the Ki (+143%, p < 0.001) and the intra-cerebroventricular injection of leucine lowered the Ki in the ischemic-reperfused cortex (−34%, p < 0.001). Leucine reduced the percentage of cortical infarct (−42%, p < 0.0001) out of the total cortical area. Ischemia-reperfusion alone significantly increased the phosphorylation of both S6 and Akt (p < 0.05). However, the administration of leucine had no further effect on the phosphorylation of S6 or Akt in the ischemic-reperfused cortex. This study suggests that an acute increase in leucine levels in the brain during early ischemia-reperfusion within a few hours of stroke may offer neuroprotection, possibly due to reduced BBB disruption being one of the major contributing factors. Leucine did not further increase the already elevated phosphorylation of S6 or Akt by ischemia-reperfusion under the current experimental conditions. Our data warrant further studies on the effects of leucine on neuronal survival and its mechanisms in the later stages of cerebral ischemia-reperfusion.

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Section: Discussioncontrasting

confidence: 99%

Leucine Reduced Blood–Brain Barrier Disruption and Infarct Size in Early Cerebral Ischemia-Reperfusion

Chi,

Liu,

Magsino

et al. 2023

Brain Sciences

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“…As PI3K/AKT/mTOR and PI3K III/Beclin-1/Bcl-2 are important signaling pathways involved in autophagy. Activate the signaling pathway of PI3K/AKT/mTOR can inhibits the autophagy of a variety of cells [20][21][22][23] . While Beclin-1 is a speci c autophagy gene in the PI3K III/Beclin-1/Bcl-2 signaling pathway, beclin-1 protein can form a compound with PI3K III to induce related autophagy proteins locate on the autophagosome membrane, thus promote the formation of autophagosomes [24] .…”

Section: Discussionmentioning

confidence: 99%

Hypothermia prevents OGD/R induced injury by activating the PI3K/AKT/mTOR signaling pathway and enhancing autophagy

Shi,

Gao,

Wang

et al. 2024

Preprint

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Objectives To evaluate the role of hypothermia in the injury of PC12 cells which induced by OGD/R. To investigate the mechanism of hypothermia intervention to alleviate OGD/R-induced injury of PC12 cells through phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway and autophagy, and to lay a foundation and provide theoretical basis for clinical application of hypothermia on protect nerve injury in the future. Methods Induce PC12 cells establish an Ischemia reperfusion injury model in vitro by OGD/R. Then, intervene PC12 cells with OGD/R and OGD/R treated with LY294002 inhibitor at 37℃, 32℃, 27℃. Valuate cell viability by CCK-8 assay, detect the phosphorylation levels of PI3K, AKT and mTOR proteins through western blotting, evaluate signaling pathway activation of PI3K/AKT/mTOR, detect protein expression of LC3I/II by immunofluorescence and western blotting, and observe the autophagosomes by fluoroscopic electron microscopy to evaluate autophagy. Detect apoptosis by flow cytometry, and evaluate the cell damage. Results Hypothermia treatment could effectively improve the cell viability of PC12 cells treated with OGD/R, and the cell viability increased with the decrease of temperature (P < 0.05). Hypothermia treatment also promoted the increase of the phosphorylation levels of PI3K, AKT and mTOR proteins in cells (P < 0.05). In addition, flow cytometry was used to detect the apoptosis rate of different treatments, and the results showed that hypothermia could inhibit the apoptosis that induced by OGD/R. In the control group, OGD/R group and LY294002 inhibitor group, autophagy specific protein LC3I/II which labeled with green fluorescently was increased significantly under the culture conditions of 32℃ and 27℃, and the fluorescence signal was enhanced. Meanwhile, the expression level of LC3I/II also increased. Autophagosome was increased under the electron microscopy. Conclusion Hypothermia can inhibit apoptosis by regulating the PI3K/AKT/mTOR axis and the level of autophagy, thus protecting PC12 cell damage that induced by OGD/R.

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“…Third, our study did not include a molecular mechanism investigation. Li et al found that dexmedetomidine activates the phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin pathway to attenuate autophagy in cerebral ischemia-reperfusion injury [ 53 ]. Another study reported that dexmedetomidine decreases reactive oxygen species production and nuclear factor kappa-B proteins to inhibit the activation of autophagy in traumatic brain injury [ 54 ].…”

Section: Discussionmentioning

confidence: 99%

Dexmedetomidine ameliorates x-ray-induced myocardial injury via alleviating cardiomyocyte apoptosis and autophagy

Zhang,

Xie,

Lian

et al. 2024

BMC Cardiovasc Disord

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Background Radiotherapy is a primary local treatment for tumors, yet it may lead to complications such as radiation-induced heart disease (RIHD). Currently, there is no standardized approach for preventing RIHD. Dexmedetomidine (Dex) is reported to have cardio-protection effects, while its role in radiation-induced myocardial injury is unknown. In the current study, we aimed to evaluate the radioprotective effect of dexmedetomidine in X-ray radiation-treated mice. Methods 18 male mice were randomized into 3 groups: control, 16 Gy, and 16 Gy + Dex. The 16 Gy group received a single dose of 16 Gy X-ray radiation. The 16 Gy + Dex group was pretreated with dexmedetomidine (30 µg/kg, intraperitoneal injection) 30 min before X-ray radiation. The control group was treated with saline and did not receive X-ray radiation. Myocardial tissues were collected 16 weeks after X-ray radiation. Hematoxylin-eosin staining was performed for histopathological examination. Terminal deoxynucleotidyl transferase dUTP nick-end labeling staining was performed to assess the state of apoptotic cells. Immunohistochemistry staining was performed to examine the expression of CD34 molecule and von Willebrand factor. Besides, western blot assay was employed for the detection of apoptosis-related proteins (BCL2 apoptosis regulator and BCL2-associated X) as well as autophagy-related proteins (microtubule-associated protein 1 light chain 3, beclin 1, and sequestosome 1). Results The findings demonstrated that 16 Gy X-ray radiation resulted in significant changes in myocardial tissues, increased myocardial apoptosis, and activated autophagy. Pretreatment with dexmedetomidine significantly protects mice against 16 Gy X-ray radiation-induced myocardial injury by inhibiting apoptosis and autophagy. Conclusion In summary, our study confirmed the radioprotective effect of dexmedetomidine in mitigating cardiomyocyte apoptosis and autophagy induced by 16 Gy X-ray radiation.

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

Cited by 9 publications

References 32 publications

Leucine Reduced Blood–Brain Barrier Disruption and Infarct Size in Early Cerebral Ischemia-Reperfusion

Leucine Reduced Blood–Brain Barrier Disruption and Infarct Size in Early Cerebral Ischemia-Reperfusion

Hypothermia prevents OGD/R induced injury by activating the PI3K/AKT/mTOR signaling pathway and enhancing autophagy

Dexmedetomidine ameliorates x-ray-induced myocardial injury via alleviating cardiomyocyte apoptosis and autophagy

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