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BACE1 gene silencing alleviates isoflurane anesthesia?induced postoperative cognitive dysfunction in immature rats by activating the PI3K/Akt signaling pathway.

ABSTRACT: Postoperative cognitive dysfunction (POCD) is a severe complication characterized by cognitive dysfunction following anesthesia and surgery. The aim of the present study was to investigate the effects of ??site amyloid precursor protein cleavage enzyme 1 (BACE1) gene silencing on isoflurane anesthesia?induced POCD in immature rats via the phosphatidylinositol?3?kinase (PI3K)/protein kinase B (Akt) signaling pathway. Rat models were established and then transfected with BACE1 small interfering RNA and wortmannin (an inhibitor of PI3K). Blood gas analysis was performed, and a series of behavioral experiments were conducted to evaluate the cognitive function, learning ability and locomotor activity of rats. Reverse transcription quantitative polymerase chain reaction and western blot analysis were employed to determine the mRNA and protein expression of the associated genes. An ELISA was used to detect the inflammatory indicators and the content of amyloid precursor protein (APP) and amyloid?? (A?). Apoptosis of the hippocampal CA1 region was observed by terminal deoxynucleotidyl transferase dUTP nick?end labeling staining. Initially, it was revealed that the percentage of stagnation time in rats was increased by BACE1 gene silencing; the escape latency and swimming distance were markedly reduced from the 4th to the 6th day, the time the rats spent in first passing the target area was shortened, and the times of passing the target area were increased by BACE1 gene silencing, demonstrating that BACE1 gene silencing enhanced the spatial memory ability of rats. Additionally, it was determined that silencing BACE1 improved the pathological state induced by isoflurane anesthesia in immature rats, and attenuated the inflammatory response and the levels of APP and A? in hippocampal tissues. Furthermore, it was suggested that silencing BACE1 may have promoted the activation of the PI3K/Akt signaling pathway, thereby inhibiting the apoptosis of the hippocampal CA1 region. Taken together, these results indicated that BACE1 gene silencing may improve isoflurane anesthesia?induced POCD in immature rats by activating the PI3K/Akt signaling pathway and inhibiting the A? generated by APP.

SUBMITTER: Wang YB

PROVIDER: S-EPMC6172366 | biostudies-other | 2018 Sep

REPOSITORIES: biostudies-other

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BACE1 gene silencing alleviates isoflurane anesthesia‑induced postoperative cognitive dysfunction in immature rats by activating the PI3K/Akt signaling pathway.

Wang Ying-Bin YB Xie Jian-Qin JQ Liu Wei W Zhang Rong-Zhi RZ Huang Sheng-Hui SH Xing Yan-Hong YH

Molecular medicine reports 20180904 5

Postoperative cognitive dysfunction (POCD) is a severe complication characterized by cognitive dysfunction following anesthesia and surgery. The aim of the present study was to investigate the effects of β‑site amyloid precursor protein cleavage enzyme 1 (BACE1) gene silencing on isoflurane anesthesia‑induced POCD in immature rats via the phosphatidylinositol‑3‑kinase (PI3K)/protein kinase B (Akt) signaling pathway. Rat models were established and then transfected with BACE1 small interfering RN ...[more]

PMID: 30221701

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Project description:Prolonged exposure to volatile anesthetics, such as isoflurane and sevoflurane, causes neurodegeneration in the developing animal brains. Recent studies showed that dexmedetomidine, a selective α2-adrenergic agonist, reduced isoflurane-induced cognitive impairment and neuroapoptosis. However, the mechanisms for the effect are not completely clear. Thus, we investigated whether exposure to isoflurane or sevoflurane at an equivalent dose for anesthesia during brain development causes different degrees of neuroapoptosis and whether this neuroapoptosis is reduced by dexmedetomidine via effects on PI3K/Akt pathway that can regulate cell survival. Seven-day-old (P7) neonatal Sprague-Dawley rats were randomly exposed to 0.75% isoflurane, 1.2% sevoflurane or air for 6 h. Activated caspase-3 was detected by immunohistochemistry and Western blotting. Phospho-Akt, phospho-Bad, Akt, Bad and Bcl-xL proteins were detected by Western blotting in the hippocampus at the end of exposure. Also, P7 rats were pretreated with various concentrations of dexmedetomidine alone or together with PI3K inhibitor LY294002, and then exposed to 0.75% isoflurane. Terminal deoxyribonucleotide transferase-mediated dUTP nick end labeling (TUNEL) and activated caspase-3 were used to detect neuronal apoptosis in their hippocampus. Isoflurane, not sevoflurane at the equivalent dose, induced significant neuroapoptosis, decreased the levels of phospho-Akt and phospho-Bad proteins, increased the expression of Bad protein and reduced the ratio of Bcl-xL/Bad in the hippocampus. Dexmedetomidine pretreatment dose-dependently inhibited isoflurane-induced neuroapoptosis and restored protein expression of phospho-Akt and Bad as well as the Bcl-xL/Bad ratio induced by isoflurane. Pretreatment with single dose of 75 µg/kg dexmedetomidine provided a protective effect similar to that with three doses of 25 µg/kg dexmedetomidine. Moreover, LY294002, partly inhibited neuroprotection of dexmedetomidine. Our results suggest that dexmedetomidine pretreatment provides neuroprotection against isoflurane-induced neuroapoptosis in the hippocampus of neonatal rats by preserving PI3K/Akt pathway activity.

Dataset Information

BACE1 gene silencing alleviates isoflurane anesthesia?induced postoperative cognitive dysfunction in immature rats by activating the PI3K/Akt signaling pathway.

Publications

BACE1 gene silencing alleviates isoflurane anesthesia‑induced postoperative cognitive dysfunction in immature rats by activating the PI3K/Akt signaling pathway.

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