Ibrutinib ameliorates cerebral ischemia/reperfusion injury through autophagy activation and PI3K/Akt/mTOR signaling pathway in diabetic mice

Abstract

Bruton's tyrosine kinase (BTK) is involved in the diabetogenic process and cerebral ischemic injury. However, it remained unclear whether BTK inhibition has remedial effects on ischemia/reperfusion (I/R) injury complicated with diabetes. We aim to investigate the regulatory role and potential mechanism of ibrutinib, a selective inhibitor of BTK, in cerebral I/R injured diabetic mice. The cytotoxicity and cell vitality tests were performed to evaluate the toxic and protective effects of ibrutinib at different incubating concentrations on normal PC12 cells or which were exposed to high glucose for 24 h, followed by hypoxia and reoxygenation (H/R), respectively. Streptozotocin (STZ) stimulation-induced diabetic mice were subjected to 1 h ischemia and then reperfusion. Then the diabetic mice received different dosages of ibrutinib or vehicle immediately and 24 h after the middle cerebral artery occlusion (MCAO). The behavioral, histopathological, and molecular biological tests were then performed to demonstrate the neuroprotective effects and mechanism in I/R injured diabetic mice. Consequently, Ibrutinib improved the decreased cell viability and attenuated oxidative stress in the high glucose incubated PC12 cells which subjected to H/R injury. In the I/R injured diabetic mice, ibrutinib reduced the cerebral infarct volume, improved neurological deficits, ameliorated pathological changes, and improved autophagy in a slightly dose-dependent manner. Furthermore, the expression of PI3K/AKT/mTOR pathwayrelated proteins were significantly upregulated by ibrutinib treatment. In summary, our finding collectively demonstrated that Ibrutinib could effectively ameliorate cerebral ischemia/reperfusion injury via ameliorating inflammatory response, oxidative stress, and improving autophagy through PI3K/Akt/mTOR signaling pathway in diabetic mice.

Schaftoside improves cerebral ischemia-reperfusion injury by enhancing autophagy and reducing apoptosis and inflammation through the AMPK/mTOR pathway

“…59 Ibrutinib reduced cerebral infarction volume, alleviated neurological impairment and CI/RI, and promoted autophagy by activating the PI3K/AKT/mTOR pathway in diabetic mice. 60 The results of our study confirmed that SS increases the LC3II/LC3I ratio and decreases p62 expression in MCAO rats and OGD/R-induced HT22 cells, which suggests an increase in autophagic flux.…”

EGCG protects the mouse brain against cerebral ischemia/reperfusion injury by suppressing autophagy via the AKT/AMPK/mTOR phosphorylation pathway

“…Basal autophagic activity exists in cells under physiological conditions, while the process turns more active induced by various stress events including CIRI and plays complex roles ( Wirawan et al, 2012 ). Some studies demonstrated that the activation of autophagy ameliorated CIRI ( Sun et al, 2020b ; Xu et al, 2020 ; Zhang B. et al, 2020 ; Chen et al, 2021 ; Jin et al, 2021 ; Yihao et al, 2021 ; Zha et al, 2021 ), while more research supported that the inhibition of autophagy activation exerted a neuroprotective effect in brain stroke ( Sun et al, 2020a ; Zhang et al, 2020b ; Li and Huang, 2020 ; Mei et al, 2020 ; Shi et al, 2020 ; Wang L. et al, 2020 ; Gu et al, 2021 ; Liu N. et al, 2021 ; Shao et al, 2021 ; Wang C. et al, 2021 ; Xu et al, 2021 ; Yao et al, 2021 ; Zhang et al, 2021 ; Zhao et al, 2021 ). Obviously, the controversial dual role of the induction of autophagy in the ischemic brain is still a hot topic in research and remains to be further investigated.…”

CircRNA CTNNB1 (circCTNNB1) ameliorates cerebral ischemia/reperfusion injury by sponging miR-96-5p to up-regulate scavenger receptor class B type 1 (SRB1) expression

“…Oxidative stress and inflammation are pronounced phenomena in IRI [ 30 ]. Therefore, regulating oxidative stress and inflammation is vital for cerebral IRI [ 31 , 32 ]. The BBB, which is composed of endothelial, astrocytes, and microglial cells, is responsible for the entry of inflammatory cells and influences the degree of brain injury and recovery [ 33 ].…”