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 pathway-related 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.

KEYWORDS:

• Ibrutinib
• cerebral ischemia/reperfusion injury
• diabetes
• autophagy
• pi3k/akt/mTOR pathway

Highlights

• Ibrutinib improved the PC12 cell viability with H/R injury in the high glucose

• Ibrutinib exerted neuroprotective effects against diabetic cerebral I/R injury

• Ibrutinib treatment improved autophagy through the PI3K/Akt/mTOR pathway

• Ibrutinib ameliorated cerebral ischemia/reperfusion injury in diabetic mice

Acknowledgements

This work was financially supported by the Natural Science Foundation of Shanghai of China, No. 17ZR1425800 (to KYL) and the Key Disciplines Construction Foundation of Health Commission of Pudong New District of China, No. PWZxk2017-25 (to KYL).

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data Availability

All data generated or analyzed during this study are included in this article.

Author contributions

Lei Jin and Yun Mo designed research and wrote the paper; Lei Jin, Yun Mo, Er-Li Yue, Yuan Liu, and Kang-Yong Liu performed research and analyzed data.