2. Academic Validation
  3. BL-918 alleviates oxidative stress in rats after subarachnoid hemorrhage by promoting mitophagy through the ULK1/PINK1/Parkin pathway

BL-918 alleviates oxidative stress in rats after subarachnoid hemorrhage by promoting mitophagy through the ULK1/PINK1/Parkin pathway

  • Free Radic Biol Med. 2024 Nov 1:224:846-861. doi: 10.1016/j.freeradbiomed.2024.10.261.
Jinshuo Yang 1,  Qiaowei Wu 1,  Yuchen Li 1,  Yongzhi Zhang 1,  Shuai Lan 1,  Kaikun Yuan 1,  Jiaxing Dai 1,  Bowen Sun 1,  Yuxiao Meng 1,  Shancai Xu 2,  Huaizhang Shi 3
Affiliations

Affiliations

  • 1 Department of Neurosurgery, First Affiliated Hospital of Harbin Medical University, Harbin, China.
  • 2 Department of Neurosurgery, First Affiliated Hospital of Harbin Medical University, Harbin, China. Electronic address: xushancai@163.com.
  • 3 Department of Neurosurgery, First Affiliated Hospital of Harbin Medical University, Harbin, China. Electronic address: huaizhangshi@163.com.
PMID: 39368518 DOI: 10.1016/j.freeradbiomed.2024.10.261
Abstract

Background and purpose: Oxidative stress plays a critical role in early brain injury (EBI) following subarachnoid hemorrhage (SAH). The small molecule ULK1 agonist, BL-918, demonstrated neuroprotective effects in Other central nervous system diseases; however, its role in SAH has not yet been explored. This study aimed to evaluate whether BL-918 could provide neuroprotective effects in rats following SAH.

Methods: An SAH model was established in Sprague-Dawley rats using endovascular perforation. BL-918 was administered intraperitoneally after SAH, while the ULK1 Inhibitor SBI was given intraperitoneally prior to SAH modeling. PINK1 siRNA was administered into the lateral ventricle before SAH induction. The neuroprotective effects and mechanisms of BL-918 were assessed through SAH grading, brain water content measurement, blood-brain barrier permeability, neurobehavioral tests, Western blot, immunofluorescence, TUNEL staining, DHE staining, and transmission electron microscopy (TEM).

Results: After SAH, the expression levels of p-ULK1, PINK1, Parkin, and LC3Ⅱ increased, peaking at 24 h post-SAH. BL-918 treatment improved neurological function in rats, reduced brain water content and blood-brain barrier permeability, and exhibited anti-oxidative stress and anti-apoptotic effects. Western blot analysis revealed that BL-918 increased the expression of p-ULK1, PINK1, Parkin, LC3Ⅱ, Bcl-xL, and Bcl-2 while inhibiting the expression of Bax and Cleaved Caspase-3. Oxidative stress-related indicators showed that BL-918 alleviated oxidative stress. Immunofluorescence and TEM results demonstrated that BL-918 promoted Mitophagy and preserved mitochondrial morphology. Furthermore, the positive effects of BL-918 were reversed by SBI and PINK1 siRNA, respectively.

Conclusion: BL-918 improved both short-term and long-term neurological impairments in rats after SAH and reduced oxidative stress by promoting Mitophagy, at least partially through the ULK1/PINK1/Parkin signaling pathway.

Keywords

Early brain injury; Mitophagy; Oxidative stress; Subarachnoid hemorrhage.

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