PINK1 agonist MTK458 attenuates cerebral edema by protecting blood-brain barrier integrity in intracerebral hemorrhage mice

Secondary blood-brain barrier (BBB) disruption and vasogenic edema drive neurological deterioration after intracerebral hemorrhage (ICH), but targeted therapies remain lacking. PTEN-induced putative kinase 1 (PINK1) is a neuroprotective kinase, yet its role in ICH-induced BBB damage is unclear. This study investigates whether MTK458, a novel PINK1 agonist, protects BBB integrity after ICH and elucidates mechanisms.

An ICH mouse model was employed and MTK458 (10, 50, 100 mg/kg) were administered intraperitoneally. The effects of MTK458 were evaluated using brain water content measurements, BBB integrity detection and neurological impairment assessments. A hemoglobin-stimulated BV2 microglia-bEnd.3 endothelial cell co-culture system was established to assess the effects of MTK458 on microglia-mediated tight junctions loss of BBB in vitro.

PINK1 expression was significantly downregulated after ICH, with its lowest level observed at 72 h. MTK458 (50 mg/kg) reduced Evans blue extravasation and brain edema, attenuated microglial activation and neuroinflammation, decreased neuronal apoptosis, and improved both acute and subacute neurological function in vivo. MTK458 reversed hemoglobin-induced PINK1 loss in BV2 cells and reduced BV2-mediated damage to bEnd.3 tight junctions in vitro.

Mechanistically, MTK458 restored microglial PINK1 expression, inhibited ROS production and cytosolic mtDNA leakage, and thereby suppressed activation of the cGAS-STING-NF-κB signalling pathway, leading to MMP-9 suppression and ZO-1/occludin protection. Consistent with this, the STING agonist dimeric amidobenzimidazole (diABZI) reversed the inhibitory effect of MTK458 on MMP-9, abolished its protection of tight junctions, and compromised BBB integrity. MTK458 activates PINK1, inhibits the cGAS-STING-NF-κB pathway, reduces microglial MMP-9 release, protects BBB integrity, alleviates edema and neuroinflammation, and improves neurological outcomes, providing a novel therapeutic strategy for secondary ICH injury.

We thank the Central Laboratory of the Second Affiliated Hospital of Chongqing Medical University for providing experimental help. This study was supported by grants from Chongqing Natural Science Foundation Project (cstc2021jcyj-msxmX0036), Project of Second Affiliated Hospital of Chongqing Medical University (kryc-yq-2216, kryc-gg-2110), Chongqing Science and Health Joint Chinese Medicine Research Project (2019ZY023458), Chunhui Project Foundation of the Education Department of China (HZKY20220218). Department of Neurosurgery, the Second Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China Ping Ma, Jinghong Yang, Guotao Zeng, Xiaowen Xu, Ning Huang & Yuan Cheng Encephalopathy Department of Qianjiang District Traditional Chinese Medicine Hospital, Chongqing, People’s Republic of China Correspondence to Jun Tang or Yuan Cheng.

The authors declare no competing interests. The study was approved by the Institutional Animal Care and Use Committee of The Second Affiliated Hospital of Chongqing Medical University. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.