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.