Harmine-induced disruption of the blood-brain barrier via excessive mitophagy in zebrafish

Stroke is a serious condition with sudden onset, high severity, and significant rates of mortality and disability, ranking as the second leading cause of death globally at 11.6%. Hemorrhagic stroke, characterized by non-traumatic rupture of cerebral vessels, can cause secondary brain injury such as neurotoxicity, inflammation, reactive oxygen species, and blood-brain barrier (BBB) damage. The integrity of the BBB plays a crucial role in stroke outcomes, as its disruption can exacerbate injury. Harmine, a natural β-carboline alkaloid, has been studied for various pharmacological effects, including its potential benefits in protecting cardiac and cognitive functions. However, its impact on cerebrovascular conditions, particularly in the context of stroke, remains underexplored. This study investigates harmine's effects on BBB integrity and its role in inducing cerebral hemorrhage in zebrafish. We found that harmine disrupts BBB permeability, leading to cerebral hemorrhage through modulation of tight junction protein Claudin-5 and cytoskeletal protein F-actin expression. Furthermore, harmine altered mitochondrial morphology, causing structural imbalance, excessive mitophagy, and cell death. Together, these data indicate that harmine can induce BBB damage and intracerebral hemorrhage in zebrafish, and provide a possible mechanism and explanation for this effect.