Neuroprotective effects of hirudin against cerebral ischemia-reperfusion injury via inhibition of CCL2-mediated ferroptosis and inflammatory pathways

Cerebral ischemia-reperfusion injury (CIRI) is a leading cause of neurological impairment in stroke, primarily correlated to oxidative stress, inflammation, and ferroptosis. This study investigates the neuroprotective effects of hirudin on CIRI, focusing on its role in modulating neuronal survival, oxidative stress, and ferroptosis markers through inhibition of CCL2. A middle cerebral artery occlusion (MCAO) model in mice and an oxygen-glucose deprivation/reoxygenation (OGD/R) model in HT22 cells were used to simulate ischemic conditions. Hirudin significantly improved neurological function and reduced cerebral edema and infarct size in the MCAO model. In vitro, hirudin enhanced neuronal viability and reduced apoptosis in OGD/R-stimulated cells. Integrative network pharmacology and transcriptomic analysis identified CCL2 as a potential target of hirudin. Hirudin treatment suppressed CCL2 expression, which in turn reduced the TLR4/NF-κB signaling activation, thereby mitigating ferroptosis and inflammatory responses in ischemic neurons. Overexpression of CCL2 partially reversed these protective effects, underscoring its role in ischemic injury. These findings suggest that hirudin alleviates CIRI by modulating CCL2 and preventing ferroptosis, offering insights into its potential as a therapeutic agent for ischemic conditions.

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Cerebral ischemia-reperfusion injury (CIRI) is a leading cause of neurological impairment in stroke, primarily correlated to oxidative stress, inflammation, and ferroptosis.

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