Chemokine CCL2 contributes to BBB disruption via the p38 MAPK signaling pathway following acute intracerebral hemorrhage

Intracerebral hemorrhage (ICH) remains a devastating type of stroke that lacks an effective treatment. Recent evidence has demonstrated that CCL2 is involved in the blood-brain barrier (BBB) disruption and propagermanium (PG) as a CCL2 receptor inhibitor is neuroprotective in ischemic stroke. However, whether PG therapy exert effective role in acute ICH still unclear. In this study, our goal was to investigate the potential role of CCL2 and the effects of PG in ICH. Differentially expressed RNAs including CCL2 were detected in human ICH. CCL2 and the activation of p-p38 MAPK and AQP4 expression were analyzed in rats after ICH. Brain water content and BBB integrity as well as neurological function were also examined after PG administration. In addition, the mechanism by which CCL2-mediated BBB injury was further investigated by cell coculture. Our findings showed that PG could effectively reduce brain edema and improve neurobehavioral functions. p-p38 MAPK and AQP4 expression were significantly inhibited by PG in vivo and in vitro. To the best of our knowledge, this is the first demonstration of PG in neuroprotecting the BBB integrity by inhibition of CCL2-CCR2-p38 MAPK pathway following ICH, targeting CCL2 could be developed as a novel treatment for hemorrhagic stroke.