Nuciferine ameliorates blood-brain barrier disruption post-ischemic stroke via inhibiting the JAK2/STAT3 pathway

Ischemic stroke frequently results in the compromise of the blood-brain barrier (BBB), a pathological occurrence strongly linked to the impairment of cerebral microvascular endothelial cells and the disintegration of tight junction (TJ) proteins. Nuciferine, a naturally occurring aporphine alkaloid extracted from the leaves of Nelumbo nucifera, exhibits favorable pharmacokinetic characteristics, including the capacity to traverse the BBB, and has demonstrated neuroprotective potential in IS models. Nevertheless, the specific mechanisms by which nuciferine modulates BBB integrity following ischemia, and the molecular pathways involved, remain inadequately understood.

This study probed into the protective function of nuciferine against BBB disruption following IS and the molecular pathways involved in its therapeutic action.

In vivo, a photothrombotic focal cerebral ischemia mouse model was established and evaluated through neurological scoring, blood flow measurement, and 2,3,5-triphenyltetrazolium chloride staining. BBB disruption was assessed utilizing Evans Blue dye and endogenous immunoglobulin G extravasation. nuciferine (10, 20, 40 mg/kg, intragastric administration, daily for 7 days) was administered post-ischemia. In vitro, oxygen-glucose deprivation (OGD, 2 h)-induced bEnd.3 cell model was employed and treated with nuciferine (10, 20, and 40 μM, 24 h) to uncover the related mechanisms.

Our findings revealed that nuciferine effectively preserved BBB integrity and prevented cerebral edema post-photothrombotic. Mechanistically, nuciferine restored the expression of ZO-1, occludin, and claudin-5, both in photothrombotic and OGD models. Meanwhile, it showed the protective effect on OGD-induced endothelial cells injury by inhibiting apoptosis and mitochondrial dysfunction. Importantly, nuciferine targeted Janus kinase 2 and suppressed p-JAK2 and p-STAT3 in IS model.

Our findings present novel evidence that nuciferine improves the BBB integrity following IS through blocking the JAK2/STAT3 pathway. Through demonstrating the targeted suppression of JAK2 activation by nuciferine, this work contributes to a more nuanced understanding of how this pathway influences endothelial barrier function in ischemic conditions. Our results offer a conceptual basis for the continued exploration of Nuciferine as a potential therapeutic agent to address BBB dysfunction in the post-stroke setting.