Poliumoside alleviates microglia-mediated inflammation and blood-brain barrier disruption via modulating the polarization of microglia after ischemic stroke in mice

Background

Ischemic stroke remains a life-threatening condition with limited therapeutic options. Microglia-mediated neuroinflammation critically exacerbates acute ischemic injury. The active compound poliumoside (Pol) in Callicarpa kwangtungensis Chun exhibits significant anti-inflammatory effects. The therapeutic potential of Pol for ischemic stroke remains unknown and promising.

Purpose

The current study aimed to investigate the effect of Pol on acute ischemic stroke in mice, and to elucidate the underlying mechanisms.

Study design and methods

Ischemic stroke mice model was induced by transient middle cerebral artery occlusion model (tMCAO). Pol was administered by intraperitoneal injection after stroke. Neurological deficits were monitored up to 3 days after stroke. Microglial polarization, and microglia-associated inflammatory cytokines and blood-brain barrier (BBB) integrity were detected in the peri‑infarct cortex at day 1 after stroke. RNA-seq analysis was performed to identify potential pathways recruited by Pol. Primary cortical neuron, BV2 microglia cell lines and mouse brain microvascular endothelial cell lines(bEnd.3) were employed to explore the underlying mechanism in vitro.

Results

Compared with the tMCAO group, Pol significantly alleviated neurological deficits and reduced infarct size in mice. In vitro and in vivo experiments demonstrated that Pol regulates microglial polarization, down-regulates inflammatory factor levels (IL-6 and TNF-α), and attenuates inflammation-mediated BBB damage while maintaining tight junction proteins expression (ZO-1, claudin-5, occludin). Through investigation of the underlying mechanism combined with RNA-seq analysis and experimental results, we established that Pol down-regulated the JAK/STAT3 pathway both in vitro and in vivo, which was corroborated by the use of the JAK inhibitor tofacitinib.

Conclusion

Pol regulates microglial polarization in ischemic stroke by down-regulating JAK/STAT3 signaling pathway, alleviating the microglia-mediated inflammatory response and the destruction of blood-brain barrier.