Kv1.3 blockade alleviates white matter injury through reshaping M1/M2 phenotypes after intracerebral hemorrhage

Abstract Background: White matter injury (WMI) in basal ganglia usually induces long-term disability after intracerebral hemorrhage (ICH). Kv1.3 is highly expressed in microglia, and exaggerates neuroinflammation in neurodegenerative diseases. The present study investigated the role of inflammatory response resulting from Kv1.3 activation in WMI, as well as the effect of Kv1.3 blockade on microglia polarization after ICH. Methods: ICH was introduced in mice using autologous blood. The expression of Kv1.3 was determined using real-time quantitative polymerase chain reaction (RT-qPCR), immunoblot and immunostaining assays. Then, the effect of administration of 5-(4-Phenoxybutoxy) psoralen (PAP-1), a selectively pharmacological inhibitor of Kv1.3, on functional recovery was investigated using open field test (OFT) and basso mouse score (BMS). Next, the RT-qPCR, immunoblot and enzyme linked immunosorbent assay (ELISA) assays were performed to elucidate the changes of pro-inflammatory and anti-inflammatory factors around hematoma with PAP-1 application after ICH. Thereafter, the role of PAP-1 in regulating microglia polarization was examined through RT-qPCR, immunoblot and immunostaining assays. Results: After ICH, the expression of Kv1.3 was significantly increased in microglia around hematoma after ICH. The administration of PAP-1 markedly improved neurological outcomes through reducing the accumulation of pro-inflammatory cytokines and upregulating the deposition of anti-inflammatory and neurotrophic factors. The reason for this beneficial effect ascribes to facilitating microglia polarization into M2-like microglia. Conclusion: Kv1.3 blockade using PAP-1 obviously reduced the accumulation of pro-inflammatory cytokines and upregulated the deposition of anti-inflammatory and neurotrophic factors through facilitating microglia polarization into M2-like microglia. The present study provides evidence Kv1.3 blockade is suitable to mitigate WMI through facilitating microglia transformation into M2-like phenotype after ICH.