Berbamine improves behavioral impairments in Huntington's disease mice models through inhibiting Src/AKT1/NFκB signaling pathway and attenuating Src-mediated mitophagy suppression

Background Investigate the effects of berbamine (BBM) on alleviating motor and cognitive impairment in animal models of Huntington's disease (HD). Methods Intraperitoneal injection of 3-nitropropionic acid (3-NP) mice and B6-hHTT130-N transgenic mice were used as the HD models. We evaluated the anti-HD effect of BBM through behavioral experiments and employed molecular biological techniques, network pharmacology analysis, to test the potential mechanisms. Results BBM improved motor and cognitive impairment in 3-NP-injected and B6-hHTT130-N mice. BBM improved pathological damage in the brain, reduced the expression of mHTT in B6-hHTT130-N mice. BBM increased the ATP and mtDNA content, attenuated PINK1/Parkin-mediated mitophagy suppression. Furthermore, network pharmacology analysis, molecular docking and CETSA identified two targets: Src and AKT1. By using the Src inhibitor KX2–391, AKT inhibitor MK-2206 and NFκB inhibitor QNZ, we found that BBM showed a similar experimental results to Src inhibitor in Q74 plasmid transfected BV2 cells. BBM could inhibit the Src/AKT1/NFκB/NLRP3 signaling pathway-mediated neuroinflammation, and enhance PINK1/Parkin expression may through inhibiting Src. Conclusion BBM ameliorates motor and cognitive impairments in HD model mice through inhibition of neuroinflammation and mHTT expression, maintenance of mitochondrial function, which was mediated by inhibiting Src/AKT1/NFκB signaling pathway and attenuating Src-mediated mitophagy suppression.