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Berbamine improves behavioral impairments in Huntington's disease mice models through inhibiting Src/AKT1/NFκB
Chunling Yuan1, Li Zheng2, Hongxia Hu3
1Department of Medicinal Chemistry, Pharmacy School, Jinzhou Medical University, No.40, Section 3, Songpo Road, Linghe District, Jinzhou 121001, China..
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.
