黄连解毒汤通过CD22/SHP-1/p-Akt信号通路调控小胶质细胞表型改善血管性痴呆髓鞘损伤和激越行为OA

Objective:To investigate the mechanisms by which Huanglian Jiedutang(HLJDT)modulates microglial(MG)phenotypes through the sialic acid-binding Ig-like lectin 2(SIGLEC2/CD22)/Src-homology-2-domain-containing protein tyrosine phosphatase-1(SHP-1)/phosphorylated protein kinase B(p-Akt)signaling pathway,thereby promoting myelin repair and alleviating agitation-like behaviors in vascular dementia(VAD).Methods:Sixty C57BL/6J mice were randomly assigned to a sham(normal)group,model group,HLJDT low-,medium-,and high-dose groups(2.5,5,and 10 g·kg-1·d-1),and a risperidone group(2 mg·kg-1·d-1),with 10 mice per group.VAD was induced by bilateral common carotid artery stenosis(BCAS).From day 42,mice received drug interventions for 2 weeks.Agitation-like behaviors were assessed using the resident-intruder test.After behavioral testing,ventrolateral part of the ventromedial hypothalamus(VMHvl)tissues were collected.Western blot was used to measure protein levels of myelin oligodendrocyte glycoprotein(MOG),myelin basic protein(MBP),proteolipid protein(PLP),inducible nitric oxide synthase(iNOS),arginase-1(Arg1),CD86,CD206,and CD22,SHP-1,and p-Akt.Immunofluorescence was used to evaluate myelin-associated glycoprotein(MAG)intensity and the proportion of iNOS+/ionized calcium-binding adapter molecule 1(Iba1)+cells.ELISA was used to detect tumor necrosis factor-α(TNF-α),interleukin(IL)-6,and IL-1β.Results:Compared with the normal group,the model group exhibited markedly increased biting and aggressive behaviors and shortened attack latency(P<0.01).MOG,MBP,and PLP protein levels and MAG fluorescence intensity were significantly reduced(P<0.05,P<0.01).INOS and CD86 expression and TNF-α,IL-6,and IL-1β levels were significantly elevated(P<0.01).CD22 and SHP-1 expression increased significantly(P<0.01),whereas p-Akt expression decreased(P<0.01).Compared with the model group,the medium-and high-dose HLJDT groups and the risperidone group showed markedly reduced biting and aggression(P<0.05,P<0.01)and prolonged attack latency(P<0.01).MOG,MBP,and PLP levels and MAG fluorescence intensity were significantly increased(P<0.05,P<0.01).INOS,CD86,TNF-α,IL-6,and IL-1β levels decreased significantly(P<0.05,P<0.01).CD22 and SHP-1 expression decreased,while p-Akt expression increased significantly(P<0.05,P<0.01).Conclusion:HLJDT may modulate CD22/SHP-1/p-Akt signaling in the VMHvl,promote the shift of MG toward an anti-inflammatory and phagocytic phenotype,enhance myelin repair,and improve agitation-like behaviors in VAD mice.