开玄解毒核心方通过调控HPA轴与神经炎症缓解束缚应激加重的IMQ诱导银屑病样皮损OA

Objective:To investigate the ameliorative effect and potential mechanisms of Kaixuan Jiedu core prescription(KXJD)on imiquimod(IMQ)-combined restraint stress-induced psoriasis-like skin lesions in mice.Methods:A total of 36 C57BL/6J mice were randomly assigned to six groups(n=6 per group):Normal group,restraint stress blank group,model group,restraint stress model group,KXJD group(30.42 g·kg-1),and methotrexate group(0.001 g·kg-1).Psoriasis-like lesions were induced by topical IMQ application combined with restraint stress.After 5 days of intervention,the severity of skin lesions was evaluated using the Psoriasis Area and Severity Index(PASI).The following parameters were assessed:Hypothalamic-pituitary-adrenal(HPA)axis-related hormones,including adrenocorticotropic hormone(ACTH),corticotropin-releasing hormone(CRH),and corticosterone(CORT),central neuronal markers,including neuronal nuclei antigen(NeuN),microtubule-associated protein 2(MAP2),and beta Ⅲ-tubulin(β-Ⅲ tubulin),microglial activation markers,including ionized calcium-binding adapter molecule-1(Iba-1)and cluster of differentiation 11b(CD11b),and skin nerve fiber markers,including protein gene product 9.5(PGP9.5)and serotonin(5-HT),as well as the expression levels of inflammatory cytokines tumor necrosis factor-alpha(TNF-α),interleukin-6(IL-6),and interleukin-1 beta(IL-1β).Results:Compared with the normal group,both the model group and the restraint stress model group exhibited more severe psoriasis-like skin lesions,with significantly elevated serum levels of ACTH,CRH,and CORT(P<0.01).The expression of glucocorticoid receptor(GR)and corticotropin-releasing hormone receptor 1(CRHR1)in the skin was significantly downregulated.The expression of NeuN,MAP2,β-Ⅲ tubulin,Iba-1,and CD11b in the hypothalamus and hippocampus was significantly upregulated,suggesting abnormal changes in neuronal number or structure and aberrant activation of glial cells(P<0.05,P<0.01).In addition,the expression of PGP9.5 and 5-HT in the skin,as well as the mRNA levels of TNF-α,IL-6,and IL-1β were all markedly elevated(P<0.05,P<0.01).Compared with the model group,the restraint stress model group showed further exacerbation in most parameters.Compared with the restraint stress model group,the KXJD group exhibited significantly reduced PASI scores(P<0.01),significantly decreased serum CRH,ACTH,and CORT levels(P<0.05,P<0.01),upregulated skin GR and CRHR1 expression,inhibited abnormal neuronal changes and microglial activation in the hypothalamus and hippocampus,attenuated skin nerve fiber hyperplasia and amine signaling molecule release,and significantly reduced pro-inflammatory cytokine mRNA expression(P<0.05,P<0.01).Conclusion:Kaixuan Jiedu Core prescription can effectively ameliorate IMQ combined with restraint stress-induced psoriasis-like skin lesions in mice by modulating HPA axis function,inhibiting central neuropathological changes,and attenuating skin nerve fiber hyperplasia,amine signaling molecule(5-HT)release and local inflammatory responses.