Exploring the Protective Effects of Guangzao Qiwei Pills on Cardiac and Cerebral Injury in Schizophrenia Model Rats and the PI3K-AKT Signaling Pathway Mechanism Based on the Brain-heart Axis Theory of Mongolian Medicine

OBJECTIVE To investigate the mechanism of action of Guangzao Qiwei Pills(GZ-7) in rats with an MK-801-induced schizophrenia(SCZ) model.

METHODS Using network pharmacology tools, the active components, core targets, and signaling pathways involved in the therapeutic effects of GZ-7 on SCZ was identified. Sixty SD rats were randomly divided into the following groups: Control group, model group, positive control(risperidone)group, low-dose GZ-7 group(GZ7-L), medium-dose GZ-7 group(GZ7-M) and high-dose GZ-7 group(GZ7-H). The model group received continuous intraperitoneal injections of MK-801 0.2 mg·kg⁻¹ for 14 d. After confirming successful modeling, the positive control group was administered a risperidone suspension at 0.36 mg·kg⁻¹ via oral gavage, while the GZ7-L, GZ7-M, and GZ7-H groups were administered GZ-7 suspensions at 0.27, 0.54, and 1.08 g·kg⁻¹, respectively; the control and model groups were administered an equal volume of distilled water. Treatment was administered continuously for 30 d. After the treatment period, behavioral changes in the rats were assessed; histopathological changes in the heart and hippocampus tissues were examined using HE staining; serum levels of interleukin-1β(IL-1β), interleukin-2(IL-2), interleukin-6(IL-6), tumor necrosis factor-α(TNF-α), and creatine kinase isoenzyme MB(CK-MB) were measured by ELISA; vascular endothelial growth factor(VEGF) expression was detected by immunohistochemistry; and phosphorylation levels of the phosphatidylinositol 3-kinase/protein kinase B(PI3K-AKT) signaling pathway in heart and hippocampus tissues were analyzed by Western blotting.

RESULTS Network pharmacology analysis identified 588 relevant targets of GZ-7 against SCZ, with core targets including AKT1, SRC, and EGFR; biological process(BP) enrichment analysis indicated that SCZ is associated with the positive regulation of the MAPK cascade and protein phosphorylation; cellular component enrichment analysis showed that SCZ is associated with cellular components such as the plasma membrane, dendrites, and synapses; molecular function enrichment analysis indicated that SCZ is associated with molecular functions such as protein tyrosine kinase activity, ATP binding, and protein kinase activity; Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analysis revealed that SCZ is associated with neuroactive ligand-receptor interactions, the CAMP signaling pathway, and the PI3K-AKT signaling pathway. Animal experimental results demonstrated that, compared with the normal group, rats in the model group exhibited increased levels of stereotyped behavior, ataxia scores, escape latency, IL-1β, IL-2, IL-6, TNF-α, and CK-MB, as well as increased VEGF expression(P<0.01); the number of crossings of the original platform, as well as the expression of P-PI3K, PI3K, p-AKT, and AKT proteins in cardiac and hippocampal tissues were reduced(P<0.01); severe pathological damage was observed in cardiac and hippocampal tissues. Compared with the model group, rats in the positive control group and the GZ7-H group exhibited reduced levels of stereotyped behavior, ataxia scores, escape latency, IL-1β, IL-2, IL-6, TNF-α, CK-MB, and VEGF expression(P<0.05 or P<0.01); increased number of crossings of the original platform, and increased expression of P-PI3K, PI3K, p-AKT, and AKT proteins in cardiac and hippocampal tissues(P<0.05 or P<0.01). In the GZ7-M group, there were reductions in stereotyped behavior, ataxia scores, escape latency, and levels of IL-2, IL-6, TNF-α, CK-MB, and VEGF expression(P<0.05 or P<0.01); there was an increased number of crossings of the original platform and increased expression of p-AKT and AKT proteins in cardiac and hippocampal tissues(P<0.05 or P<0.01); in the GZ7-L group, stereotyped behavior, ataxia scores, escape latency, IL-6, TNF-α levels, and VEGF expression were reduced(P<0.05 or P<0.01), the number of crossings of the original platform and the expression of p-AKT and AKT proteins in hippocampal tissue increased(P<0.05); pathological damage in cardiac and hippocampal tissues was reduced in the GZ-7 group and the positive control group.

CONCLUSION GZ-7 exerts reparative and protective effects on myocardial cell and hippocampal neuronal damage in a rat model of schizophrenia(SCZ) by activating the PI3K-AKT signaling pathway, thereby improving learning, memory, and cognitive function. The heart can serve as an important target organ for the pathogenesis and treatment of SCZ.