RESUMEN
Inflammatory reactions after acute intracerebral hemorrhage (AICH) contribute significantly to a poor prognosis. Liangxue Tongyu Prescription (LTP) has been proven to be clinically effective in treating AICH. Numerous studies have shown that LTP suppresses brain inflammatory damage in AICH, while the internal mechanisms underlying its action remain unclear. The aim of this study was to verify the anti-inflammatory effects of LTP on an AICH rat model and investigate the potential mechanisms. The AICH rat models were created by injecting autologous blood into the right caudate nucleus. LTP markedly decreased cerebral hematoma and brain water content and recovered from neurological deficits. Meanwhile, LTP prevented microglial activation and reduced the inflammatory reaction caused by pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß) and interleukin-6 (IL-6). Notably, the expression of cholecystokinin octapeptide (CCK-8) in the brain and intestine was increased by LTP or CCK-8 treatment. LTP further suppressed nuclear factor kappa B (NF-κB) in the brains of rats with AICH. Moreover, LTP increased the protein and mRNA expression of Occludin and Claudin-1 in the intestine and decreased the levels of lipopolysaccharide (LPS) and diamine oxidase (DAO) in serum. Furthermore, the results showed that LTP increased the protein and mRNA expression of Claudin-5 and zonula occludens-1 (ZO-1) in the brain. CCK-8 receptor antagonists increased the expression of NF-κB and the concentration of pro-inflammatory cytokines. These findings suggested that LTP attenuated neuroinflammation by increasing CCK-8 in the brain and intestine, and its mechanism might be related to alterations in the gut-brain axis (GBA).
RESUMEN
Aim: Chaihu-jia-Longgu-Muli-tang (CLM) is derived from "Shang Han Lun" and is traditionally prescribed for treating depression. However, there is still a lack of evidence for its antidepressant effects, and the underlying mechanism is also unclear. This study aimed to assess clinical evidence on the efficacy of CLM in patients with depression using a meta-analysis and to explore its underlying antidepressant molecular mechanisms via network pharmacology. Methods: Eight open databases were searched for randomized controlled trials (RCTs) comparing the effects of CLM alone or combined with serotonin-norepinephrine reuptake inhibitors (SNRIs) and selective serotonin reuptake inhibitors (SSRIs) in patients with depression, evaluating the total effective rate of the treatment group (CLM alone or combined with SSRIs/SNRIs) and the control group (SNRIs or SSRIs), and comparing changes in depression scale, anxiety scale, sleep scale, inflammation indicators and adverse effects. Subsequently, the active ingredients and target genes of CLM were screened through six databases. Then Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis and protein-protein interaction (PPI) network and topology analysis were performed. Finally, Molecular docking was applied to evaluate the binding affinity between components and predicted targets. Results: Twenty-four RCTs with a total of 2,382 patients were included. For the efficacy of antidepression and adverse effects, whether CLM alone or in combination with SSRIs/SNRIs, the treatment group has no inferior to that of the control group. Additionally, the intervention of CLM + SSRI significantly improved the symptoms of anxiety and insomnia, and reduced serum IL-6 and TNF-α levels. For network pharmacology, a total of 129 compounds and 416 intersection targets in CLM were retrieved. The interaction pathway between CLM and depression is mainly enriched in PI3K-Akt, JAK-STAT, and NF-κB signaling pathway, PIK3R1, MAPK3, and AKT1 may be the potential targets of Stigmasterol, ß-stiosterol, coumestrol. Conclusion: Compared to SSRIs/SNRIs alone, CLM is more effective and safe in treating depression. It not only significantly alleviates depressive mood, but improves symptoms such as anxiety and insomnia, with fewer side effects, especially in combination with SSRI. Its antidepressant mechanism may be correlated with the regulation of the PI3K/Akt signaling pathway and inhibiting inflammatory response.