Catalpol rescues LPS-induced cognitive impairment via inhibition of NF-Κb-regulated neuroinflammation and up-regulation of TrkB-mediated BDNF secretion in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Septic-associated encephalopathy (SAE) is a key manifestation of sepsis. Nevertheless, specific treatment for SAE is still lacking. Catalpol is an active component derived from Rehmanniae Radix, and has been demonstrated to be a potential neuroprotective agent. However, its effect on SAE still needs to be fully explored. AIM: To address the benefits of catalpol on post-sepsis cognitive deterioration and related mechanisms. MATERIALS AND METHODS: Novel object recognition test, temporal order task, histopathology, and immunochemistry were applied to address the benefits of catalpol on LPS-triggered post-sepsis cognitive decline in mice. Xuebijing injection (10 ml/kg) has been utilized as a positive control in the above animal studies. After treatment, the catalpol content in the hippocampus was determined using LC-MS/MS. Finally, the mechanisms of catalpol were further assessed in BV2 and PC12 cells in vitro using Western blot, RT-PCR, flow cytometry, molecular docking tests, thermal shift assay, transmission electron microscopy, and immunofluorescence analysis. RESULTS: Behavior tests showed that catalpol therapy could lessen the cognitive impairment induced by LPS damage. HE, Nissl, immunofluorescence, transmission electron microscopy, and Golgi staining further reflected that catalpol treatment could restore lymphocyte infiltration, blood-brain barrier (BBB) degradation, and the decreasing complexity of dendritic trees. According to LC-MS/MS analysis, catalpol had a 136 ng/mg concentration in the hippocampus. In vitro investigation showed that catalpol could inhibit microglia M1 polarization via blocking NF-κB phosphorylation, translocation and then reducing inflammatory cytokine release in BV2 microglia cells. Brain-derived neurotrophic factor (BDNF) release up-regulation and TrkB pathway activation were observed in the catalpol treatment group in vivo and in vitro. The effect of catalpol on enhancing BDNF expression was inhibited by the specific inhibitor of TrkB (GNF-5837) in PC12 cells. Further molecular docking tests showed that catalpol formed weak hydrophobic bonds with TrkB. Besides, thermal shift assay also reflected that catalpol incubation caused a considerable change in the melting temperature of the TrkB. CONCLUSION: Catalpol alleviates LPS-triggered post-sepsis cognitive impairment by reversing neuroinflammation via blocking the NF-κB pathway, up-regulating neurotrophic factors via the activation of TrkB pathway, and preserving BBB integrity.

Blueberry anthocyanin­enriched extract ameliorates transverse aortic constriction­induced myocardial dysfunction via the DDAH1/ADMA/NO signaling pathway in mice.

Blueberry anthocyanin­enriched extract (BAE) has been demonstrated to protect against cardiovascular diseases by activating multiple target genes. The present study investigated the effects of BAE on transverse aortic constriction (TAC)­induced myocardial dysfunction in mice and explored its possible molecular mechanisms. A total of 30 male mice were divided randomly into control, TAC and TAC + BAE groups. Mice in the TAC + BAE groups were administered BAE by oral gavage for 6 consecutive weeks. Myocardial dysfunction was assessed using echocardiogram, histopathology, TUNEL assay, immunofluorescence staining, reverse transcription­quantitative PCR and western blot analysis. The results demonstrated that BAE treatment significantly ameliorated heart weight, left ventricular weight, myocardial dysfunction, left ventricular hypertrophy and fibrosis. In addition, BAE treatment alleviated TAC­induced inflammation, oxidative stress and apoptosis. Notably, BAE treatment markedly reduced asymmetric dimethylarginine (ADMA) concentration and significantly increased dimethylarginine dimethylaminohydrolase 1 (DDAH1) expression and nitric oxide (NO) production. The present data indicated that BAE treatment ameliorated TAC­induced myocardial dysfunction, oxidative stress, inflammatory response and apoptosis via the DDAH1/ADMA/NO signaling pathway.