Cumulative evidence suggests that pyroptosis, a new sort of programmed cell death, is closely related to cerebral ischemia/reperfusion (I/R) injury. Our previous studies have testified that vagus nerve stimulation (VNS) was involved in many different neuroprotective and neuroplasticity pathways via α7 nicotinic acetylcholine receptor (α7nAchR), a vital node of the cholinergic anti-inflammatory pathway during cerebral I/R injury. We aimed to determine the neuroprotective effects of VNS through α7nAchR-mediated inhibition of pyroptosis. Focal cerebral ischemic stroke rat models were obtained by middle cerebral artery occlusion for 120 min. Expression of the NLRP3 inflammasome was evaluated using western blotting and immunofluorescence (IF) staining. The neurological deficit score, infarct volume, TUNEL staining findings, transmission electron microscopy findings, and expression of inflammatory cytokines were assessed 3 days after I/R injury. Our findings suggested that the protein expression levels of NLRP3, GSDMD-N, cleaved caspase-1, and ASC gradually increased until they peaked on day 3 after I/R injury. VNS inhibited the expression of pyroptosis-related molecules and decreased the number of pyroptotic cells and membrane pores. Administration of α7nAchR-antagonist and agonist helped in further assessment of the role of α7nAchR in pyroptosis. α7nAchR-agonist mimicked VNS’s neuroprotective effects on the improvement of neurological deficits, the reduction of infarct volumes, and the inhibition of neuronal pyroptosis after cerebral I/R injury. Conversely, the neuroprotection provided by VNS could be reversed by the administration of α7nAchR-antagonist. In conclusion, VNS-induced neuroprotection via inhibition of neuronal pyroptosis was α7nAchR-dependent, highlighting the pivotal role of α7nAChR in suppressing cellular pyroptosis and neuroinflammation. These findings may allow a better understanding of treatment principles for cerebral I/R injury.

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Background 7,8-dihydroxyflavone (7,8-DHF), a selective agonist of tropomyosin related kinase receptor B (TrkB), is known to exert protective effects in neurodegenerative diseases. However, the role of 7,8-DHF in TrkB signaling after ischemic stroke has remained elusive. Methods In the vitro model of ischemic stroke, we investigated the neuroprotective effect of 7,8-DHF through activation of TrkB signaling. Neurons subjected to oxygen and glucose deprivation/reperfusion were treated with the protein kinase inhibitor K252a and a knockdown of TrkB. Cell counting kit-8 (CCK-8) assay, Flow Cytometric Analysis (FACS), TdT-mediated dUTP nick end labeling (TUNEL) assay were conducted for measuring cell viability and numbers of apoptotic cells. And apoptosis-associated proteins were analyzed by Western blotting. Results Compared with the Control group, OGD/R group revealed lower cell viability by CCK-8 assay FACS and TUNEL assay showed increased rates of neuronal apoptosis. However, 7,8-DHF treatment increased cell viability and reduced neuronal apoptosis. Western blotting indicated upregulated Bax and cleaved caspase-3 and but downregulated Bcl-2 following OGD/R. Whereas 7,8-DHF treatment downregulated Bax and cleaved caspase-3 but upregulated Bcl-2. These changes were accompanied by a significant increase in the phosphorylation of TrkB and Akt following 7,8-DHF administration. However, the administration of K252a and knockdown of TrkB could alleviate those effects. Conclusion Our study demonstrates that activation of TrkB signaling by 7,8-DHF protects neurons against OGD/R injury via the TrkB/Akt pathway, which provides the evidence for the role of TrkB signaling in OGD-induced neuronal damage and may become a potential therapeutic target for ischemic stroke.

Post-stroke depression (PSD) is the most common and severe neuropsychiatric complication after stroke. However, the molecular mechanism of PSD is still unclear. Previous studies have identified peripheral tissues metabolites associated with PSD using metabolomics techniques. We searched and systematically summarized metabolites that may be involved in metabolic changes in peripheral tissues of patients with PSD from the Metabolite Network of Depression Database (MENDA) and other biomedical databases. MetaboAnalyst5.0 software was used for pathway analysis and enrichment analysis of differential metabolites, and subgroup analyses were performed according to tissue types and metabolomics techniques. We identified 47 metabolites that were differentially expressed between patients with and without PSD. Five differential metabolites were found in both plasma and urine, including L-glutamic acid, pyroglutamic acid, palmitic acid, L-phenylalanine, and L-tyrosine. We integrated these metabolites into metabolic pathways, and six pathways were significantly altered. These pathways could be roughly divided into three modules including amino acid metabolism, nucleotide metabolism, and glucose metabolism. Among them, the most significantly altered pathway was “phenylalanine metabolism” and the pathway containing the most associated molecules was “aminoacyl-tRNA biosynthesis”, which deserve further study to elucidate their role in the molecular mechanism of PSD. In summary, metabolic changes in peripheral tissues are associated with PSD, especially the disruption of “phenylalanine metabolism” and “aminoacyl-tRNA biosynthesis” pathways. This study provides clues to the metabolic characteristics of patients with PSD, which may help to elucidate the molecular pathogenesis of PSD.