Protective Effect of GM1 Attenuates Hippocampus and Cortex Apoptosis After Ketamine Exposure in Neonatal Rat via PI3K/AKT/GSK3β Pathway

et al. 2022

IJMS

Mangiferin (MF), a xanthone that extensively exists in many herbal medicines, processes significant activities of anti-inflammation and immunomodulation. The potential regulatory effect and mechanism of mangiferin on cell pyroptosis remain unclear. In this study, mouse bone-marrow-derived macrophages (BMDMs) were stimulated with 1 μg/mL LPS to induce cell pyroptosis and were treated with 10, 50, or 100 μg/mL MF for regulating pyroptosis. The cell supernatants TNF-α, IL-1β, IL-6, and IL-18 were detected by enzyme-linked immunosorbent assay (ELISA); gene expression of TNF-α, IL-1β, IL-6, IL-18, Caspase-1, Caspase-11, and gasdermin D (GSDMD) was tested by real-time polymerase chain reaction (RT-PCR), and protein expression levels of apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC), nod-like receptor protein-3 (NLRP3), caspase-1, caspase-11, GSDMD, and NF-κB were detected by Western blot. The results showed that MF significantly inhibited the secretion and gene expression of TNF-α, IL-6, IL-1β, and IL-18 that were elevated by LPS. Moreover, MF significantly suppressed the gene expression of Caspase-1, Caspase-11, and GSDMD, and decreased the protein levels of NLRP3, caspase-1, caspase-11, full-length GSDMD (GSDMD-FL), GSDMD N-terminal (GSDMD-N), and NF-κB. In conclusion, mangiferin has a multi-target regulating effect on inflammation and pyroptosis by inhibiting the NF-κB pathway, suppressing inflammatory caspase-mediated pyroptosis cascades, and reducing GSDMD cleavage in LPS-induced BMDMs.

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Anti-Inflammation and Anti-Pyroptosis Activities of Mangiferin via Suppressing NF-κB/NLRP3/GSDMD Signaling Cascades

Feng

Wei

et al. 2022

IJMS

“…Immunohistochemical analysis was performed as described previously [27]. Brie y, para n-embedded brain tissue slices were dewaxed with xylene, dehydrated with gradient alcohol, incubated with hydrogen peroxide, and sealed with goat serum.…”

Section: Immunohistochemistry Analysismentioning

confidence: 99%

Dexmedetomidine Alleviates Lipopolysaccharide-Induced Hippocampal Neuronal Apoptosis via Inhibiting the p38 MAPK/c-Myc/CLIC4 Signaling Pathway in Rats

Chen

et al. 2021

Mol Neurobiol

Dexmedetomidine (DEX) reportedly possessed multiple bioactivities. Here, we mainly investigated the neuroprotective role and detailed molecular mechanism of DEX against lipopolysaccharide (LPS)-induced hippocampal neurons apoptosis. In vivo, Sprague Dawley rats were administered with LPS (10 mg/kg) and/or DEX (30 µg/kg). We found that DEX improved LPS-induced hippocampal microstructure (necrosis and number reduction of neurons in the CA1 and CA3 regions) and ultrastructure (mitochondrial damage) lesions. DEX also attenuated LPS-induced hippocampal apoptosis by down-regulating the expression of mitochondrial apoptosis pathway-related proteins. Moreover, DEX prevented the activation of c-Myc/chloride intracellular channel 4 (CLIC4) pathway induced by LPS. Notably, DEX inhibited p38 MAPK pathway, not JNK and ERK. To further clarify whether DEX alleviated LPS-induced neuronal apoptosis through the p38 MAPK/c-Myc/CLIC4 pathway, PC12 cells were treated with p38 MAPK inhibitor SB203582 (10µM). As expected, DEX had the same effect as SB203582 in reducing the protein and mRNA expression of c-Myc and CLIC4. Furthermore, DEX and SB203582 diminished LPS-induced apoptosis, showing decreased Bax and Tom20 uorescent double-stained positive cells, reduced Annexin V-FITC/PI apoptosis rate, and lessened protein expression levels of Bax, cytochrome C, cleaved caspase-9 and cleaved caspase-3. Taken together, DEX attenuates LPS-induced hippocampal neuronal apoptosis by regulating the p38 MAPK/c-Myc/CLIC4 signaling pathway, which will provide new insights into the mechanism research and drug development of Alzheimer's disease and depression.

“…Ketamine-induced 7-day-old neurotoxicity rats were produced according to a previously reported method [ 31 , 32 ]. All rats were randomized into six groups: Con , the normal saline control group that received normal saline only.…”

Section: Methodsmentioning

confidence: 99%

“…Ketamine-induced 7-day-old neurotoxicity rats were produced according to a previously reported method [31,32]. All rats were randomized into six groups:…”

Section: Ketamine-induced Neurotoxicity Model and Drugs Treatmentmentioning

confidence: 99%

Blockade of the NLRP3/caspase-1 axis attenuates ketamine-induced hippocampus pyroptosis and cognitive impairment in neonatal rats

Bai

et al. 2021

J Neuroinflammation

Self Cite

Background Multiple studies have revealed that repeated or long-term exposure to ketamine causes neurodegeneration and cognitive dysfunction. Pyroptosis is an inflammatory form of programmed cell death that has been linked to various neurological diseases. However, the role of NLRP3/caspase-1 axis-related pyroptosis in ketamine-induced neurotoxicity and cognitive dysfunction remains uncertain. Methods To evaluate whether ketamine caused NLRP3/caspase1-dependent pyroptosis, flow cytometry analysis, western blotting, ELISA test, histopathological analysis, Morris water maze (MWM) test, cell viability assay, and lactate dehydrogenase release (LDH) assay were carried out on PC12 cells, HAPI cells, and 7-day-old rats. In addition, the NLRP3 inhibitor MCC950 or the caspase-1 inhibitor VX-765 was used to investigate the role of the NLRP3/caspase-1 axis in ketamine-induced neurotoxicity and cognitive dysfunction. Results Our findings demonstrated that ketamine exposure caused cell damage and increased the levels of pyroptosis in PC12 cells, HAPI cells, and the hippocampus of neonatal rats. After continuous exposure to ketamine, targeting NLRP3 and caspase-1 with MCC950 or VX765 improved pyroptosis, reduced neuropathological damages, and alleviated cognitive dysfunction. Conclusion NLRP3/Caspase-1 axis-dependent pyroptosis is involved in ketamine-induced neuroinflammation and cognitive dysfunction, and it provides a promising strategy to treat ketamine-related neurotoxicity.