Low-dose ketamine inhibits neuronal apoptosis and neuroinflammation in PC12 cells via α7nAChR mediated TLR4/MAPK/NF-κB signaling pathway

Zhao, Jinghua; Zhang, Ruxin; Wang, Wei; Jiang, Sheng; Liang, Huimei; Chen, Guo; Qi, Jingyi; Zeng, Huan; Song, Houhui

doi:10.1016/j.intimp.2023.109880

Cited by 8 publications

(8 citation statements)

References 33 publications

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“…Conversely, low-dose ketamine has been shown to inhibit the TLR4/MAPK/NF-κB pathway, thereby exerting a protective effect against neuroinflammation and neuronal apoptosis in PC12 cells. 22 Collectively, these findings support the role of the TLR4/MyD88/p38 MAPK axis in mediating the ameliorative effects of esketamine in aged mice with POCD.…”

Section: Discussionsupporting

confidence: 60%

“…Consistent with this mechanism, the administration of esketamine and p38 MAPK activator to aged POCD mice resulted in severe cognitive dysfunction, enhanced neuronal apoptosis, and elevated inflammatory levels. Conversely, low‐dose ketamine has been shown to inhibit the TLR4/MAPK/NF‐κB pathway, thereby exerting a protective effect against neuroinflammation and neuronal apoptosis in PC12 cells 22 . Collectively, these findings support the role of the TLR4/MyD88/p38 MAPK axis in mediating the ameliorative effects of esketamine in aged mice with POCD.…”

Section: Discussionmentioning

confidence: 59%

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Role and mechanism of esketamine in improving postoperative cognitive dysfunction in aged mice through the TLR4/MyD88/p38 MAPK pathway

Xu,

Li,

Han

2023

The Kaohsiung J of Med Scie

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Postoperative cognitive dysfunction (POCD) is a significant concern for the elderly population worldwide. This study explored the effects of esketamine on aged mice with POCD and investigate its mechanism of action involving the TLR4/MyD88/MAPK pathway. We administrated esketamine, along with lipopolysaccharide or anisomycin, to the aged POCD mouse models. We assessed their cognitive function using the Morris water maze test. Additionally, we evaluated histopathological changes/neuronal apoptosis in the mouse hippocampal CA1 area through HE/TUNEL stainings. Furthermore, we measured IL‐1β/IL‐6/TNF‐α/TLR4/MyD88/MAPK (p‐p38/p38) levels in mouse hippocampal tissues using ELISA/RT‐qPCR/Western blotting. Lastly, we analyzed the interaction between TLR4 and MyD88 using a co‐immunoprecipitation assay. Our findings showed that esketamine effectively mitigated POCD in aged mice. This was evident from the improved cognitive performance observed in the Morris water maze test, characterized by reduced escape latency/increased number of platform crossing/a higher percentage of time spent in the target quadrant. Furthermore, esketamine exhibited a protective effect against neuronal apoptosis and reduced the levels of inflammatory factors. These findings suggest that esketamine exerts an anti‐inflammatory effect by downregulating TLR4/MyD88, thereby attenuating the inflammatory response associated with POCD. Additionally, esketamine suppressed the p38 MAPK pathway by inhibiting the TLR4/MyD88 signaling cascade. Esketamine demonstrated its efficacy in improving postoperative inflammation and cognitive impairment in aged mice by inhibiting the TLR4/MyD88 pathway. The activation of p38 MAPK signaling diminished the beneficial effects of esketamine in aged POCD mice. Collectively, the underlying mechanism of esketamine in mitigating POCD in aged mice involves the suppression of the TLR4/MyD88/p38 MAPK pathway.

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Section: Discussionsupporting

confidence: 60%

Section: Discussionmentioning

confidence: 59%

Role and mechanism of esketamine in improving postoperative cognitive dysfunction in aged mice through the TLR4/MyD88/p38 MAPK pathway

Xu,

Li,

Han

2023

The Kaohsiung J of Med Scie

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“…To uncover corresponding mechanisms behind CAD’s performance in oxidation resistance and inflammation inhibition, we considered whether its beneficial role was related to crucial antioxidant enzymes and predicted pathways in Figure D. Importantly, previous reports repeatedly confirmed that CAD could enhance antioxidant capacity via upregulating antioxidant enzymes and inhibit inflammation through regulating MAPK or NF-κB signaling pathway to confer its positive role. ,− ,, The MAPK/NF-κB pathway was frequently verified to regulate inflammation-induced apoptosis in various diseases. , Combining the existing reports and enrichment analysis in Figure , we detect the expression of the MAPK/NF-κB pathway, which was evidently activated during renal I/R injury as evidenced by the increased phosphorylation of p38, ERK, JNK, and NF-κB. However, CAD pretreatment clearly prevented the activation of the MAPK/NF-κB pathway in mice with renal I/R surgery (Figure A).…”

Section: Resultsmentioning

confidence: 96%

“…Mitogen-activated protein kinase (MAPK), one serine/threonine kinase family that includes P38, ERK1/2, and JNK, was proven to regulate physiological activities including cell differentiation, inflammatory response, and cell death . In response to acute or chronic kidney injury, the MAPK pathway was obviously activated as evidenced by the increased phosphorylation of P38, ERK1/2, and JNK, which exerts proinflammatory, proapoptotic, and profibrotic impacts during renal I/R injury and renal fibrosis. , Inhibiting the activation of the MAPK pathway was authenticated to significantly ameliorate AKI and renal fibrosis. ,, The enriched top 5 pathways of those 40 intersected genes in order are pathways in cancer, MAPK, PI3K-Akt, human cytomegalovirus infection, and chemical carcinogenesis-receptor activation pathways during KEGG enrichment analysis.…”

Section: Discussionmentioning

confidence: 99%

“…13,[17][18][19]29,30 The MAPK/NF-κB pathway was frequently verified to regulate inflammation-induced apoptosis in various diseases. 31,32 Combining the existing reports and enrichment analysis in Figure 3, we detect the expression of the MAPK/NF-κB pathway, which was evidently activated during renal I/R injury as evidenced by the increased phosphorylation of p38, ERK, JNK, and NF-κB. However, CAD pretreatment clearly prevented the activation of the MAPK/NF-κB pathway in mice with renal I/R surgery (Figure 6A).…”

Section: Cardamonin Application Enhanced Antioxidative Capability And...mentioning

confidence: 94%

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Nephroprotective Effects of Cardamonin on Renal Ischemia Reperfusion Injury/UUO-Induced Renal Fibrosis

Zhang,

Chen,

Jiang

et al. 2023

J. Agric. Food Chem.

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Acute kidney injury and chronic renal fibrosis are intractable pathological processes to resolve, yet limited strategies are able to effectively address them. Cardamonin (CAD) is a flavonoid with talented antioxidant, anti-inflammatory capacity, and satisfactory biosafety. In our study, animal and cellular models of renal ischemia/reperfusion (I/R) and unilateral ureteral obstruction (UUO) were successfully constructed to confirm whether CAD confers protective effects and underlying mechanisms. Animal experiments demonstrated that CAD application (100 mg/kg) distinctly ameliorated tissue damage and improved renal function. Meanwhile, the continuous oral administration of CAD after UUO surgery efficiently inhibited renal fibrosis as confirmed by hematoxylin−eosin (H&E), Sirius red, and Masson staining as well as the downregulated mRNA and protein expression of collagen I, α-smooth muscle actin (α-SMA), collagen III, and fibronectin. Interestingly, in transforming growth factor β1 (TGF-β1)stimulated and hypoxia/reoxygenation (H/R)-exposed human kidney-2 (HK-2) cells, protective effects of CAD were again authenticated. Meanwhile, we performed bioinformatics analysis and constructed the "ingredient−target−pathway−disease" network to conclude that the potential mechanisms of CAD protection may be through the regulation of oxidative stress, inflammation, apoptosis, and mitogen-activated protein kinase (MAPK) pathway. Furthermore, experimental data validated that CAD evidently decreased the reactive oxygen species (ROS) production and malondialdehyde (MDA) content while depressing the mRNA and protein expression of inflammatory markers (tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and Il-1β) and inhibiting apoptosis as evidenced by decreased levels of P53, BAX, cleaved caspase-3, and apoptotic rate in renal I/R and UUO models. In addition, the impact of CAD on restraining oxidative stress and inflammation was attributed to its ability to elevate antioxidant enzyme activities including catalase, superoxide dismutase 1 (SOD1), and superoxide dismutase 2 (SOD2) and to inhibit the inflammation-associated MARK/nuclear factor-κB (MAPK/NF-κB) signaling pathway. In conclusion, cardamonin restored the antioxidative capacity to block oxidative stress and suppressed the MAPK/NF-κB signaling pathway to alleviate inflammatory response, thus mitigating I/R-generated acute kidney injury/UUO-induced renal fibrosis in vivo and in vitro, which indicated the potential therapeutic advantage of cardamonin in attenuating acute and chronic kidney injuries.

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Methamphetamine-induced impairment of memory and fleeting neuroinflammation: Profiling mRNA changes in mouse hippocampus following short-term and long-term exposure

Wu,

Liu,

Jiang

et al. 2024

Neuropharmacology

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Low-dose ketamine inhibits neuronal apoptosis and neuroinflammation in PC12 cells via α7nAChR mediated TLR4/MAPK/NF-κB signaling pathway

Cited by 8 publications

References 33 publications

Role and mechanism of esketamine in improving postoperative cognitive dysfunction in aged mice through the TLR4/MyD88/p38 MAPK pathway

Role and mechanism of esketamine in improving postoperative cognitive dysfunction in aged mice through the TLR4/MyD88/p38 MAPK pathway

Nephroprotective Effects of Cardamonin on Renal Ischemia Reperfusion Injury/UUO-Induced Renal Fibrosis

Methamphetamine-induced impairment of memory and fleeting neuroinflammation: Profiling mRNA changes in mouse hippocampus following short-term and long-term exposure

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