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Yuk-Gunja-Tang attenuates neuronal death and memory impairment via ERK/CREB/BDNF signaling in the hippocampi of experimental Alzheimer's disease model.

ABSTRACT: Yuk-Gunja-Tang (YG) is the Korean traditional medicine in East Asia for gastrointestinal disorders. In the present study, we determined the protective effects of YG on glutamate-induced cytotoxicity in HT22 hippocampal neuronal cells and mice with scopolamine-induced memory impairment. In vitro assessments were performed using a cell viability assay, flow cytometry, and Western blotting, while in vivo assessments were performed in C57BL/6 mice administered with YG for 7 days and injected with scopolamine (1 mg/kg) for 7 days. We assessed the memory function using the Y-maze, novel object recognition, and passive avoidance tests. Protein expression analyses and histological analyses were performed using hippocampal tissues. YG treatment significantly restored cell viability against glutamate-induced apoptosis. It significantly suppressed glutamate-induced reactive oxygen species accumulation and mitochondrial dysfunction. It also increased Bcl-2 protein expression and decreased HO-1 protein expression. It activated the extracellular signal-regulated kinase/cAMP response element binding protein (ERK/CREB) signaling pathway and increased the expression of brain-derived neurotrophic factor (BDNF) under excitotoxic conditions. In the scopolamine-injected mice, YG ameliorated memory impairment in the Y-maze, novel object recognition, and passive avoidance tests; restored dysfunction in the acetylcholine, acetylcholinesterase expression levels; reduced neuronal damage in Nissl staining; and increased BDNF and phosphorylated ERK and CREB levels in Western blotting and immunofluorescence staining. Thus, YG exerted neuroprotective effects by activating ERK/CREB/BDNF signaling in the hippocampus, indicating its potential cognition-enhancing effects, especially in Alzheimer's disease.

SUBMITTER: Pak ME

PROVIDER: S-EPMC9643579 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Yuk-Gunja-Tang attenuates neuronal death and memory impairment via ERK/CREB/BDNF signaling in the hippocampi of experimental Alzheimer's disease model.

Pak Malk Eun ME Yang Hye Jin HJ Li Wei W Kim Jae Kwang JK Go Younghoon Y

Frontiers in pharmacology 20221026

Yuk-Gunja-Tang (YG) is the Korean traditional medicine in East Asia for gastrointestinal disorders. In the present study, we determined the protective effects of YG on glutamate-induced cytotoxicity in HT22 hippocampal neuronal cells and mice with scopolamine-induced memory impairment. In vitro assessments were performed using a cell viability assay, flow cytometry, and Western blotting, while in vivo assessments were performed in C57BL/6 mice administered with YG for 7 days and in ...[more]

PMID: 36386241

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Project description:(R,S)-ketamine elicits rapid-acting and sustained antidepressant actions in treatment-resistant patients with depression. (R)-ketamine produces longer-lasting antidepressant effects than (S)-ketamine in rodents; however, the precise molecular mechanisms underlying antidepressant actions of (R)-ketamine remain unknown. Using isobaric Tag for Relative and Absolute Quantification, we identified nuclear receptor-binding protein 1 (NRBP1) that could contribute to different antidepressant-like effects of the two enantiomers in chronic social defeat stress (CSDS) model. NRBP1 was localized in the microglia and neuron, not astrocyte, of mouse medial prefrontal cortex (mPFC). (R)-ketamine increased the expression of NRBP1, brain-derived neurotrophic factor (BDNF), and phosphorylated cAMP response element binding protein (p-CREB)/CREB ratio in primary microglia cultures thorough the extracellular signal-regulated kinase (ERK) activation. Furthermore, (R)-ketamine could activate BDNF transcription through activation of CREB as well as MeCP2 (methyl-CpG binding protein 2) suppression in microglia. Single intracerebroventricular (i.c.v.) injection of CREB-DNA/RNA heteroduplex oligonucleotides (CREB-HDO) or BDNF exon IV-HDO blocked the antidepressant-like effects of (R)-ketamine in CSDS susceptible mice. Moreover, microglial depletion by colony-stimulating factor 1 receptor (CSF1R) inhibitor PLX3397 blocked the antidepressant-like effects of (R)-ketamine in CSDS susceptible mice. In addition, inhibition of microglia by single i.c.v. injection of mannosylated clodronate liposomes (MCLs) significantly blocked the antidepressant-like effects of (R)-ketamine in CSDS susceptible mice. Finally, single i.c.v. injection of CREB-HDO, BDNF exon IV-HDO or MCLs blocked the beneficial effects of (R)-ketamine on the reduced dendritic spine density in the mPFC of CSDS susceptible mice. These data suggest a novel ERK-NRBP1-CREB-BDNF pathways in microglia underlying antidepressant-like effects of (R)-ketamine.

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Dataset Information

Yuk-Gunja-Tang attenuates neuronal death and memory impairment via ERK/CREB/BDNF signaling in the hippocampi of experimental Alzheimer's disease model.

Publications

Yuk-Gunja-Tang attenuates neuronal death and memory impairment <i>via</i> ERK/CREB/BDNF signaling in the hippocampi of experimental Alzheimer's disease model.

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