Mongolian Medicine Areca Thirteen Pill (GY-13) Improved Depressive Syndrome via upregulating cAMP/PKA/CREB/BDNF signaling pathway

Cai, Ming-Yang; Yang, Zhen; Huang, Xian-Ju; Li, Jing; Bao, Wu-Ye; Hurilebagen,; Wu-Lanqiqige,; Wu-Yunsiriguleng,; Cui, Jing-Wen; Ma, Li-Qun; Tong, Haiying

doi:10.1016/j.jep.2022.115310

Cited by 12 publications

(7 citation statements)

References 22 publications

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“…Selective serotonin reuptake inhibitors (SSRIs) are the common first-line treatments for major depressive disorder (MDD) [ 2 ], although they are generally well-tolerated, SSRIs have known adverse effects, including movement problems, alopecia, somnipathy, and gastrointestinal problems [ 3 , 4 ]. Other antidepressants used in clinic commonly show narrow-spectrum effects, high recurrence and inevitable adverse reactions [ 5 , 6 ]. Dopamine (DA) is also proposed to play an important role in the pathophysiology of depression as well as in the mechanism of antidepressant drugs.…”

Section: Introductionmentioning

confidence: 99%

β-Arrestin2-biased Drd2 agonist UNC9995 alleviates astrocyte inflammatory injury via interaction between β-arrestin2 and STAT3 in mouse model of depression

Yang

Song

Yao

et al. 2022

J Neuroinflammation

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Background Major depressive disorder (MDD) is a prevalent and devastating psychiatric illness. Unfortunately, the current therapeutic practice, generally depending on the serotonergic system for drug treatment is unsatisfactory and shows intractable side effects. Multiple evidence suggests that dopamine (DA) and dopaminergic signals associated with neuroinflammation are highly involved in the pathophysiology of depression as well as in the mechanism of antidepressant drugs, which is still in the early stage of study and well worthy of investigation. Methods We established two chronic stress models, including chronic unpredictable mild stress (CUMS), and chronic social defeat stress (CSDS), to complementarily recapitulate depression-like behaviors. Then, hippocampal tissues were used to detect inflammation-related molecules and signaling pathways. Pathological changes in depressive mouse hippocampal astrocytes were examined by RNA sequencing. After confirming the dopamine receptor 2 (Drd2)/β-arrestin2 signaling changes in the depressive mice brain, we then established the depressive mouse model using the β-arrestin2 knockout mice or administrating the β-arrestin2-biased Drd2 agonist to investigate the roles. Label-free mass spectrometry was used to identify the β-arrestin2-binding proteins as the underlying mechanisms. We modeled neuroinflammation with interleukin-6 (IL-6) and corticosterone treatment and characterized astrocytes using multiple methods including cell viability assay, flow cytometry, and confocal immunofluorescence. Results Drd2-biased β-arrestin2 pathway is significantly changed in the progression of depression, and genetic deletion of β-arrestin2 aggravates neuroinflammation and depressive-like phenotypes. Mechanistically, astrocytic β-arrestin2 retains STAT3 in the cytoplasm by structural combination with STAT3, therefore, inhibiting the JAK–STAT3 pathway-mediated inflammatory activation. Furtherly, pharmacological activation of Drd2/β-arrestin2 pathway by UNC9995 abolishes the inflammation-induced loss of astrocytes and ameliorates depressive-like behaviors in mouse model for depression. Conclusions Drd2/β-arrestin2 pathway is a potential therapeutic target for depression and β-arrestin2-biased Drd2 agonist UNC9995 is identified as a potential anti-depressant strategy for preventing astrocytic dysfunctions and relieving neuropathological manifestations in mouse model for depression, which provides insights for the therapy of depression.

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Section: Introductionmentioning

confidence: 99%

β-Arrestin2-biased Drd2 agonist UNC9995 alleviates astrocyte inflammatory injury via interaction between β-arrestin2 and STAT3 in mouse model of depression

Yang

Song

Yao

et al. 2022

J Neuroinflammation

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“…Brain-derived neurotrophic factor is a direct target of CREB ( Barco et al, 2005 ), and cAMP-activated phosphorylated CREB regulates the expression of neurotrophic factors such as BDNF and NGF ( Ortega-Martinez, 2015 ). The cAMP/CREB/BDNF pathway has been shown to be an important mechanism of action in traditional Chinese medicine ( Cai et al, 2022 ) and novel antidepressants such as vortioxetine ( Ramezany et al, 2019 ). In the hippocampal mRNA sequencing of Sig-1R knockout mice, the cAMP signaling pathway was significantly enriched.…”

Section: Discussionmentioning

confidence: 99%

Gut microbiota from sigma-1 receptor knockout mice induces depression-like behaviors and modulates the cAMP/CREB/BDNF signaling pathway

Liu

et al. 2023

Front. Microbiol.

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IntroductionDepression is a common mental disorder that affects approximately 350 million people worldwide. Much remains unknown about the molecular mechanisms underlying this complex disorder. Sigma-1 receptor (Sig-1R) is expressed at high levels in the central nervous system. Increasing evidence has demonstrated a close association between the Sig-1R and depression. Recently, research has suggested that the gut microbiota may play a crucial role in the development of depression.MethodsMale Sig-1R knockout (Sig-1R KO) and wild-type (WT) mice were used for this study. All transgenic mice were of a pure C57BL/6J background. Mice received a daily gavage of vancomycin (100 mg/kg), neomycin sulfate (200 mg/kg), metronidazole (200 mg/kg), and ampicillin (200 mg/kg) for one week to deplete gut microbiota. Fecal microbiota transplantation (FMT) was conducted to assess the effects of gut microbiota. Depression-like behaviors was evaluated by tail suspension test (TST), forced swimming test (FST) and sucrose preference test (SPT). Gut microbiota was analyzed by 16s rRNA and hippocampal transcriptome changes were assessed by RNA-seq.ResultsWe found that Sig-1R knockout induced depression-like behaviors in mice, including a significant reduction in immobility time and an increase in latency to immobility in the FST and TST, which was reversed upon clearance of gut microbiota with antibiotic treatment. Sig-1R knockout significantly altered the composition of the gut microbiota. At the genus level, the abundance of Alistipes, Alloprevotella, and Lleibacterium decreased significantly. Gut microbiota dysfunction and depression-like phenotypes in Sig-1R knockout mice could be reproduced through FMT experiments. Additionally, hippocampal RNA sequencing identified multiple KEGG pathways that are associated with depression. We also discovered that the cAMP/CREB/BDNF signaling pathway is inhibited in the Sig-1R KO group along with lower expression of neurotrophic factors including CTNF, TGF-α and NGF. Fecal bacteria transplantation from Sig-1R KO mice also inhibited cAMP/CREB/BDNF signaling pathway.DiscussionIn our study, we found that the gut-brain axis may be a potential mechanism through which Sig-1R regulates depression-like behaviors. Our study provides new insights into the mechanisms by which Sig-1R regulates depression and further supports the concept of the gut-brain axis.

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“…Additionally, through sucrose preference tests, open field tests, and body weight measurements conducted on rats, it has been observed that the effects of GY-13 treatment on CREB mRNA and BDNF mRNA levels can be counteracted by inhibiting PKA. This suggests that GY-13 treatment exhibits a strong antidepressant action by activating the cAMP/CREB/BDNF signaling pathway, promoting cell proliferation, and suppressing cell death [ 72 ].…”

Section: Biomedical Applicationsmentioning

confidence: 99%

Biological Effects and Biomedical Applications of Areca Nut and Its Extract

Tong,

Xu,

Tan

et al. 2024

Pharmaceuticals

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The dried, mature fruit of the palm tree species Areca catechu L. is known as the areca nut (AN) or betel nut. It is widely cultivated in the tropical regions. In many nations, AN is utilized for traditional herbal treatments or social activities. AN has historically been used to address various health issues, such as diarrhea, arthritis, dyspepsia, malaria, and so on. In this review, we have conducted a comprehensive summary of the biological effects and biomedical applications of AN and its extracts. Initially, we provided an overview of the constituents in AN extract. Subsequently, we summarized the biological effects of AN and its extracts on the digestive system, nervous system, and circulatory system. And we elucidated the contributions of AN and its extracts in antidepressant, anti-inflammatory, antioxidant, and antibacterial applications. Finally, we have discussed the challenges and future perspectives regarding the utilization of AN and its extracts as emerging pharmaceuticals or valuable adjuncts within the pharmaceutical field.

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Mongolian Medicine Areca Thirteen Pill (GY-13) Improved Depressive Syndrome via upregulating cAMP/PKA/CREB/BDNF signaling pathway

Cited by 12 publications

References 22 publications

β-Arrestin2-biased Drd2 agonist UNC9995 alleviates astrocyte inflammatory injury via interaction between β-arrestin2 and STAT3 in mouse model of depression

β-Arrestin2-biased Drd2 agonist UNC9995 alleviates astrocyte inflammatory injury via interaction between β-arrestin2 and STAT3 in mouse model of depression

Gut microbiota from sigma-1 receptor knockout mice induces depression-like behaviors and modulates the cAMP/CREB/BDNF signaling pathway

Biological Effects and Biomedical Applications of Areca Nut and Its Extract

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