Antidiabetic Drug Metformin Ameliorates Depressive-Like Behavior in Mice with Chronic Restraint Stress via Activation of AMP-Activated Protein Kinase

Ai, Hui; Fang, Weiqing; Hu, Hai Feng; Hu, Xupang; Lu, W. T.

doi:10.14336/ad.2019.0403

Cited by 23 publications

(4 citation statements)

References 71 publications

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“…The open field test was performed as described previously with minor modifications (Ai et al 2020 ; Ai et al 2017 ). The open field chamber was made of white plastic with dimensions of 40 cm height × 40 cm length × 40 cm width.…”

Section: Methodsmentioning

confidence: 99%

Targeting PSD95/nNOS by ZL006 alleviates social isolation-induced heightened attack behavior in mice

et al. 2021

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Rationale Deregulated attack behaviors have devastating social consequences; however, satisfactory clinical management for the behavior is still an unmet need so far. Social isolation (SI) has been common during the COVID-19 pandemic and may have detrimental effects on mental health, including eliciting heightened attack behavior. Objectives This study aims to explore whether injection of ZL006 can alleviate SI-induced escalation of attack behavior in mice. Methods Pharmacological tools, biochemical methods, and behavioral tests were used to explore the potential therapeutic effects of ZL006 targeting postsynaptic density 95 (PSD95)/neuronal nitric oxide synthase (nNOS) pathway on escalation of attack behavior induced by SI in mice. Results ZL006 mitigated SI-induced escalated attack behaviors and elevated nitric oxide (NO) level in the cortex of the SI mice. The beneficial effects of ZL006 lasted for at least 72 h after a single injection of ZL006. Potentiation of NO levels by L-arginine blocked the effects of ZL006. Moreover, a sub-effective dose of 7-NI in combination with a sub-effective dose of ZL006 decreased both SI-induced escalated attack behaviors and NO levels in mice subjected to SI. Conclusions Our study highlights the importance of the PSD95/nNOS pathway in mediating SI-induced escalation of attack behavior. ZL006 may be a promising therapeutic strategy for treating aggressive behaviors. Supplementary Information The online version contains supplementary material available at 10.1007/s00213-021-06000-9.

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Section: Methodsmentioning

confidence: 99%

Targeting PSD95/nNOS by ZL006 alleviates social isolation-induced heightened attack behavior in mice

et al. 2021

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“…Moreover, MET reduced cognitive dysfunction in animal models treated with scopolamine (Mostafa et al, 2016), cisplatin , or hypobaric hypoxia (Zhao et al, 2019). Also, MET had antidepressant-like effects in naïve mice and mice subjected to chronic restraint stress (Ai et al, 2020). Overall, the diverging outcomes in different studies are likely linked to the type of disease model investigated or the underlying biological pathways involved in different animal prototypes (Rotermund et al, 2018).…”

Section: Effects Of Metformin On Cognitive Function In Animal Studiesmentioning

confidence: 99%

Promise of metformin for preventing age-related cognitive dysfunction

2022

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The expanded lifespan of people, while a positive advance, has also amplified the prevalence of age-related disorders, which include mild cognitive impairment, dementia, and Alzheimer’s disease. Therefore, competent therapies that could improve the healthspan of people have great significance. Some of the dietary and pharmacological approaches that augment the lifespan could also preserve improved cognitive function in old age. Metformin, a drug widely used for treating diabetes, is one such candidate that could alleviate age-related cognitive dysfunction. However, the possible use of metformin to alleviate age-related cognitive dysfunction has met with conflicting results in human and animal studies. While most clinical studies have suggested the promise of metformin to maintain better cognitive function and reduce the risk for developing dementia and Alzheimer’s disease in aged diabetic people, its efficacy in the nondiabetic population is still unclear. Moreover, a previous animal model study implied that metformin could adversely affect cognitive function in the aged. However, a recent animal study using multiple behavioral tests has reported that metformin treatment in late middle age improved cognitive function in old age. The study also revealed that cognition-enhancing effects of metformin in aged animals were associated with the activation of the energy regulator adenosine monophosphate-activated protein kinase, diminished neuroinflammation, inhibition of the mammalian target of rapamycin signaling, and augmented autophagy in the hippocampus. The proficiency of metformin to facilitate these favorable modifications in the aged hippocampus likely underlies its positive effect on cognitive function. Nonetheless, additional studies probing the outcomes of different doses and durations of metformin treatment at specific windows in the middle and old age across sex in nondiabetic and non-obese prototypes are required to substantiate the promise of metformin to maintain better cognitive function in old age.

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“…The open field test was performed as described previously with minor modifications (Ai et al, 2020). Briefly, after 1-h habituation in the testing room, the mice were placed into the corner of a 40 cm × 40 cm × 40 cm square box.…”

Section: Open Field Testmentioning

confidence: 99%

Targeting GluN2B/NO Pathway Ameliorates Social Isolation–Induced Exacerbated Attack Behavior in Mice

et al. 2021

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Exacerbated attack behavior has a profound socioeconomic impact and devastating social consequences; however, there is no satisfactory clinical management available for an escalated attack behavior. Social isolation (SI) is widespread during this pandemic and may exert detrimental effects on mental health, such as causing heightened attack behavior. To explore the therapeutic approaches that alleviate the SI-induced heightened attack behavior, we utilized pharmacological methods targeting the GluN2B/NO signaling pathway during the attack behavior. Ifenprodil and TAT-9C peptide targeting GluN2B showed that the inhibition of GluN2B mitigated the SI-induced escalated attack behavior and the SI-induced aberrant nitric oxide (NO) level in the brain. Additionally, the potentiation of the NO level by L-arginine reversed the effects of the inhibition of GluN2B. Moreover, we showed that high doses of L-NAME and 7-NI and subeffective doses of L-NAME in combination with ifenprodil or TAT-9C or subeffective doses of 7-NI plus ifenprodil or TAT-9C all decreased the SI-induced escalated attack behavior and reduced the NO level, further supporting the idea that GluN2B/NO signaling is a crucial modulator of the escalated attack behavior.

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Antidiabetic Drug Metformin Ameliorates Depressive-Like Behavior in Mice with Chronic Restraint Stress via Activation of AMP-Activated Protein Kinase

Cited by 23 publications

References 71 publications

Targeting PSD95/nNOS by ZL006 alleviates social isolation-induced heightened attack behavior in mice

Targeting PSD95/nNOS by ZL006 alleviates social isolation-induced heightened attack behavior in mice

Promise of metformin for preventing age-related cognitive dysfunction

Targeting GluN2B/NO Pathway Ameliorates Social Isolation–Induced Exacerbated Attack Behavior in Mice

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