Metformin reverses the schizophrenia-like behaviors induced by MK-801 in rats

Wang, Xu; Luo, Chao; Mao, Xiao‐Yuan; Xi, Li; Yin, Ji‐Ye; Zhang, Wei; Zhou, Hong‐Hao; Liu, Zhao‐Qian

doi:10.1016/j.brainres.2019.05.023

Cited by 15 publications

(8 citation statements)

References 69 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Both of the triple-drug combinations gave moderate improvements of depressive and schizophrenia-related behaviors. To further improve efficacy, we added metformin because murine models suggest that it exerts antipsychotic (Wang et al, 2019), anxiolytic, and antidepressant activities (Zemdegs et al, 2019); and enhances the antidepressant activity of fluoxetine, a serotonin reuptake inhibitor (Poggini et al, 2019). Our results supported our hypothesis by showing that the addition of metformin to both triple-drug psychotropic combinations brought further behavioral benefit.…”

Section: Introductionsupporting

confidence: 65%

Metformin Enhances Antidepressant/Antipsychotic Combination Therapy of Schizophrenia With Comorbid Depression in a Murine Model

et al. 2020

View full text Add to dashboard Cite

Comorbid depressive disorders confound the diagnosis and therapy of schizophrenia. Using a murine model incorporating both MK801 and chronic unpredictable mild stress exposures, we successfully replicated both psychosis and depression. Ex vivo patch clamp recordings and in vivo calcium imaging demonstrated impaired neural activity in the prefrontal cortex (PFC). We then administered triple-drug combinations consisting of two antidepressants (mirtazapine and venlafaxine) plus an antipsychotic (either clozapine or olanzapine), and found improved PFC neuronal activity and performance in behavioral assays. Moreover, the addition of metformin to both psychotropic drug combinations brought further improvements in depressive and schizophrenic-like behaviors and physiological parameters. In summary, our data modeled the neuropathophysiology of schizophrenia with comorbid depression, and may inform drug intervention strategies.

show abstract

Section: Introductionsupporting

confidence: 65%

Metformin Enhances Antidepressant/Antipsychotic Combination Therapy of Schizophrenia With Comorbid Depression in a Murine Model

et al. 2020

View full text Add to dashboard Cite

show abstract

“…In MK801-induced schizophrenia-like rats, metformin attenuated the olanzapine- and risperidone-induced metabolic dysfunctions without reducing the therapeutic effects of the antipsychotics( Luo et al, 2020 ). Furthermore, in MK-801-induced schizophrenia-like models, metformin ameliorated the pre-pulse inhibition deficits, alleviated hyperactivity, the anxiety-like behaviors, recognition and spatial memory impairment through normalizing the phosphorylation of Akt and GSK3β in the cerebral cortex of rats( Wang et al, 2019 ).…”

Section: Repurposing Of Anti-diabetic Agents As a Potential Treatment Targeting Cognitive Function In Ad And Schizophreniamentioning

confidence: 99%

Repurposing of Anti-Diabetic Agents as a New Opportunity to Alleviate Cognitive Impairment in Neurodegenerative and Neuropsychiatric Disorders

Chen

Cao

et al. 2021

Front. Pharmacol.

View full text Add to dashboard Cite

Cognitive impairment is a shared abnormality between type 2 diabetes mellitus (T2DM) and many neurodegenerative and neuropsychiatric disorders, such as Alzheimer’s disease (AD) and schizophrenia. Emerging evidence suggests that brain insulin resistance plays a significant role in cognitive deficits, which provides the possibility of anti-diabetic agents repositioning to alleviate cognitive deficits. Both preclinical and clinical studies have evaluated the potential cognitive enhancement effects of anti-diabetic agents targeting the insulin pathway. Repurposing of anti-diabetic agents is considered to be promising for cognitive deficits prevention or control in these neurodegenerative and neuropsychiatric disorders. This article reviewed the possible relationship between brain insulin resistance and cognitive deficits. In addition, promising therapeutic interventions, especially current advances in anti-diabetic agents targeting the insulin pathway to alleviate cognitive impairment in AD and schizophrenia were also summarized.

show abstract

“…This potentiating effect on activity was not observed in MK-801 + PA-Glu treated rats (Figure 3A) or in the highest dose of MS-249 applied with MK-801 (Figure 3B). PA-Glu had no adverse effects on locomotion despite its negative modulation of NMDARs as NMDAR antagonists are well-known for their hyperlocomotion-inducing effects [48][49][50].…”

Section: Discussionmentioning

confidence: 95%

Pitfalls of NMDA Receptor Modulation by Neuroactive Steroids. The Effect of Positive and Negative Modulation of NMDA Receptors in an Animal Model of Schizophrenia

et al. 2021

View full text Add to dashboard Cite

Evidence from clinical and preclinical studies implicates dysfunction of N-methyl-D-aspartate receptors (NMDARs) in schizophrenia progression and symptoms. We investigated the antipsychotic effect of two neuroactive steroids in an animal model of schizophrenia induced by systemic application of MK-801. The neuroactive steroids differ in their mechanism of action at NMDARs. MS-249 is positive, while PA-Glu is a negative allosteric NMDAR modulator. We hypothesized that the positive NMDA receptor modulator would attenuate deficits caused by MK-801 co-application more effectively than PA-Glu. The rats were tested in a battery of tests assessing spontaneous locomotion, anxiety and cognition. Contrary to our expectations, PA-Glu exhibited a superior antipsychotic effect to MS-249. The performance of MS-249-treated rats in cognitive tests differed depending on the level of stress the rats were exposed to during test sessions. In particular, with the increasing severity of stress exposure, the performance of animals worsened. Our results demonstrate that enhancement of NMDAR function may result in unspecific behavioral responses. Positive NMDAR modulation can influence other neurobiological processes besides memory formation, such as anxiety and response to stress.

show abstract

Metformin reverses the schizophrenia-like behaviors induced by MK-801 in rats

Cited by 15 publications

References 69 publications

Metformin Enhances Antidepressant/Antipsychotic Combination Therapy of Schizophrenia With Comorbid Depression in a Murine Model

Metformin Enhances Antidepressant/Antipsychotic Combination Therapy of Schizophrenia With Comorbid Depression in a Murine Model

Repurposing of Anti-Diabetic Agents as a New Opportunity to Alleviate Cognitive Impairment in Neurodegenerative and Neuropsychiatric Disorders

Pitfalls of NMDA Receptor Modulation by Neuroactive Steroids. The Effect of Positive and Negative Modulation of NMDA Receptors in an Animal Model of Schizophrenia

Contact Info

Product

Resources

About