Metformin restores hippocampal neurogenesis and learning and memory via regulating gut microbiota in the obese mouse model

Ma, Xiaoyi; Xiao, Wenjing; Li, Hao; Pang, Pei; Xue, Feixiao; Pei, Lei; Yan, Haimeng

doi:10.1016/j.bbi.2021.02.011

Cited by 44 publications

(34 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Likewise, this drug could prevent the deterioration of newborn neurons in the hippocampus and therefore improve the learning process and memory in obese mice. These results reinforce the hypothesis of the benefit of acting at the microbiota level to improve the cognitive process in LOAD [ 121 ].…”

Section: Molecular Mechanism Involved In Neuroprotective Effects Of Metformin In Alzheimer’s Diseasesupporting

confidence: 89%

“…However, the authors propose that its protective effect against scopolamine-induced cognitive impairment is probably through the signaling pathway of Akt/GSK3 beta and prevention of phosphorylation of tau protein. Likewise, according to some trials, scopolamine therapy has been shown to decrease pAMPK and CREB levels, and metformin treatment has successfully restored pAMPK and the transcription factor CREB levels in the hippocampus [ 71 , 121 ]. Furthermore, metformin was able to increase the hippocampal levels of antioxidant enzymes, such as superoxide dismutase levels [ 121 ].…”

Section: Molecular Mechanism Involved In Neuroprotective Effects Of Metformin In Alzheimer’s Diseasementioning

confidence: 99%

“…Likewise, according to some trials, scopolamine therapy has been shown to decrease pAMPK and CREB levels, and metformin treatment has successfully restored pAMPK and the transcription factor CREB levels in the hippocampus [ 71 , 121 ]. Furthermore, metformin was able to increase the hippocampal levels of antioxidant enzymes, such as superoxide dismutase levels [ 121 ]. These results give support to the hypothesis that metformin could be a potential preventive drug against cognitive and memory impairment [ 94 , 95 , 121 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 , 132 ] ( Table 1 ).…”

Section: Molecular Mechanism Involved In Neuroprotective Effects Of Metformin In Alzheimer’s Diseasementioning

confidence: 99%

“…Furthermore, metformin was able to increase the hippocampal levels of antioxidant enzymes, such as superoxide dismutase levels [ 121 ]. These results give support to the hypothesis that metformin could be a potential preventive drug against cognitive and memory impairment [ 94 , 95 , 121 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 , 132 ] ( Table 1 ). Similarly, metformin was shown to prevent cognitive damage in the chronic L-methionine model of memory impairment, probably by normalizing oxidative damage [ 124 ].…”

Section: Molecular Mechanism Involved In Neuroprotective Effects Of Metformin In Alzheimer’s Diseasementioning

confidence: 99%

See 3 more Smart Citations

Metformin a Potential Pharmacological Strategy in Late Onset Alzheimer’s Disease Treatment

et al. 2021

View full text Add to dashboard Cite

Alzheimer’s disease (AD) is one of the most devastating brain disorders. Currently, there are no effective treatments to stop the disease progression and it is becoming a major public health concern. Several risk factors are involved in the progression of AD, modifying neuronal circuits and brain cognition, and eventually leading to neuronal death. Among them, obesity and type 2 diabetes mellitus (T2DM) have attracted increasing attention, since brain insulin resistance can contribute to neurodegeneration. Consequently, AD has been referred to “type 3 diabetes” and antidiabetic medications such as intranasal insulin, glitazones, metformin or liraglutide are being tested as possible alternatives. Metformin, a first line antihyperglycemic medication, is a 5′-adenosine monophosphate (AMP)-activated protein kinase (AMPK) activator hypothesized to act as a geroprotective agent. However, studies on its association with age-related cognitive decline have shown controversial results with positive and negative findings. In spite of this, metformin shows positive benefits such as anti-inflammatory effects, accelerated neurogenesis, strengthened memory, and prolonged life expectancy. Moreover, it has been recently demonstrated that metformin enhances synaptophysin, sirtuin-1, AMPK, and brain-derived neuronal factor (BDNF) immunoreactivity, which are essential markers of plasticity. The present review discusses the numerous studies which have explored (1) the neuropathological hallmarks of AD, (2) association of type 2 diabetes with AD, and (3) the potential therapeutic effects of metformin on AD and preclinical models.

show abstract

Section: Molecular Mechanism Involved In Neuroprotective Effects Of Metformin In Alzheimer’s Diseasesupporting

confidence: 89%

Section: Molecular Mechanism Involved In Neuroprotective Effects Of Metformin In Alzheimer’s Diseasementioning

confidence: 99%

Section: Molecular Mechanism Involved In Neuroprotective Effects Of Metformin In Alzheimer’s Diseasementioning

confidence: 99%

Section: Molecular Mechanism Involved In Neuroprotective Effects Of Metformin In Alzheimer’s Diseasementioning

confidence: 99%

See 2 more Smart Citations

Metformin a Potential Pharmacological Strategy in Late Onset Alzheimer’s Disease Treatment

et al. 2021

View full text Add to dashboard Cite

show abstract

“…A molecular basis for the effects of metformin on cognitive function is suggested by data using adult murine neural stem cells in culture that shows metformin in the concentration range 500 nM to 1 μM enhanced proliferation and self renewal dependent on the transcription factor, Tap73, and enhanced neuronal differentiation via the AMPK-atypical protein kinase C (aPKC)-CREB-binding protein (CBP) pathway [( 117 ): Table 2 ]. Data from a study with high-fat diet mice has also linked the learning and memory restorative benefits of metformin in the diet (250 mg/kg/day) to the microbiota with positive data from a fecal transplantation protocol [( 118 ): Table 2 ]. The potential to use metformin to treat Alzheimer’s is also provided by data indicating that metformin targets monoacylglycerol lipase, an enzyme responsible for generating pro-inflammatory eicosanoids from 2-arachidonoyl glycerol ( 258 ).…”

Section: The Connection Between Metformin and Improved Neurological Functionmentioning

confidence: 99%

A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan

et al. 2021

View full text Add to dashboard Cite

The numerous beneficial health outcomes associated with the use of metformin to treat patients with type 2 diabetes (T2DM), together with data from pre-clinical studies in animals including the nematode, C. elegans, and mice have prompted investigations into whether metformin has therapeutic utility as an anti-aging drug that may also extend lifespan. Indeed, clinical trials, including the MILES (Metformin In Longevity Study) and TAME (Targeting Aging with Metformin), have been designed to assess the potential benefits of metformin as an anti-aging drug. Preliminary analysis of results from MILES indicate that metformin may induce anti-aging transcriptional changes; however it remains controversial as to whether metformin is protective in those subjects free of disease. Furthermore, despite clinical use for over 60 years as an anti-diabetic drug, the cellular mechanisms by which metformin exerts either its actions remain unclear. In this review, we have critically evaluated the literature that has investigated the effects of metformin on aging, healthspan and lifespan in humans as well as other species. In preparing this review, particular attention has been placed on the strength and reproducibility of data and quality of the study protocols with respect to the pharmacokinetic and pharmacodynamic properties of metformin. We conclude that despite data in support of anti-aging benefits, the evidence that metformin increases lifespan remains controversial. However, via its ability to reduce early mortality associated with various diseases, including diabetes, cardiovascular disease, cognitive decline and cancer, metformin can improve healthspan thereby extending the period of life spent in good health. Based on the available evidence we conclude that the beneficial effects of metformin on aging and healthspan are primarily indirect via its effects on cellular metabolism and result from its anti-hyperglycemic action, enhancing insulin sensitivity, reduction of oxidative stress and protective effects on the endothelium and vascular function.

show abstract

Urolithin A Attenuates Diabetes‐Associated Cognitive Impairment by Ameliorating Intestinal Barrier Dysfunction via N‐glycan Biosynthesis Pathway

Xiao

Bian

et al. 2022

Molecular Nutrition Food Res

View full text Add to dashboard Cite

Scope This study aims to investigate the effect of Urolithin A (UA) on diabetes‐associated cognitive impairment in type 2 diabetes mellitus (T2DM) mouse model induced by high‐fat diet (HFD) and streptozotocin (STZ). Methods and Results The UA‐treated T2DM mice display an attenuated cognitive impairment as well as reduced levels of metabolic endotoxemia and proinflammatory cytokines in serum. A systemic restraint of gut/brain inflammation in UA‐treated T2DM mice is also observed as the downregulation of TLR4 and Myd88 in colon along with the inhibition of GFAP, Iba‐1, NLRP3, and inflammation‐related genes in brain. Moreover, UA ameliorates gut barrier dysfunction by upregulating tight‐junction proteins levels. Furthermore, UA restores the hyperglycemia‐mediated downregulation of genes involved in N‐glycan biosynthesis both in vivo and in vitro, which plays a crucial role in barrier integrity. Although UA shares similar beneficial effects on diabetes with metformin, unlike metformin, the effect of UA is independent of gut microbiome and short chain fatty acids. Taken together, these data suggest that feeding UA can attenuate diabetes‐associated cognitive impairment by ameliorating systemic inflammation and intestinal barrier dysfunction via N‐glycan biosynthesis pathway. The study implies UA as a potential novel pharmaceutic target for diabetes therapy via manipulating gut‐brain axis and N‐glycan metabolism.

show abstract

Metformin restores hippocampal neurogenesis and learning and memory via regulating gut microbiota in the obese mouse model

Cited by 44 publications

References 47 publications

Metformin a Potential Pharmacological Strategy in Late Onset Alzheimer’s Disease Treatment

Metformin a Potential Pharmacological Strategy in Late Onset Alzheimer’s Disease Treatment

A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan

Urolithin A Attenuates Diabetes‐Associated Cognitive Impairment by Ameliorating Intestinal Barrier Dysfunction via N‐glycan Biosynthesis Pathway

Contact Info

Product

Resources

About