Metformin Activates an Atypical PKC-CBP Pathway to Promote Neurogenesis and Enhance Spatial Memory Formation

Wang, Jing; Gallagher, Denis; DeVito, Loren M.; Cancino, Gonzalo I.; Tsui, David Chun Cheong; He, Liang; Keller, Gordon; Frankland, Paul W.; Kaplan, David R.; Miller, Freda D.

doi:10.1016/j.stem.2012.03.016

Cited by 412 publications

(327 citation statements)

References 28 publications

Supporting

Mentioning

299

Contrasting

Unclassified

Order By: Relevance

“…Several studies have shown that metformin is effective in reducing ischemic injury 12. The mechanisms underlying this protection include the following: inflammation inhibition,14 blood‐brain barrier protection,13 promotion of neurogenesis and enhancement of spatial memory formation,38 promotion of the growth of nerve and recovery,39, 40 and improvement of poststroke angiogenesis and recovery 40. Consistent with previous studies, herein, our data demonstrate that long‐term metformin pretreatment affords strong neuroprotection and can be lifesaving under the conditions of CA/CPR.…”

Section: Discussionmentioning

confidence: 99%

Metformin Improves Neurologic Outcome Via AMP‐Activated Protein Kinase–Mediated Autophagy Activation in a Rat Model of Cardiac Arrest and Resuscitation

Zhu

Liu

Huang

et al. 2018

JAHA

View full text Add to dashboard Cite

BackgroundSudden cardiac arrest (CA) often results in severe injury to the brain, and neuroprotection after CA has proved to be difficult to achieve. Herein, we sought to investigate the effects of metformin pretreatment on brain injury secondary to CA and cardiopulmonary resuscitation.Methods and ResultsRats were subjected to 9‐minute asphyxial CA after receiving daily metformin treatment for 2 weeks. Survival rate, neurologic deficit scores, neuronal loss, AMP‐activated protein kinase (AMPK), and autophagy activation were assessed at indicated time points within the first 7 days after return of spontaneous circulation. Our results showed that metformin pretreatment elevated the 7‐day survival rate from 55% to 85% and significantly reduced neurologic deficit scores. Moreover, metformin ameliorated CA‐induced neuronal degeneration and glial activation in the hippocampal CA1 region, which was accompanied by augmented AMPK phosphorylation and autophagy activation in affected neuronal tissue. Inhibition of AMPK or autophagy with pharmacological inhibitors abolished metformin‐afforded neuroprotection, and augmented autophagy induction by metformin treatment appeared downstream of AMPK activation.ConclusionsTaken together, our data demonstrate, for the first time, that metformin confers neuroprotection against ischemic brain injury after CA/cardiopulmonary resuscitation by augmenting AMPK‐dependent autophagy activation.

show abstract

Section: Discussionmentioning

confidence: 99%

Metformin Improves Neurologic Outcome Via AMP‐Activated Protein Kinase–Mediated Autophagy Activation in a Rat Model of Cardiac Arrest and Resuscitation

Zhu

Liu

Huang

et al. 2018

JAHA

View full text Add to dashboard Cite

show abstract

“…Studies suggesting a variety of benefi cial effects of metformin on aging ( 23 ), memory ( 112 ), and cardiovascular function ( 113 ) would argue that such trials should examine nononcologic health outcomes as well. However, many of the antineoplastic mechanisms of action of biguanides that operate in preclinical models may not be addressed in these trials, as drug accumulation in target tissues may not be suffi cient.…”

Section: Challenges For Future Researchmentioning

confidence: 99%

Investigating Metformin for Cancer Prevention and Treatment: The End of the Beginning

2012

View full text Add to dashboard Cite

Laboratory research and pharmacoepidemiology are providing converging evidence that the widely used antidiabetic drug metformin has antineoplastic activity, but there are caveats. Although population studies suggest that metformin exposure is associated with reduced cancer risk and/or improved prognosis, these data are mostly retrospective and nonrandomized. Laboratory models show antineoplastic activity, but metformin concentrations used in many experiments exceed those achieved with conventional doses used for diabetes treatment. Ongoing translational research should be useful in guiding design of clinical trials, not only to evaluate metformin at conventional antidiabetic doses, where reduction of elevated insulin levels may contribute to antineoplastic activity for certain subsets of patients, but also to explore more aggressive dosing of biguanides, which may lead to reprogramming of energy metabolism in a manner that could provide important opportunities for synthetic lethality through rational drug combinations or in the context of genetic lesions associated with hypersensitivity to energetic stress. Significance: There are tantalizing clues that justify the investigation of antineoplastic activities of biguanides. The complexity of their biologic effects requires further translational research to guide clinical trial design. Cancer Discov; 2(9); 778–90. ©2012 AACR.

show abstract

“…Therefore, metformin has been used for life extension in mammals and, in some studies although not all, has demonstrated gerosuppressive effects (Smith et al 2010;Anisimov et al 2011;Berstein 2012). Interestingly, 12 days of treatment with metformin has been shown to increase adult neurogenesis and spatial memory (Wang et al 2012). However, the effect of longer term treatment remains unknown.…”

Section: Introductionmentioning

confidence: 99%

Contrasting effects of chronic, systemic treatment with mTOR inhibitors rapamycin and metformin on adult neural progenitors in mice

Kusne

Goldberg

Parker

et al. 2013

AGE

View full text Add to dashboard Cite

The chronic and systemic administration of rapamycin extends life span in mammals. Rapamycin is a pharmacological inhibitor of mTOR. Metformin also inhibits mTOR signaling but by activating the upstream kinase AMPK. Here we report the effects of chronic and systemic administration of the two mTOR inhibitors, rapamycin and metformin, on adult neural stem cells of the subventricular region and the dendate gyrus of the mouse hippocampus. While rapamycin decreased the number of neural progenitors, metforminmediated inhibition of mTOR had no such effect. Adult-born neurons are considered important for cognitive and behavioral health, and may contribute to improved health span. Our results demonstrate that distinct approaches of inhibiting mTOR signaling can have significantly different effects on organ function. These results underscore the importance of screening individual mTOR inhibitors on different organs and physiological AGE

show abstract

Metformin Activates an Atypical PKC-CBP Pathway to Promote Neurogenesis and Enhance Spatial Memory Formation

Cited by 412 publications

References 28 publications

Metformin Improves Neurologic Outcome Via AMP‐Activated Protein Kinase–Mediated Autophagy Activation in a Rat Model of Cardiac Arrest and Resuscitation

Metformin Improves Neurologic Outcome Via AMP‐Activated Protein Kinase–Mediated Autophagy Activation in a Rat Model of Cardiac Arrest and Resuscitation

Investigating Metformin for Cancer Prevention and Treatment: The End of the Beginning

Contrasting effects of chronic, systemic treatment with mTOR inhibitors rapamycin and metformin on adult neural progenitors in mice

Contact Info

Product

Resources

About