Metformin May Help Renew Neurons

Pauline Anderson

July 10, 2012

July 10, 2012 — New research suggests that the widely used type 2 diabetes drug metformin may be useful in stroke, Alzheimer's disease, and other conditions involving injured or degenerating brain cells.

Animal studies showed that metformin activates a key pathway (aPKC-CBP) that promotes neurogenesis and enhanced hippocampus-dependent spatial memory formation in study animals. Results also showed that the drug has similar activity on human neural precursors, increasing the likelihood that it might enhance neurogenesis in the human brain as well.

These findings could provide the basis for a therapeutic strategy for human nervous system disorders, according to the study authors from the University of Toronto and Hospital for Sick Children (HSC) in Toronto, Ontario, Canada.

The research was published online July 5 in Cell Stem Cell.

"What this gives us then is a very widely used, safe human drug that recruits endogenous neural stem cells, at least in rodents, to promote the genesis of new neurons, and gives us the chance to test the idea that if we could do that same thing in humans, we may be able to promote repair or recovery at least in some situations," Freda D. Miller, PhD, senior author on the paper, said in a video commentary on the Cell Stem Cell site.

Alternative to Growth Factors

There's growing evidence that neural stem cells play a role in repair of the injured or degenerating brain, and that if adult neural stems cells could be recruited, this might provide a novel therapeutic strategy, the authors write. Some studies have attempted to recruit these stem cells using growth factors, but this approach has not been successful, in part because of the difficulty involved in delivering growth factors to the nervous system.

An alternative to growth factors are small molecules that promote stem cell self-renewal and/or differentiation by defining relevant signaling pathways. Previous research showed that the CREB-binding protein (CBP) maximizes embryonic neural precursor cell development, and that this protein is activated by atypical protein kinase C (aPKC).

In liver cells, this aPKC-CBP pathway is activated by metformin, which suggests that this drug might activate aPKCs in neural stem cells, and by doing so may recruit adult neural precursors and enhance neural function.

"Thus, metformin represents a candidate pharmacological approach for recruitment of neural stem cells in the adult human brain, a strategy that might be of therapeutic value for the injured or degenerating nervous system," the authors note.

A series of experiments conducted by Dr. Miller and colleagues, with first author Jing Wang, demonstrated that compared with mice given a control substance, those treated with metformin had about a third more new neurons in the hippocampus, and almost double the number of new neurons produced by stem cells.

And in a spatial learning maze test, mice given metformin (200 mg/kg) were significantly better able to learn the location of a submerged platform compared with those given a sterile saline solution.

Researchers also carried out experiments that suggested that metformin could promote neurogenesis from human neural stem cells.

Among other things, findings of the experiments support the conclusions that metformin

  • Activates the aPKC-CBP pathway in neural precursors, and that this activation promotes genesis of both human and rodent neurons in culture

  • Promotes neurogenesis in the adult brain, enhancing the number of newly differentiated neurons in both the olfactory bulb and the hippocampus

  • Enhances spatial memory function coincident with a long-term increase in the number of new adult dentate gyrus neurons

The authors note that there is "widespread interest" in using metformin in patients with early-stage Alzheimer's disease because "an increasing proportion of these individuals are also diabetic, and hyperinsulinemia may enhance the onset and progression of neurodegeneration."

Recent cancer research has also focused on the potential antitumor effects of metformin.

Cell Stem Cell. 2012; Published July 5, 2012. Abstract.

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