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Injured Brains Repaired with Metformin

Jul 6, 2012

Metformin might offer a therapy for nervous system damage…. 

In a recent study, in just 12 days of metformin, the number of new neurons involved with the ability to make new memories increased by about 30%.

According to Freda Miller, PhD, of the Hospital for Sick Children in Toronto, in a series of experiments in culture and in animals, the drug promoted the growth of new neurons, and in a classic behavioral test, mice treated with metformin formed new memories faster that those given a control substance.

A number of studies using stem cells to create new neurons may be shown to be an effective approach, but using either growth factors or small molecules have so far not panned out, they noted.

Miller and colleagues had previously showed that a molecule called CREB-binding protein, or CBP, was needed for the best development of embryonic neural precursor cells. They also showed that – to perform that task – CBP needed activation by another molecule, atypical protein kinase C, or aPKC.

In liver cells, they noted, the aPKC-CBP pathway is downstream of the AMP kinase and is turned on by metformin, which activates the AMP kinase.

Miller and colleagues hypothesized that metformin might activate the aPKC-CBP pathway in neural stem cells, thereby creating new neurons.

In a series of experiments in culture, they showed that, in fact, metformin treatment promotes neurogenesis, both in mouse and human neural stem cells.

In one experiment in mice, for example, metformin nearly doubled the number of new neurons produced by stem cells, compared with controls, a difference that was significant (P<0.05).

In living mice, 12 days of metformin increased the number of new neurons in the hippocampus – a region closely involved with the ability to make new memories – by about 30%, compared with controls, Miller and colleagues reported.

The process required normal levels of CBP; in animals with only one gene for the protein, metformin had no effect.

In the key experiment, mice were forced to learn the position of a platform hidden under the surface in a water-filled maze and then asked rapidly to learn a new position.

Mice were injected with 200 milligrams per kilogram of metformin or with saline for 38 days; on days 22 through 38, they learned the initial position of the platform, which provided an escape from the water-filled maze. Then the platform was moved to the opposite quadrant of the maze, and the animals were asked again to learn its position. In both tasks, the mice learned the platform positions with equivalent speed.

But when they were put back in the maze – this time with the platform removed — control mice spent more time searching for it in the original quadrant, while the metformin-treated animals preferentially looked in the new region (P=0.05 and P=0.04, respectively).

Both groups of animals spent the same amount of time looking in the other two quadrants, where the platform had never been.

The implication, Miller and colleagues argued, is that metformin helped the mice form their new memories of the second position. Analysis showed that their enhanced ability was paralleled by an increase in the number of newborn adult dentate gyrus neurons.

To confirm the link, the researchers repeated the experiment, but this time the metformin mice were also given a drug that selectively kills actively dividing cells, such as neural precursor cells. That combination blocked the effect of metformin on memory and also reduced the number of new neurons, they reported.

The implication, they concluded, is that metformin or something like it might be a “candidate pharmacological approach for nervous system therapy” in such disorders as ischemic stroke and Alzheimer’s disease.

Practice Pearls
  • This study in the mouse brain shows that metformin, by activating an aPKC-CBP pathway, recruits neural stem cells and enhances neural function.
  • Note that the ability to exogenously recruit adult neural stem cells might provide a novel therapeutic strategy to enhance endogenous repair of the injured or degenerating brain.

Wang J, et al “Metformin activates an atypical PKC-CBP pathway to promote neurogenesis and enhance spatial memory formation” Cell Stem Cell 2012; 11: 23-35.