Metformin Seen to Aid Cognition, Brain Biology in MS Rat Model

Treatment with the diabetes medication metformin was seen to lessen cognitive impairment, improve coordination, and normalize neuronal activity in a rat model of multiple sclerosis (MS).

The study reporting these findings, “Evaluation of the effects of metformin as adenosine monophosphate-activated protein kinase activator on spatial learning and memory in a rat model of multiple sclerosis disease,” was published in the journal Biomedicine & Pharmacotherapy.

Metformin, an oral treatment of type 2 diabetes, is thought to work mainly by activating a protein called AMPK (adenosine monophosphate-activated protein kinase), which has a variety of effects on different tissues. Several of these effects work to lower blood sugar levels.

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AMPK activation also has antioxidant and anti-inflammatory properties, and metformin’s effects on neurological disorders like MS has become a subject of exploration for researchers.

A pair of scientists at Zahedan University of Medical Sciences in Iran conducted a series of tests to evaluate metformin in animals with MS-like disease.

To model MS, the researchers injected a chemical called ethidium bromide (EB) directly into the rats’ hippocampus — a part of the brain that is important in memory, and that often becomes damaged in MS. EB destroys the myelin sheath, the fatty coating around neurons (nerve cells) that helps them send electric signals. MS is caused by the immune system launching erroneous inflammatory attacks that damage the myelin sheath.

Rats injected with EB showed deficits in coordination and cognition, as measured with standards like the rotarod test, where animals are placed on a rotating rod and evaluated by how long they can stay balanced before falling, and the Morris water maze, which tests memory and learning by training rats to swim to a hidden platform in a pool.

When rats in this model rats were treated with metformin — given in the days following EB injection for two weeks — their ability to perform on these tests improved significantly.

EB injection into the hippocampus causes abnormalities in neuronal activity, such as a reduced rate of firing (sending electrical signals). These alterations are reflective of similar changes that occur in MS. When rats in this MS model were treated with metformin, their firing rate increased.

In addition to treating the rats with metformin alone, some animals were given metformin and another chemical, called Compound C (CC), which blocks AMPK, the protein metformin activates. Co-treatment with CC was found to inhibit the beneficial effects of metformin to some extent.

“Interestingly, while AMPK activation by [metformin] improved cell recording and behavioral studies in our study, inhibition of AMPK by CC decreased the hippocampus neuronal firing and behavioral parameters,” the researchers wrote.

Based on this finding, the scientists speculated that AMPK activation may be a useful treatment approach for MS. They called for more research on the topic.