GLP-1 receptor agonists can dial down inflammation in the brain, raising hopes for treating neurodegenerative diseases

A recent review listed more than 20 clinical trials that are exploring the drugs as therapies for the two conditions.

“The next generation of drugs could be even more targeted to reduce these new inflammation pathways that we’ve identified,” says Daniel Drucker, an endocrinologist at the University of Toronto in Canada who co-authored a study investigating how the drugs dampen inflammation. “Maybe they would be more effective.”

The GLP-1 receptor agonists include semaglutide, which is marketed as Ozempic for diabetes and Wegovy for obesity, and tirzepatide, marketed as Zepbound for obesity and Mounjaro for diabetes. The drugs mimic a gut hormone called glucagon-like peptide 1, which acts on the brain to dampen appetite, in addition to controlling blood sugar levels. But many previous studies have showcased the ability of the hormone and its mimics to calm inflammation, caused by an onslaught of immune cells and immune-system chemicals.

In one experiment, a GLP-1 receptor agonist called liraglutide reduced liver inflammation in mice with fatty liver. A similar effect was seen in a pilot study with people. In other experiments in mice, liraglutide demonstrated anti-inflammatory potential in the heart and the kidneys. GLP-1 itself reduces inflammation in fat tissue in obese and diabetic mice.

The reductions in blood sugar and body weight that the drugs trigger probably help to control inflammation. However, some of the drugs’ anti-inflammatory effects start even before meaningful weight loss is achieved. This is why scientists think there’s a separate mechanism at play.

Drucker and his team observed a potential clue: receptors for GLP-1 are scarce in immune cells in many tissues in which the hormone and its mimics reduce inflammation, but are abundant in the brain. To test the role of the nervous system, Drucker’s team began by inducing system-wide inflammation in mice.

“Multiple GLP-1 drugs made those mice better and reduced inflammation,” Drucker says. However, when the researchers used either genetic methods or drugs to block GLP-1 receptors in the animals’ brains, the GLP-1 drugs no longer reduced inflammation in multiple tissues. The findings were published in Cell Metabolism on December 2.

The anti-inflammatory powers of the GLP-1 drugs are promising for treating neurodegenerative diseases such as Alzheimer’s and Parkinson’s. Both are characterized by neuroinflammation that is not effectively targeted by current therapies. In both disorders, pathological proteins — for example, alpha-synuclein in Parkinson’s and beta-amyloid in Alzheimer’s — interact with certain receptors in the brain to induce a cascade of events that cause inflammation.

Excessive inflammation can contribute to disease, says Nigel Greig, a pharmacologist at the National Institutes of Health in Baltimore, Maryland. But GLP-1 receptor agonists seem to have the ability to knock back inflammation in the brain so that important processes, such as the birth of new neurons, can continue to occur, he notes.

In one clinical trial, a GLP-1 receptor agonist called exenatide resulted in greater improvement in the abilities of patients with Parkinson’s than did a placebo. The medication is now being assessed in a trial involving a larger population of people with Parkinson’s and should conclude this year. At least two clinical trials are investigating semaglutide as a therapy for early-stage Alzheimer’s disease.

The drugs’ anti-inflammatory action might also help to boost their effectiveness against diabetes and obesity, says Vinicius de Frias Carvalho, a biologist at the Inflammation Laboratory at the Oswaldo Cruz Institute in Rio de Janeiro, Brazil.

Both conditions “are also inflammatory diseases”, he says. Semaglutide’s anti-inflammatory action might play a part in an effect that recently made headlines: the drug provides strong protection against cardiovascular disease in people with obesity.

The use of GLP-1 drugs to treat inflammation-related diseases could expand even further, Greig says, especially given the drugs’ lack of significant side effects. “There are so many systemic disorders where there’s an inflammatory component,” he says. It only makes sense, he says, to try the drugs against such disorders if there’s no effective treatment.

Reference:

Lenharo, M. (2024). Obesity drugs have another superpower: Taming inflammation. https://doi.org/10.1038/d41586-024-00118-4