The way an obesity medication treats Parkinson’s and Alzheimer’s diseases
Sarah-Jane Szikora. Prisoner (excerpt) / sarah-janeszikora.com
The latest generation of anti-obesity medications has captivated the world for their effectiveness in reducing weight and treating diabetes. But recently, according to a report in Nature, these drugs were found to have another fantastic ability: to suppress inflammation in various human organs, including the brain.
Semaglutide, which was presented to the world just over a year ago, has opened the era of a new generation of obesity drugs that can radically reduce weight without serious side effects.
The new medications imitate hormones known as incretins, which lower blood sugar levels and restrain appetite. This is a significant breakthrough in medical science, as the number of obese people around the world has grown exponentially. Since 1975, it has tripled.
According to the World Health Organization (WHO), in 2016, about 40% of adults were overweight, and 13% were obese. Being overweight often comes with an increased risk of diseases such as type 2 diabetes, heart disease, and some types of cancer.
Often, a healthy diet, physical activity, and willpower are not enough to manage obesity. There is growing evidence that most people’s bodies are naturally sized, and it is as if the body is «protecting its weight». But, unfortunately, even in this case, it is not without problems, mostly psychological. Since such a phenomenon as weight stigmatization and body image, no one has eliminated it.
However, the fight against obesity is essential not only in terms of physical and psychological health. Some scientists emphasize that it will allow healthcare systems to save huge amounts of money by reducing the multitude of conditions associated with this disease.
However, anti-obesity drugs classified as GLP-1 receptor agonists have another benefit discovered. Electron micrograph data show that they reduce inflammation in any tissue, including the surface of the skin, liver, heart, kidneys, lungs, tonsils, and teeth.
In addition, these drugs appear to be able to even reduce inflammation in the brain. And this gives scientists hope that they can be used effectively to treat at least two other diseases — Parkinson’s and Alzheimer’s. Because these diseases are known to be characterized by inflammation in the brain. There have already been more than 20 clinical trials in which obesity drugs are being studied as treatments for these two conditions.
GLP-1 receptor agonists include semaglutide, marketed under the brand names Wegovy for obesity and Ozempic for diabetes, and tirzepatide, marketed as Mounjaro for diabetes and Zepbound for obesity.
The drugs imitate an intestinal hormone called glucagon-like peptide 1 (GLP-1), which acts on the brain to reduce appetite as well as control blood sugar levels.
But a host of discoveries, many made in the past few years, demonstrate the ability of the hormone and its mimics to calm inflammation caused by attack by immune cells and immune system chemicals.
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In one experiment, a GLP-1 receptor agonist called liraglutide alleviated liver inflammation in mice with obese livers. A similar effect was observed in a pilot study in humans.
In other mice experiments, liraglutide showed anti-inflammatory potential in the kidney and heart. And GLP-1 itself reduced adipose tissue inflammation in obese and diabetic mice.
«We know from animal and human studies that GLP-1 appears to reduce inflammation almost across the board», says Dr. Drucker is the head of the experiment.
Reducing body weight and blood sugar levels caused by medications probably helps control inflammation. However, some of the drugs’ anti-inflammatory effects begin before significant weight loss is achieved. That’s why scientists believe a separate mechanism is at work here.
Drucker and his colleagues noticed a potential clue: GLP-1 receptors are absent from immune cells in many tissues in which the hormone and its mimics reduce inflammation, but they are abundant in the brain. To test the role of the nervous system, Drucker’s team started by inducing system-wide inflammation in mice.
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«Several GLP-1 drugs improved these mice and reduced inflammation», says Drucker. However, when the researchers used either genetic techniques or drugs to block GLP-1 receptors in the animals’ brains, the GLP-1 drugs no longer reduced inflammation in many tissues. The findings were published in the journal Cell Metabolism on Dec. 2.
The work helps move the field forward by demonstrating that, at least in mice, the drugs’ anti-inflammatory effects are achieved directly through GLP-1 receptors and mediated by the brain, said Nigel Greig, a pharmacologist at the National Institutes of Health in Baltimore, Maryland. He notes that previous studies 8 have found that only small amounts of these drugs can actually penetrate the brain.
«It’s quite remarkable that brain penetration is so low, but it’s so important for anti-inflammatory action, both systemic and within the brain», Greig says.
TARGETING PATHOLOGIC PROTEINS
The anti-inflammatory properties of GLP-1 drugs hold promise for the treatment of neurodegenerative diseases such as Parkinson’s and Alzheimer’s. Both are characterized by neuroinflammation that is ineffectively targeted by current therapies.
And in both diseases, abnormal proteins — such as beta-amyloid in Alzheimer’s disease and alpha-synuclein in Parkinson’s disease — interact with specific receptors in the brain, triggering a cascade of inflammation-inducing events.
According to Greig, excessive inflammation can contribute to disease. But agonists of the GLP-1 receptor appear to have the ability to suppress inflammation in the brain so that important processes, such as the birth of new neurons, can continue to occur, he notes.
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In one clinical trial, a GLP-1 receptor agonist called exenatide led to more significant improvement in the motor skills of people with Parkinson’s disease than placebo.
A study of the drug in a larger population of people with Parkinson’s disease is underway and is expected to be completed this year. Meanwhile, at least two clinical trials are testing semaglutide as a therapy for early-stage Alzheimer’s disease.
The drugs’ anti-inflammatory effects may also help make them more effective against diabetes and obesity, says Vinicius de Frias Carvalho, a biologist at the Inflammation Laboratory of the Oswaldo Cruz Institute in Rio de Janeiro, Brazil.
Semaglutide may play a key role here, providing strong protection against cardiovascular disease in people with obesity.
The usage of GLP-1 drugs to treat inflammation-related diseases could expand even further, especially given the drugs’ lack of significant side effects.
«There are many systemic diseases that have an inflammatory component», Greig says. He says it only makes sense to try drugs for such disorders when there is no effect of treatment, he says.
Original research: Obesity drugs have another superpower: taming inflammation