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The current breakthrough weight-loss drugs are only the beginning, according to Danish researchers hard at work on a new treatment that targets the brain's natural plasticity, which could offset bad side effects and provide more long-term benefits. "I consider the drugs available on the market today as the first generation of weight-loss drugs," said Christoffer Clemmensen, Associate Professor at the Novo Nordisk Foundation Center for Basic Metabolic Research, at the University of Copenhagen, and senior author of the study. "Now we have developed a new type of weight-loss drug that affects the plasticity of the brain and appears to be highly effective." Where current GLP-1 drugs mimic the natural hormonal response following eating, signaling 'fullness' and slowing the emptying of the stomach, the new treatment instead uses GLP-1 peptide to "smuggle" molecules across the blood-brain barrier and into the appetite control center, to then block the NMDA receptor protein. This receptor has previously gained interest among researchers for its ability to aid in changing up brain connections to aid learning and memory. And unlike what's currently on the market, this new approach could harness the brain's plasticity to cement new pathways in its appetite center - pathways that would remain in place long after treatment had ceased. "What is spectacular - on a cellular level - about this new drug is the fact that it combines GLP-1 and molecules that block the NMDA receptor," said researcher Jonas Petersen, the study's first author and the chemist who synthesized the molecules. "It exploits GLP-1 as a Trojan Horse to smuggle these small molecules exclusively into the neurons that affect appetite control. Without GLP-1, the molecules that target the NMDA receptor would affect the entire brain and thus be non-specific." It still has a GLP-1 backbone, but it's an entirely new approach requiring a much smaller dose and potentially stamps out the unpleasant side-effects that many experience while taking GLP-1 agonists like semaglutide and tirzepatide. And, given the current cost and invasiveness of frequent treatment needed to keep the weight off, this drug could offer long-term benefits, with intermittent doses enough to maintain its effectiveness. "This family of molecules can have a permanent effect on the brain," said Clemmensen. "Studies have demonstrated that even a relative infrequent treatment can lead to persistent changes to the brain pathologies. We also see molecular signatures of neuroplasticity in our work, but in this case in the context of weight loss." The catch? It's still at the stage of helping obese mice lose weight. But in these pre-clinical trials, it's far outperforming what's on the market now and is expected to move to tests on humans. "The effect of GLP-1 combined with these molecules is very strong," Clemmensen said. "In some cases, the mice lose twice as much weight as mice treated with GLP-1 only. "Our studies in mice show side effects similar to those experienced by patients treated with the weight loss drugs available on the market today, including nausea," he added. "But because the drug is so effective, we may be able to lower the dosage and thus mitigate some of the side effects in the future - though we still don't know how humans respond to the drug." The researchers note that while this study is focused on obesity, this drug-delivery system has potential to offer similar site-specific treatment for conditions such as neurodegenerative diseases or psychiatric disorders. Meanwhile, last week the Danish pharmaceutical powerhouse Novo Nordisk, which brought Ozempic into the spotlight, announced it would soon begin a human trial using the GLP-1 agonist drugs as a potential treatment for alcohol use and liver damage. They're already being considered as a new treatment for Alzheimer's disease. The current study was published in the journal Nature. Source: University of Copenhagen