13 May 2020

Burning fat with brain-sparing amphetamines without harmful side effects

Researchers developed a new weight loss amphetamine that could potentially avoid the side effects of older treatments. Historically, amphetamine-like drugs such as FDA-approved phentermine have been some of the most popular anti-obesity drugs that have ever been prescribed. They work in the brain by suppressing appetite but, besides being addictive, can also have dangerous side effects such as increased heart rate, hypertension and hyperthermia. Now, the team of Ana Domingos, principal investigator at the Instituto Gulbenkian de Ciência (IGC) and Associate Professor of the University of Oxford, together with Gonçalo Bernardes, principal investigator at the Instituto de Medicina Molecular (IMM) and Reader at the University Cambridge, have modified amphetamine so that does not enter the brain while avoiding its known side effects.

Despite being officially declared a chronic disease there are very few long-lasting and cost-effective treatments for obesity. Amphetamines are one of the few and they reportedly act in the brain to reduce appetite and increase locomotion or stamina. However, these drugs are also known for strongly activating the sympathetic nervous system, the peripheral part of the nervous system known to accelerate the heart rate, constrict blood vessels and raise blood pressure. Amphetamines are thus infamously coined as sympathomimetic. “It was  always thought that amphetamine’s noxious effects on the cardiovascular system resulted from a their direct stimulation of the cardiac sympathetic nerves themselves, rather than from an central action in the brain, where we know it acts, for instance, to supress appetite”, highlights Ana Domingos, “despite the lack of experimental evidence favouring one mechanism over the other”. However, the researchers suspected that the cardiac side effects of amphetamines could indeed originate in the brain. And if this was true, they imagined that if they could design a drug that did not pass the blood-brain barrier, they could avoid these unwanted outcomes, while perhaps retaining an anti-obesity action.

To test their hypothesis, they attached polyethylene glycol (PEG) polymer chains to amphetamine, in a process known as PEGylation. Through this process, they created a larger, PEGylated amphetamine, which they dubbed PEGyAMPH. Because of its larger size, PEGyAMPH cannot penetrate the blood-brain barrier and the team showed that it is indeed absent is the brains of mice treated with PEGyAMPH, which did not show suppressed feeding nor increased locomotion. This lack of behavioural effects was another confirmation that the PEGyAMPH did not indeed cross the blood-brain barrier.

PEGyAMPH can still favour the activation of sympathetic neurons and increase peripheral sympathetic output onto adipose tissues. The researchers demonstrated that PEGyAMPH protected mice against obesity despite the absence of behavioural effects, such us decreased appetite and increased locomotor activity. “It was extremely exciting when we saw that, while untreated mice readily store excess fat the ones receiving treatment resisted weight gain” stated Inês Mahú, PhD student at the IGC and the first author of this study.

The newly designed drug has several advantages over traditional amphetamine treatments for weight loss. Because it does not pass the blood-brain barrier, PEGyAMPH is not addictive and it also does not affect cardiovascular function, thus avoiding the worrying side effects that amphetamines can cause. Moreover, it also improved blood glucose levels in mice by increasing sensitivity to insulin, thus preventing hyperinsulinemia, a condition that precedes the development of type 2 diabetes. Hence, PEGyAMPH reduces obesity with a size-effect comparable to that of AMPH, yet with a distinct mechanism in that it spares effects relating to brain action, overriding caloric intake by increasing energy expenditure.

Obesity is a major health issue across the world and is implicated in many serious health conditions such as diabetes, heart disease and cancer. Although PEGyAMPH is only validated pre-clinically, this new weight-loss drug brings hope for a safer and more cost-effective treatment than those currently available.  The IGC and IMM Innovation and Technology Transfer Units are working to license this technology, already patented, to industrial partners ensuring that this discovery reaches society.

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