Researchers at the University of California San Francisco (UCSF) have developed a new molecule that may help reduce dangerous side effects in a drug that could be useful for treating alcohol use disorder. Essentially, the molecule disarms the drug in most of the body, but can’t cross the blood-brain barrier, letting the drug get to work treating neurological triggers for alcohol misuse.
Rapamycin is an FDA-approved drug that’s being tested for a range of uses. As an immunosuppressant, it’s often given to patients after an organ transplant to help prevent their bodies from rejecting the new organ. It also shows promise in treating some forms of cancer, and mouse studies suggest it may improve healthspan and cognition.
Previous work by the UCSF team suggested that rapamycin could help reduce cravings in alcohol-dependent mice. It seemed to do so by blocking an enzyme called mTORC1 in the brain – in effect, disrupting the pleasurable but problematic associations that a person might have with a substance like alcohol.
Unfortunately, mTORC1 plays other vital roles throughout the body, so rapamycin carries the risk of some serious side effects, including liver and lung toxicity, sepsis, blood clots, and even a diabetes-like glucose intolerance. So for the new study, researchers developed a novel way to make sure the drug only targets the brain.
The work involved two new molecules. The first is called RapaLink-1, a version of rapamycin that binds to mTORC1 even more tightly, to inhibit it more strongly. The second molecule is called Rapablock, which cancels out the effect of the drug.
That might sound counterintuitive, but the idea is clever – RapaLink-1 can get into the brain no problem, but Rapablock is too big to get through the blood-brain barrier. That means that the only place the drug can get to work is in the brain, while the anti-drug renders it inert in the rest of the body, minimizing side effects.
The team tested the drug combo in mice engineered to model alcohol use disorder. Mice were given either no drug, RapaLink-1 alone, Rapablock alone, or both drugs. They were given the choice to consume alcohol, and their health was measured in a few ways.
And it seemed to work. Mice given both drugs had the best outcomes, reducing their alcohol intake and preference without causing liver toxicity, changing their glucose tolerance or other side effects. RapaLink-1 alone had similar benefits but with adverse effects. Rapablock on its own was not seen to have any effect, as was expected.
“We could see these side effects in mice who are taking rapamycin or RapaLink-1, and then when you give Rapablock, it’s like magic, the side effects are gone,” says Dorit Ron, senior author of the study.
The team says that the study could potentially be used to treat addictions to other drugs, which may work on the same neurological mechanism. But for now, it’s important to keep in mind that it’s only been tested in mice, so there’s no guarantee that the same results would be seen in humans.
The research was published in the journal Nature Communications.
Source: UCSF
