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Engineered Enzyme eliminates nicotine dependence in preclinical tests

Researchers at Scripps Research have successfully tested a possible new treatment with smoking cessation in rodents. In a study published…

Researchers at Scripps Research have successfully tested a possible new treatment with smoking cessation in rodents.

In a study published online at Science Advances on October 17, 2018, researchers gave nicotine-dependent rats a constructed enzyme that breaks down nicotine in the blood before it reaches the brain. The treatment quickly reduced the animals’ motivation to take nicotine, reversed their signs of nicotine addiction, and prevented them from returning when they got access to nicotine again.

“This is a very exciting approach because it can reduce nicotine addiction without requiring desires and other severe withdrawal symptoms, and it works in the blood, not the brain, so its side effects should be minimal,” says research scientist Olivier George, Scripps Research .

Nicotine addiction is what prevents smokers smoking despite all the harm it does for their health. Researchers estimate that about 60 percent of people trying to get cigarettes quit as daily smokers &#821

1; and about 75 percent of the daily smokers fall back to end.

Reverse nicotine addiction by preventing nicotine in tobacco smoke from reaching the brain has long been considered a promising strategy. However, earlier efforts have not given drugs that reduce levels of blood levels to be effective.

The enzyme tested in this study, NicA2-J1, is a version of a natural enzyme produced by the bacterium Pseudomonas putida . It was modified – to optimize its strength, its residence time in the blood and other pharmacological properties – through the laboratory of Kim Janda, Ely R. Callaway, Jr. Professor of Chemistry at Scripps Research. Studies published in recent years by Janda and colleagues have shown that NicA2-J1 greatly reduces blood levels of nikotin in rodents, and it is effective in a simple rat model of nicotine addiction.

For the new study, researchers tested the enzyme in more sophisticated animal models, developed in Georges laboratory, which better mimic people’s smokers addicted to nicotine.

For a set of experiments, lab rats used 21 hours a day for 12 days in a chamber where they could press a lever to give an intravenous infusion of nicotine. In this way, they learned how to administer nicotine and became addicted to it. After the twelve days, they only gained access to nicotine every 48 hours, resulting in withdrawal symptoms between access periods and escalating their intake – a classic sign of deepening of addiction – when they recovered.

Animals treated with the highest dose of NicA2-J1 (10 mg / kg) continued to administer nicotine when they could, but showed very low blood levels in the molecule as compared to controls that did not receive the enzyme. Signs of nicotine withdrawal, such as susceptibility to pain and aggressive behavior, were reduced correspondingly during non-access periods, compared to untreated controls.

“It’s as if they smoke 20 cigarettes but receive a nicotine dose of just one or two, so it made their withdrawal process much less serious,” says study author Marsida Kallupi, a doctor, a postdoctoral researcher at George Laboratory.

Surprisingly, the acute effect of NicA2-J1 on the nicotine rats was also beneficial. Typically, when an animal is highly nicotine-dependent, a drug will suddenly block all nicotine activity to trigger withdrawal symptoms immediately. “It’s like quitting” cold turkey “- the subject will feel awful, says George.” What’s unique with this enzyme, however, is that it removes enough nicotine to reduce dependence, but leaves enough for the animals to to be difficult. “

One of the other characteristics of nicotine addiction is Continuation of nicotine-seeking, despite serious adverse consequences. Impacts for human tobacco smokers include short-term worsening of lung function and physical fitness as well as long term risks for cancer, heart disease, stroke and many other diseases George, Kallupi and colleagues showed that NicA2-J1 could reduce this compulsive motivation for nicotine in the dependent rats. When each pressurized nicotine pushed a 30 percent chance of electric shock on the feet, they reduced the NicA2-J1 treated rats – unlike untreated controls – fast their guns.

The researchers mode laced yet another important aspect of nicotine addiction, the resilience sensitivity: They took the rats of nicotine for 10 days and gave them an injection of nicotine to resurrect their desire for the drug and recovered access via the hackers. Untreated rats that were primed in this manner increased their staple presses with a large amount of NicA2-J1-treated rats much less so. The same beneficial effect of NicA2-J1 was seen when researchers triggered relapse with a stress inducing drug, similar to the way stress causes relapse in humans.

With such promising results in preclinical tests, Scripp’s Research Team now hopes to take NicA2-J1 in human clinical trials. Before that, researchers will do further work to optimize NicA2-J1’s properties as a drug. They also plan to test it on rats against varenicline (Chantix), a compound that blocks nikotin activity in the brain and is currently seen as the most effective drug for smoking cessation.

Source: Scripps Research

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