Using an anti-smoking drug to control neurons — ScienceDaily

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Now, a new job in anti-smoking drugs – as a chemical switch, can turn selected neurons on or off.

The drug locks in the design of proteins, called ion channels, to control whether neurons send information. By placing these proteins only in certain neuronal groups, scientists can target specific cells while keeping other neurons unaffected.

The system, developed by Scott Sternson, head of the Janelia Research Park at the Howard Hughes Medical Institute, has helped researchers unravel the brain circuits of mice and primates. One day, Sternson and his colleagues reported in the March 14, 2019 issue of the journal Science that it may lead to more treatments for diseases such as epilepsy or pain.

Other scientists who study this method, called chemical genetics, "often use molecules that are not suitable for human therapy," Sternson said. “This is still a lot of steps in the clinic, but we are trying to shorten this route.”

Chemical genetics has existed for about two decades: scientists have designed a pair of matched drugs and receptors that can alter the activity of mouse neurons. The drugs used in Sternson's system enter the brain and have been approved by humans. Its goal is ion channel protein, which directly affects neuronal activity, so the likelihood of side effects is small. He said that this may make it ultimately used in the clinic, which is an obstacle that chemical tools have not yet crossed.

Sternson's team has sorted out dozens of approved drugs before harvesting varenicline, a drug that reduces nicotine cravings. The researchers then adjusted the structure of two different ion channel proteins to make varenicline easier to bind. When the varenicline is locked, a protein triggers the neuron to send information. When varenicline is present, the other prevents neurons from sending messages.

"These are the most effective chemoreceptors described so far," Sternson said. Even low doses of varenicline – far below the level used to quit smoking – can have a major impact on neural activity.

Currently, scientists can use the system to map the link between neural activity and animal behavior. Sternson's team also designed varenicline variants that work better at targeting proteins and work at lower doses than the original dose.

"For research applications, you need the most selective tools," Sternson said.

On the road, the ability to selectively open or close cells can provide more precise treatment for certain diseases. For example, some patients with severe epilepsy undergo surgery to remove affected brain parts. Drugs directed only to neurons in this area may be a less invasive way to treat these patients. Sternson also envisions that future pain relief treatments will only deliver the drug to the injured area, not the entire body. He said that this is very important to reduce the incidence of painkiller addiction.

Janelia has licensed Sternson's technology to Redpin Therapeutics, a new company that is conducting preclinical research. These experiments are the first step in testing technology in people.

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