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The Upside to Nicotine?

New drugs that target the brain’s nicotine receptors, without the addictiveness of cigarettes, might help memory impairment in Alzheimer’s disease and schizophrenia.
July 28, 2006

Could drugs that mimic nicotine help boost brain power? Several companies and academic research groups are banking on it, with a handful of compounds showing promising results in preliminary human tests.

Nicotine, even without the carcinogenic effects of smoking, has major downsides: it’s addictive and can increase heart rate and blood pressure. But now scientists are trying to develop drugs that target the brain’s nicotine receptors to treat an array of cognitive impairments without these side effects. Several candidates are now being tested or about to be tested in clinical trials to treat Alzheimer’s disease, schizophrenia, and age-related memory loss.

“Everyone knows that smoking does good things and bad,” says David Lowe, chief scientific officer at Memory Pharmaceuticals, a biopharmaceutical company based in Montvale, NJ. “We’re trying to focus on receptors that mediate the good things.”

The good things include a positive effect on memory and attention, as evidenced both by cognitive testing and by the legions who file outside for smoke breaks before an exam or an important meeting. Meanwhile, smokers have a lower risk of developing Parkinson’s and possibly Alzheimer’s diseases. And people with schizophrenia and attention deficit disorder are much more likely to smoke than the general population; scientists believe that these patients may be unconsciously self-medicating to make up for some kind of deficit in the brain.

Several companies hope to turn these observations into therapies. Targacept, a drug development company based in North Carolina, has developed a compound that targets a specific type of nicotine receptor known as the alpha-4/beta-2 receptor. In a study of almost 200 people, both patients with age-related memory problems and healthy controls, researchers found that those who had taken the drug performed significantly better on tests of memory and attention. The company is now planning a larger trial of approximately 1,400 people, in collaboration with pharmaceutical manufacturer AstraZeneca, to determine whether the drug can improve cognitive problems in both Alzheimer’s disease and schizophrenia. Pharmaceutical giant Abbott is testing similar compounds in Alzheimer’s disease, schizophrenia, and ADHD.

Memory Pharmaceuticals is targeting a different type of nicotine receptor, known as the alpha-7 receptor. Preliminary studies in healthy volunteers showed that the compound could improve some types of memory. And a similar compound, developed at the University of Florida, has shown success in a small trial against the memory and attention problems that make it difficult for many people with schizophrenia to work and have meaningful relationships. (Schizophrenia medications currently on the market treat only the hallucinations and delusions that characterize the disease.) Like Targacept, Memory Pharmaceuticals plans to test its compounds in both Alzheimer’s and schizophrenia patients.

Experts caution that it’s still too soon to say if any of these drugs will prove successful enough to make it to market. “There have been nicotinic drugs studied clinically, but there is still a question of whether they are really effective,” says Steven Ferris, an Alzheimer’s expert at New York University Medical Center. He adds that such drugs are likely to have a high safety hurdle. “People who are going to take a cognitive enhancer because they are forgetful due to aging are going to want a very safe drug,” he says.

But there are plenty of reasons to believe the drugs could be effective. Nicotine stimulates neurons by mimicking acetylcholine, one of the brain’s major signaling molecules. When acetylcholine binds to specific receptors on brain cells, it triggers an electrical message that travels down the neuron and throughout the brain. Smoking a cigarette shoots a wave of nicotine into the brain, activating a subset of these receptors, known as the nicotinic acetylcholine receptors. The resulting jump in neural activity is the likely source of cigarettes’ concentration-boosting quality. “Things that enhance nicotinic receptor function may enhance overall synaptic function,” says Adam Boxer, a neurologist at the Memory and Aging Center at the University of California, San Francisco.

A shortage of acetylcholine could account for the cognitive problems seen in Alzheimer’s patients, according to one theory. Acetylcholine works in the brain to enhance information flow from the senses into the cortex, says Boxer, so a shortage of this neurotransmitter may block the brain’s ability to properly encode information into short-term memory. Scientists know from post-mortem studies that Alzheimer’s patients have fewer nicotinic acetylcholine receptors in their brains, though scientists aren’t sure how this deficit relates to the buildup of abnormal proteins that is the disease’s hallmark.

Alzheimer’s is currently treated with drugs known as cholinesterase inhibitors, which block the breakdown of acetylcholine so that more of the neurotransmitter is available to stimulate the neurons. These drugs can help some of the cognitive symptoms of Alzheimer’s, but it’s unclear whether they can slow or stop the progression of the disease. Worse, cholinesterase inhibitors have a relatively modest effect and don’t work for all patients.

Scientists studying nicotine say that selectively activating the nicotinic acetylcholine receptors might provide a more effective way to treat memory problems. “This is a very important target for early Alzheimer’s disease,” says Ken Kellar, a neuroscientist at Georgetown University in Washington, D.C. “It might slow down the progression of the disease and allow whatever function is there to be maintained, though it’s probably not going to reverse full-blown Alzheimer’s.”

Others, however, are skeptical that any cognitive enhancers are the best route for treatment. “Even if you find something that enhances the ability to form memories, damage from Alzheimer’s disease is still going on,” says Boxer. “If a large portion of cells die out or stop working, cognitive enhancers might stop working.”

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