Researchers hope to turn lemon into lemonade
21 August 2002 11:15 EST
by Tabitha M. Powledge,
BioMedNet News
A
common and inexpensive drug, in everyday use for hundreds of years
by hundreds of millions of people, shows signs of being
therapeutic for a long list of ills - attention-deficit
hyperactivity disorder, Alzheimer's disease, pain, depression and
anxiety, and even obesity, among others. Yet research interest in
this potential cure-all has been slow to develop.
One reason is that the drug in its current forms offers drug
companies no possibility of substantial profit. A second reason,
perhaps more important, is that it is reviled as the world's most
addictive drug: nicotine.
Nevertheless, nicotine may at last be transformed from sow's
ear to silk purse, building on foundations laid in the past 20
years by a few researchers fascinated by the drug's properties,
both good and evil. There is now strong evidence, for example,
that nicotine affects appetite regulation and attentional focusing
and distractibility, says Neil E. Grunberg, long-time nicotine
researcher at the Uniformed Services University of the Health
Sciences in Bethesda, Maryland.
"Another one I think looks really good based on data I've seen
- but I don't know if anyone is trying to develop it - is nicotine
as an analgesic, perhaps on its own or as an adjunct," Grunberg
said. Because of nicotine's addiction potential, the Food and Drug
Administration would probably balk at permitting the addition of
nicotine to aspirin. But he speculates that the agency might go
along with adding it to morphine in a controlled hospital
situation: "It might potentiate the analgesic action and decrease
the amount of these other powerful drugs."
Kenneth Kellar of Georgetown University in Washington, DC,
reported two decades ago that nicotine administration increases
the number of nicotinic receptors in rat brains. He points out
that in vitro and animal studies have shown that nicotine
can protect neurons against damage and death. "It probably
interferes with apoptosis, but no one knows for sure," Kellar
said. In any case, the potential applications which include
stroke and spinal-cord injury - are many.
Along with two other long-time nicotine researchers, Paul
Newhouse of the University of Vermont College of Medicine, and
Edward D. Levin of Duke University, Kellar is planning to study
the effects of nicotine on older people with minimal cognitive
impairment (MCI), a mild condition that some view as a precursor
to Alzheimer's disease. "We're not going to cure or reverse
Alzheimer's, " Kellar said, "but if we can slow things down for a
year, we will have done a great service."
Kellar says the MCI study will employ nicotine skin patches,
which are widely sold without prescription as temporary aids to
quitting smoking. But nicotine in a patch is a blunt instrument.
The drug affects a huge array of neurotransmitter systems, with
the result, for example, that it increases heart rate and blood
pressure. So researchers have been looking for nicotine-like drugs
that will affect the various subtypes of nicotinic receptors
selectively.
This is no simple search. "It's taking a lot of work to try to
determine which neurotransmitter interactions and which nicotine
receptor subtypes are involved with which functional effects,"
Levin said. Still, "if we can separate out the effects of nicotine
stimulation on increasing blood pressure or heart rate or
addiction liability from those that improve cognitive performance
or reduce weight or anxiety or pain, then we can help with the
drug development effort as well as get some more basic information
about how the brain works." Several pharmaceutical companies are
reportedly working on synthetic nicotine analogs that target a
single receptor (and thus are patentable).
Newhouse thinks the work is proving difficult because the
receptors are ion channels. "This system seems to be a little
harder and more tricky to push around than, say, the G
protein-linked systems that many of our psychotropic drugs work
on," he said.
The hottest preclinical research areas for possible
nicotine-based treatment, according to Grunberg, are
schizophrenia, anxiety, and depression. Some 90% of schizophrenics
smoke, leading to speculation that they might be trying to
self-medicate with nicotine. But in two years of work with an
animal model of schizophrenia, researchers in his lab have failed
to show that nicotine alleviates schizophrenic-like symptoms. They
continue to believe in the drug's therapeutic potential, however.
"It may not be affecting the thought disorder," Grunberg said,
"but rather the mood-altering effects of schizophrenia - which
then brings us to anxiety and depression."
Smokers have long reported that cigarettes simultaneously calm
them down and pep them up, which is one reason researchers are now
investigating a relationship between those mood states and
nicotine. One of them is Khandra Tyler, a graduate student in the
lab of Yousef Tizabi at the Howard University School of Medicine
in Washington, DC. In studies with Wistar-Kyoto rats, an animal
model of depression, she has reported significantly reduced
immobility (a measure of rat depression) in rats dosed with
nicotine for nine days - the same effect researchers see when the
rats get standard antidepressant drugs.
"My goal was to look and see if nicotine had an antidepressant
effect in these animals," Tyler said. Having shown that, she now
has turned her attention to the rats' prefrontal cortex. "I'm
trying to pinpoint a brain region of interest and trying to
uncover a possible theory of how this may be happening."
"We have this entire new receptor system in the brain that we
really haven't quite figured out how to take advantage of," said
Vermont's Newhouse. "Think of this as like where they were with
benzodiazepines in the early '60s.
"The possibility exists that we're on the threshold of a whole
new way of influencing how the brain functions with this whole new
class of drugs," he explained. "Nicotine modulates the activity of
a lot of other receptor systems and brain circuits and so it
offers opportunity to tune brain circuits to get the kinds of
effects you want."
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