Nathan R. Tykocki
Graduate Student, Pharmacology and Toxicology

I know all-to-well the addictive powers of cigarettes, and trying to quit is a Sisyphean task to say the least.  The hardest thing to overcome are those cravings – the need to have the pleasure caused by lighting up.  But now a new option exists to combat that drive to smoke, and it’s not what you would think.

NicotineNicotine (ironically similar to niacin, an essential human nutrient), can cross the blood-brain barrier and ultimately increase dopamine levels in the reward circuits in the brain.  This increase in dopamine leads to relaxation, euphoria, and the continued urge to smoke.  Repeated nicotine use causes a downregulation of dopamine synthesis, but becomes more sensitive to nicotine’s ability to release dopamine in the reward pathways in the brain.  Thus, the “lows” are lower, the “highs” are higher, and a bad habit rapidly becomes an addiction shared by more than 44 million Americans.

Current pharmaceuticals used to aid in smoking cessation work in the brain in two ways: drugs like bupropion (“Zyban”) that help maintain the levels of dopamine in the brain to prevent the between-smoke “lows”, or those like varenicline (“Chantix”) that decrease the sensitivity to nicotine and prevent the during-smoking “highs”.  While these drugs have been shown clinically to decrease the rate of smoking versus placebo in the short-term, they both come with a myriad of unpleasant side-effects that decreases patient compliance and lower long-term cessation dramatically.  Nausea, vomiting, lethargy, and vivid dreams (and trust me – the dreams can be V-I-V-I-D!!)  make cigarettes seem not-so-bad in comparison.  So what can we do??

Here’s where the new idea comes in.

NicVAX (click image to visit microsite)

Instead of fighting the effects caused by nicotine, a new drug called NicVAX (currently in stage III clinical trials) combats nicotine itself.  In fact, the drug doesn’t work in the brain at all!  According to the company’s website, NicVAX stimulates the body’s immune system to create antibodies against nicotine.  These antibodies will specifically recognize nicotine and bind to it, forming a complex that is too large to cross into the brain and activate the reward centers associated with smoking.  In short: no reward equals decreased smoking.  Because this new drug stimulates the body to produce antibodies against nicotine, it may work much longer than traditional smoking therapies which lose their efficacy relatively rapidly if use is discontinued.  Since it is a vaccine, the body will continue making antibodies to nicotine for 6-12 months after initial drug treatment.  The most interesting bit about this drug is the extremely low incidence of side-effects.  Since it does not work to counter the effects of nicotine in the brain, there are apparently very few psychological side-effects.  This increases patient compliance, and will hopefully lead to greater long-term cessation success.

Now if only there were a jelly doughnut vaccine…

by James J. Galligan, Ph.D., Associate Chair,
Department of Pharmacology and Toxicology

As described previously,  anti-oxidants from unusual sources (hydrogen sulfide, rotten egg gas) may be helpful in reducing the damage caused by heart attacks and strokes.  The use of hydrogen sulfide produced by the human body as an anti-oxidant illustrates the great lengths we will go to protect ourselves against injury.   A recent study (https://www.sciencemag.org/cgi/content/full/325/5946/1380) published in Science magazine shows that some bacteria are also smart enough to use self produced anti-oxidants to protect them against injury caused by antibiotic drugs.

Nitric Oxide molecule

Nitric Oxide molecule

Nitric oxide (NO) is produced by an enzyme called nitric oxide synthase (NOS).  NOS uses the amino acid L-arginine as the precursor for NO production.  NO is used as a signaling molecule in the nervous system, in blood vessels and by immune cells that use NO to kill invading organisms.  It seems that some bacteria also have their own version of NOS called bacterial NOS (bNOS) that  produces NO from L-arginine.  In addition to its’ role as a signaling molecule in the nervous, cardiovascular and immune systems, NO can act as an anti-oxidant.  NO combines with oxygen radicals reducing the injury that these radicals can cause to cells and tissues.

Nitric Oxide structure (Nitric Oxide at the Chemical Database)

Nitric Oxide structure (Nitric Oxide at the Chemical Database)

What is interesting about bNOS is that many antibiotic drugs kill bacteria by producing oxygen radicals.  Different kinds of bacteria also live in competition with one another.  Bacteria compete for nutrients, and eliminating the competition helps one kind of bacteria survive – at the expense of other bacteria.  Bacteria can generate oxygen radicals to kill off their competitors.  However, the targets of these oxygen radicals have evolved their own anti-oxidant protective mechanism in the form of bNOS and NO production.  NO interacts with oxygen radicals produced by antibiotics and by other bacteria.  This interaction inactivates the oxygen radicals protecting the bacteria against these toxic chemicals.

This is a very interesting study of the biology of bacteria and their interaction with their environment.  The study also provides new insights into how we might best attack bacteria that infect humans, animals and plants.  Perhaps in addition to conventional antibiotic drugs, we could add on an inhibitor of bNOS removing their protection against oxygen radicals.  Treatments for human disease can come from the most unexpected places.  Basic research comes to the rescue again.

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