From Toxins to Therapies

From Toxins to Therapies Is nitric oxide the next tool for pain management? Rui Wang, vice president of research at Lakehead University in Thunder Bay, Ontario. For years, nitric oxide, hydrogen sulfide, and carbon monoxide got a bad rap. Scientists considered them to be toxins, little more— that is, until Robert Furchgott, Louis Ignarro and Ferid Murad discovered that NO was both endogenous and a signaling molecule in the cardiovascular system, earning them the 1998 Nobel Prize in Physiology or Medicine. Since then, scientists have found that H2S and CO, too, act as signaling molecules—and the entire group may have therapeutic potential in conditions as diverse as heart failure, pain, and Alzheimer’s disease. “As soon as the biological importance of H2S became recognized, it became accepted that this group of molecules in our body are critical. We cannot live without them,” says Rui Wang, vice president of research at Lakehead University in Thunder Bay, Ontario. An Idea Spreads NO, CO, and H2S regulate functions such as inflammation, vasculature growth, and insulin production. Scientists are taking two approaches in drug development: They are either developing compounds that act on the enzymes that produce the molecules, or developing compounds that deliver the molecules directly to where they’re needed in the body. The three molecules are often called gaseous neurotransmitters because they act as signaling molecules in the body, but Wang says they are not true neurotransmitters and prefers the term “gasotransmitter,” or gaseous mediator. Nitric oxide is the most studied of the three gaseous mediators. Perhaps the most well characterized effect of NO is as a vasodilator, widening blood vessels—key to its role as the main ingredient of Viagra. But NO also has a critical role in heart function and embryonic heart development. Qingping Feng, an associate professor of medicine, physiology, and pharmacology at the University of Western Ontario in London, has found that NO is necessary for fetal heart development, and also for preventing heart failure following a heart attack. Mice that lack an enzyme that produces NO in their hearts often die soon after birth (Am J Physiol Cell Physiol, 291:1240–46, 2006). “Basically, they have holes in their hearts,” says Feng. In addition, following heart attack, mice without a different NO-producing enzyme, located in the nervous tissue, are more likely to die due to arrhythmia, he notes (Circulation, 120:1345–54, 2009). "All the work has really made people start to believe that there's this new class of substances that affects our body in ways beyond our imagination," says Rui Wang. Feng plans to collaborate with cardiologists to determine whether there are heart patients who lack the nervous system–associated enzyme. If so, this could be a potential target for new cardiology drugs. He has also begun studying the role of NO in diabetes, for which there appears to be an association. And then there is pain, in which NO appears to play an important role. A Toronto-based company, NeurAxon, is currently working on five different compounds, all of which inhibit the NO enzyme in the nervous tissue, which can interact with nociceptors to cause pain. NeurAxon’s most advanced compound, for the treatment of acute migraines, is in Phase II clinical trials. James Henry, the director of the Michael G. DeGroote Institute for Pain Research and Care at McMaster University in Hamilton, Ontario, who also serves on NeurAxon’s scientific advisory board, says he is encouraged by the company’s early results. Not only are the compounds effective at reducing pain, but they also seem to produce fewer side effects than other types of drugs for chronic pain. The company was recently awarded a grant by The Michael J. Fox Foundation for $267,000 to study inhibition of the neuronal form of the enzyme in Parkinson’s disease, where it acts on a pathway that induces neuronal death (Brain Res, 1261:7–19, 2009). Certainly, new approaches to pain are needed. “There’s many different types of chronic pain that are still very difficult to treat,” says Cathy Cahill, the research chair of chronic pain at Queen’s University in Kingston, Ontario. However, by reducing NO, these pain drugs may potentially have cardiovascular effects, she cautions. The drugs being developed by NeurAxon, though, specifically inhibit an NO-producing enzyme in the nervous tissue called neuronal nitric oxide synthase, which has less of an effect on blood pressure than another NO-producing enzyme found in the endothelium, thus should limit side effects, says Henry. In Phase I trials, the migraine drug did not have any adverse cardiovascular effects (Clin Ther, 32:146–50, 2010). Lakehead University Resarch Team Another Pipeline Other companies developing pain relievers are taking a different approach, targeting the same pathways as current pain medications but using NO to reduce the side effects of those medications, such as increased blood pressure and gastrointestinal problems. Instead of inhibiting the neuronal NO enzyme, which primarily affects the brain and neuropathic pain, a traditional anti-inflammatory is coupled to a compound that releases NO to act as a vasodilator and help keep blood pressure low. John Wallace, the director of the Farncombe Family Digestive Health Research Institute at McMaster University, has been involved with several pharmaceutical companies that are taking this approach. A company he cofounded, NicOx, currently has a marketing application for an osteoarthritis drug under review by the US Food and Drug Administration. “It’s very similar to a drug already on the market, naproxen, except that it’s modified chemically so that it releases nitric oxide after the drug has been absorbed,” he says. Lakehead University’s Wang is also excited about the prospects of H2S. He has found that H2S plays an important role in blood vessel growth and wound healing (Proc Nat Acad Sci, 106:21972–77, 2009). Another company Wallace founded, Antibe Therapeutics, is focused entirely on developing H2S-based drugs for the treatment of inflammatory bowel disease, acute and chronic joint pain, and irritable bowel syndrome. Wallace says Antibe Therapeutics is currently running toxicology tests and expects to begin human trials within the next 6 months. Meanwhile, Wang is also examining how H2S can be used as a biomarker for asthma, diabetes, atherosclerosis, and even neurodegenerative disease. Like NO, the role of H2S is complex, and in some areas of the body it can be harmful, says Wang. In type 1 diabetes, the pancreas produces too much H2S, which destroys the cells responsible for producing insulin and causes the remaining beta cells to release less insulin. Still, the changing science is generating a substantial amount of excitement. “All the work has really made people start to believe that there’s this new class of substances that affects our body in ways beyond our imagination,” Wang says.

From Toxins to Therapies

From Toxins to Therapies

Is nitric oxide the next tool for pain management?

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Monica Heger

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December 2010

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