- Contact: Kathy Keatley Garvey
A team of nine entomology, cancer and nutrition researchers, in work published in the June 25 edition of Proceedings of the National Academy of Sciences, found that this new class of drug molecules stabilized the natural molecules and "effectively blocked neuropathic pain" - or pain caused by nerve damage. The research, conducted on rodents, is expected to lead to an orally active drug candidate for human clinical trials.
"This discovery offers a promising new approach to controlling chronic pain in diabetics," said lead author and project scientist Bora Inceoglu of the Bruce Hammock lab based in the Department of Entomology. "We were initially looking at anti-inflammatory compounds which regulate a key branch of an inflammatory pathway. These compounds are highly selective and inhibit a key enzyme called soluble epoxide hydrolase. Inhibition of this enzyme successfully blocks pain sensations."
"Our data indicate that this drug candidate is more effective on neuropathic pain caused by diabetes than any of the prescription drugs now on the market," said Hammock, a distinguished professor of entomology who holds a joint appointment with the UC Davis Comprehensive Cancer Center.
The research is significant in that in the United States alone, diabetics total 25.8 million or 8.3 percent of the population, and millions more - estimated at 79 million - are pre-diabetic, according to the American Diabetes Association. The Centers for Disease Control and Prevention tallies the economic burden of diabetes at approximately $170 billion a year.
Professor Daniele Piomelli, director of drug discovery and development at UC Irvine and who holds the Louise Turner Arnold Chair in Neurosciences, said that the study holds promise. He was not involved with the UC Davis research.
"Current medicines do not control well chronic pain produced by damage to the nerves," said Piomelli, professor of anatomy, neurobiology, and biological chemistry. "The study by Hammock and collaborators identifies a new class of chemical compounds that could change this situation. These compounds act by boosting natural signals, produced by the body, which curb both inflammation and pain. Exploiting the body's own 'medicines' is a great approach to creating safer medicines."
Piomelli cautioned that the experiments "were conducted in animals and need therefore to be confirmed by clinical trials."
UC Davis School of Veterinary Medicine anesthesiologist and pain specialist Alonso Guedes, also not involved in the study, said that the research shows that "stabilization of a class of bioactive lipid greatly reduces pain derived from nerve lesions. This novel and emerging knowledge may help fulfill a critical medical need for millions of animals and people afflicted by such pain modalities."
For the study, the UC Davis researchers used the Type I diabetes-induced pain model.
"Although Type II diabetes, associated with obesity, hypertension and metabolic disorders, is more prevalent in humans, to study the analgesic effects we selected Type I diabetes since pain manifests in an accelerated manner," said co-researcher and pharmacology doctoral candidate Karen Wagner. "In Type II diabetes patients, the occurrence of pain is delayed by many years of pre-diabetic or diabetic state, whereas our model affords a very rapid onset of pain."
Team member Fawaz Haj of the Departments of Nutrition and Internal Medicine, a leading nutrition and diabetes expert and a collaborator with the Hammock lab on diabetes, said that, "Intriguingly, in this study, acute treatments with soluble epoxide hydrolase inhibitors did not significantly affect the diabetic status of the animals, such as blood glucose levels and responses to insulin, indicating a selective effect on pain sensation. Neuropathic pain is a major co-morbidity of diabetes and an important debilitating factor that reduces the quality of life and this study accomplished a first in showing analgesic effects of soluble epoxide hydrolase inhibitors."
The researchers worked on a physiological pathway that was largely unknown until recently. When the enzyme, soluble epoxide hydrolase, is inhibited, "what happens is that the biological effects of a group of lipid metabolites, that are degraded by this enzyme, accumulate to effective levels," Hammock said.
"It turns out that a major function of these lipid metabolites is to selectively block pain sensation while sparing other types of sensations," Hammock said.
Inceoglu described neuropathic pain as "a debilitating condition and very difficult to treat with available painkillers or analgesics. Most analgesics are ineffective while those that reduce neuropathic pain often come with a variety of side effects that negatively affect the quality of life."
Nerve damage may be the result of trauma and chemotherapy agents or even diabetes itself. In diabetes, high levels of blood glucose damage the fine endings of sensory neurons that normally transmit pain-related information, the scientists explained. The aberrant signaling from the damaged neurons is interpreted as extreme sensitivity to touch and sometimes insensitivity to heat. "Even an innocuous touch, such as buttoning a shirt or the collar rubbing against the neck, or the vibration of being in a bumpy car ride can result in extreme pain," Inceoglu said.
"Almost half of advanced diabetic patients suffer from this painful condition which worsens as diabetes progresses," Inceoglu said.
Nerve and vascular damage can lead to gangrene and amputation. In advanced stages, the nerve damage leads to life-threatening heart and kidney diseases.
Physicians face a dilemma in selecting the right painkillers for the right conditions and with the least possible side effects, the UC Davis researchers said. Over-the-counter non-steroidal anti-inflammatory drugs (NSAIDs), for example, are completely ineffective for neuropathic conditions, Hammock said. Narcotics, like opium, can be addictive; withdrawal is difficult.
"Therefore, there is a great need to discover new approaches in combating pain," Hammock said. "New medications will effectively increase the number of choices for patients and physicians in treating intractable pain. Our study shows that the novel approach is effective and may not lead to the known side effects of narcotics or anti-depressants."
"It is still too early for these new compounds to reach the stores as analgesic drugs, since FDA approval takes a decade with very thorough evaluations," Inceoglu said. "However, once the feasibility of this approach is demonstrated, hopefully a major hurdle in moving toward clinical application is overcome."
The research, funded by the National Institutes of Health, supports earlier studies at UC Davis and later at Medical College of Wisconsin that showed the natural epoxy-fatty acids are analgesic molecules.
"Although very effective in blocking pain, unlike narcotics, these molecules do not affect coordination skills of animals," Inceoglu said.
The research team included Bora Inceoglu, Karen Wagner, Jun Yang, Nils Schebb, Sung Hee Hwang and Christophe Morisseau, all of the Department of Entomology; Bruce Hammock, Department of Entomology and UC Davis Comprehensive Cancer Center; Ahmed Bettaieb of the Department of Nutrition; and Fawaz Haj of the Departments of Nutrition and Internal Medicine.
"This is an interdisciplinary effort among neurobiologists, diabetes specialists, organic chemics and analytical chemists," said Hammock. "We could not have done this without sophisticated mass spectrometry equipment."
"The emerging mass spectrometric technique allowed us to analyze the tiny amounts of natural bioactive compounds, contributing to this pain discovery," said Yang.
Hammock directs the campuswide Superfund Research Program, the National Institutes of Health Biotechnology Training Program and the NIEHS Combined Analytical Laboratory. He is a Fellow of the Entomological Society of America, a member of the prestigious National Academy of Sciences, and the recipient of the UC Davis Faculty Research Lecture Award in 2001 and the Distinguished Teaching Award for Graduate and Professional Teaching in 2008.
Hammock's initial research involved regulating the development of insect larvae.
- Posted By: Brenda Dawson
- Written by: Kathy Keatley Garvey, (530) 754-6894, email@example.com
October 5, 2011
DAVIS — Integrated pest management (IPM) specialist Frank Zalom, professor and former vice chair of the UC Davis Department of Entomology and soon-to-be president of the 6000-member Entomological Society of America, is one of three Americans invited to speak at an international IPM workshop, Oct. 16-19, in Berlin, Germany.
Zalom, invited by the Federal Ministry of Food, Agriculture and Consumer Protection of Germany, will speak on “Stimulating Use of Professional IPM Consultants in Agriculture, Benefits for Farmers and Society,” on Monday, Oct. 17.
The event is sponsored by the Organization for Economic Co-Operation and Development (OECD), which helps governments of the developed countries tackle the economic, social and governance challenges of a globalized economy. The OECD is celebrating its 50th anniversary this year.
At the OECD workshop, to be held in the Julius Kuhn Institute, Federal Research Center for Cultivated Plants, invitees will develop recommendations related to the workshop themes, adoption and implementation of IPM in agriculture, contributing to the sustainable use of pesticides and to pesticide-risk reduction.
Wolfgang Zornback, chair of the OECD Working Group on Pesticides, German Federal Ministry of Food, Agriculture and Consumer Protection, will welcome the group.
The speakers will include noted IPM specialists from Australia, Denmark, Canada, Germany, Japan, Korea, New Zealand, The Netherlands and the UK. About 100 participants were either nominated by their governments or invited by the OECD. Half of the participants will include government representatives working on pesticide regulation, and half of the participants will include representatives from international/regional organizations: European Commission, Food and Agriculture Organization (FAO), European and Mediterranean Plant Protection Organization (EPPO), International Organization for Biological Control (IOBC), bio-pesticide industries, environmental and consumer organizations and academia.
Americans joining Zalom in Berlin will be Tom Green of the US/IPM Institute of North America in Madison, Wis., who will discuss “IPM in U.S. Schools: Challenges, Opportunities and Implications for IPM in Agriculture” and James VanKirk of the Southern Region IPM Center, North Carolina State University, who will address “IPM Pest Information Platform for Extension and Education.”
The OECD workshop will conclude with a visit to the German chancellery.
Zalom will begin a four-year commitment to the Entomological Society of America (ESA) this fall when he will be inducted as vice president-elect at the organization’s 59th annual meeting set Nov. 13-16 in Reno. He will subsequently move up to vice president and president and then serve a year fulfilling the duties of past president. The UC Davis entomologist will become president at the end of the 2013 annual meeting and then will serve as president at the 2014 meeting in Portland, Ore.
Zalom has been heavily involved in research and leadership in integrated pest management (IPM) activities at the state, national and international levels. He directed the UC Statewide IPM Program for 16 years (1986 -2001) and is currently experiment station co-chair of the Association of Public and Land-Grant Universities (APLU) National IPM Committee.
Zalom focuses his research on California specialty crops, including tree crops (almonds, olives, prunes, peaches), small fruits (grapes, strawberries, caneberries), and fruiting vegetables (tomatoes), as well as international IPM programs.
The IPM strategies and tactics Zalom has developed include monitoring procedures, thresholds, pest development and population models, biological controls and use of less toxic pesticides, which have become standard in practice and part of the UC IPM Guidelines for these crops.
In his three decades with the UC Davis Department of Entomology, Zalom has published almost 300 refereed journal articles and book chapters, and 340 technical and extension articles. The articles span a wide range of topics related to IPM, including invasive species management, biological control, insect population dynamics, pesticide runoff mitigation, impacts and management of newer, soft insecticides, development of economic thresholds and sampling methods, and determination of insect host feeding and oviposition preferences.
The Zalom lab has responded to six important pest invasions in the last decade, with research projects on glassy-winged sharpshooter, olive fruit fly, a new biotype of greenhouse whitefly, invasive saltcedar, light brown apple moth, and the spotted wing Drosophila.
Zalom is a fellow of ESA, American Association for the Advancement of Science, and the California Academy of Sciences.
Highly honored for his work, Zalom received the Entomological Foundation’s 2010 “Award for Excellence in IPM,” an award sponsored by Syngenta Crop Protection and given for “the most outstanding contributions to IPM.” In 2008 he was part of a team receiving an International IPM “Excellence Award” at the sixth International IPM Symposium. Also in 2008, Zalom was part of the seven-member UC Almond Pest Management Alliance IPM Team that received the Entomological Foundation’s "Award for Excellence in IPM.” The Pacific Branch of the ESA awarded Zalom its greatest honor, the C. W. Woodworth Award, in 2011.