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Extramural papers of the month

By Jerry Phelps
November 2010

Cause of vioxx-induced cardiovascular events determined

An international research team with funding from NIEHS has discovered a novel mechanism that may explain the heart attacks and strokes suffered by some long-term, high-dosage users of the arthritis drug Vioxx. This groundbreaking discovery may lead to safer drugs for millions of people who suffer chronic pain.

The team employed metabolomic profiling to analyze the plasma of laboratory mice given Vioxx. It found dramatic accumulations of an arachidonic acid metabolite known as 20-HETE. The metabolite is known to be a potent vasoconstrictor, and high levels of it could cause increases in the risk of heart attack and stroke. The research team believes that similar increases might be seen with other non-steroidal anti-inflammatory drugs.

Vioxx was pulled from the marketplace in 2004 after reports of heart attacks and stroke in patients taking the drug. It had been used by millions of people worldwide and showed great promise for disease and conditions marked by chronic pain and inflammation such as arthritis. The UC Davis scientists believe that their findings will open new paths for developing safer COX2 inhibitors. Agents that reduce the circulating levels of 20-HETE while providing the same pain relief may reduce the risk of adverse cardiovascular events.

Citation: Liu JY, Li N, Yang J, Li N, Qiu H, Ai D, et al. (http://www.ncbi.nlm.nih.gov/pubmed/20837537) Exit NIEHS 2010. Metabolic profiling of murine plasma reveals an unexpected biomarker in rofecoxib-mediated cardiovascular events. Proc Natl Acad Sci U S A 107(39):17017-17022.

Promising target for Parkinson's disease treatment

New research from Johns Hopkins University, with support from NIEHS, demonstrates that certain commercially-available drugs protect nerve cells from the lethal effects of Parkinson's disease in a mouse model. These drugs were shown to be an effective treatment in inhibiting the production of a protein known as LRRK2. This protein is known to be overactive in some Parkinson's patients and causes nerve cells to die.

The researchers monitored LRRK2 autophosphorylation and LRRK2-mediated phosphorylation of myelin basic protein with and without treatment with 70 kinase and phosphorylase inhibitors. Of the 70 tested, eight were found to block the effects of LRRK2 and two of those are known to cross the blood-brain barrier.

These two compounds, known as GW5074 and indirubin-3'-monooxine, were tested in a mouse model of LRRK2 neurotoxicity. Injections of these two drugs twice a day substantially prevented nerve cell death; one was almost completely effective and the other prevented cell loss by about 80 percent. The two drugs have similar structures leading the researchers to envision developing additional compounds around their core structure. The researchers are currently working to design more specific inhibitors of LRRK2 and they plan to license the technology they develop.

Citation: Lee BD, Shin JH, VanKampen J, Petrucelli L, West AB, Ko HS, et al. (http://www.ncbi.nlm.nih.gov/pubmed/20729864) Exit NIEHS 2010. Inhibitors of leucine-rich repeat kinase-2 protect against models of Parkinson's disease. Nat Med 16(9):998-1000.

Prenatal PAH exposure lowers IQ

New findings from a Columbia University study conducted in Krakow, Poland show that prenatal exposure to polycyclic aromatic hydrocarbons reduces IQ in children at five years of age. The study results recapitulate an epidemiologic study done by the same researchers on a population of women and children from New York City.

Healthy, pregnant non-smoking women were recruited into the study from 2001 to 2006. During pregnancy, the women completed a questionnaire and carried a personal air monitor for 48 hours to estimate their babies' exposure to air pollutants. They also provided a blood sample or cord blood sample at delivery. A total of 214 children were followed through 5 years of age. At that time the children were given a standardized intelligence exam called the Raven Coloured Progressive Matrices (RCPM) test.

The median prenatal exposure to PAHs was 17.96 nanograms per cubic meter of air. Children exposed to levels higher than this had an average decrease in IQ by 3.8 points. Adjusting for maternal intelligence, lead exposure or dietary intake of PAH did not alter the results. These findings cause concern because RCPM scores measured during the preschool period correlate with academic achievement later in life. The research team is continuing to follow these children to determine longer-term effects of PAH exposure.

Citation: Edwards SC, Jedrychowski W, Butscher M, Camann D, Kieltyka A, Mroz E, et al. (http://www.ncbi.nlm.nih.gov/pubmed/20406721) Exit NIEHS 2010. Prenatal exposure to airborne polycyclic aromatic hydrocarbons and children's intelligence at 5 years of age in a prospective cohort study in Poland. Environ Health Perspect 118(9):1326-1331.

(Jerry Phelps is a program analyst in the NIEHS Division of Extramural Research and Training.)



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