Merle G. Paule, PhD

SmartTots Steering Committee Member | Steering Committee, FDA Alternate
Merle G. Paule, PhD

Merle G. Paule, PhD

U.S. Food and Drug Administration

Scientific Profile

Areas of Specialty: Dr. Paule specializes in neuropharmacology/toxicology and developmental neurotoxicology. He has extensive experience conducting cognitive function assessments and pediatric studies in animal models, including non-human primates.

Research Activities: As the FDA’s Director of the Division of Neurotoxicology at the National Center for Toxicological Research (NCTR), Dr. Paule leads research focused on identifying approaches and methods for assessing the neurotoxicity of known or suspected neuroactive chemicals responsible for inducing brain-related disorders. His division facilitates FDA chemical evaluation and regulation, elucidating neurotoxic effects of therapeutic drugs, food additives and products, and other chemical substances. The ultimate goal of this research is to determine ideal dosage levels or conditions at which these chemicals can be used most effectively with minimal adverse side effects, securing the safety of the consumer. Dr. Paule’s division employs multidisciplinary approaches to develop quantitative biomarkers and identify biological pathways associated with neurotoxicity, permitting opportunities for improved risk assessment and the development of novel therapeutics.

 

Currently, Dr. Paule is conducting research projects directly related to SmartTots, including animal-based studies regarding the potential effects of anesthetics on the developing brain. His research in rodents and non-human primates has been instrumental in alerting the medical and scientific communities of the potential neurotoxic properties of commonly used anesthetics and sedatives. Dr. Paule’s direct experience with anesthetic-induced neurotoxicity is a significant asset to the SmartTots Scientific Advisory Board.

SmartTots

Scientific Advisory Board, Member
Steering Committee, FDA Alternate

National Center for Toxicological Research, U.S. Food and Drug Administration

Director, Division of Neurotoxicology
Head, Behavioral Toxicology Laboratory
Senior Biomedical Research Scientist, Division of Neurotoxicology

Education

University of California, Davis School of Medicine – PhD, Pharmacology and Toxicology (1983)
University of California, Davis – BS, Biochemistry (1976)

Training

Staff Fellow, Division of Teratogenesis Research, National Center for Toxicological Research (1983-1986)
Post Doctoral Fellow, Department of Pharmacology and Interdisciplinary Toxicology, University of Arkansas for Medical Sciences (1982-1983)

Q&A

When and why did you become interested in your field?
During training for my PhD, I studied the effects of chronic anticonvulsant treatment during development on the brain function of the genetically epileptic baboon, Papio papio. It was during that time that I became interested in the potential for powerful psychotropic medications, when given to young, developing animals to permanently alter the trajectory of brain growth and subsequent function. Adverse events occurring during development can have effects that last for the entire lifespan and, thus, need to be taken very seriously and thoroughly understood.

Why SmartTots?
SmartTots seems to be an ideal vehicle for providing critical information and supporting the research necessary to obtain data on the use and effects of anesthetic agents in the pediatric population.

Are there any specific goals you would like to see SmartTots accomplish?
I would like to see SmartTots fund a variety of preclinical studies aimed at identifying agents (e.g., xenon) that can induce anesthesia without also causing abnormal apoptotic responses (neurotoxicity). These studies should range from in vitro to whole animal studies, including mice and nonhuman primates. Also, I would like SmartTots to support retro- and pro-spective studies in children that have been/will be exposed for extended periods of time (days or longer) to NMDA receptor antagonists and/or GABA agonists during stays in neonatal intensive care units, particularly in premature infants. Endpoints should focus on functional outcomes such as cognitive functions and social skills. By focusing on children that are most likely to be at risk for the adverse effects of these agents, it should be possible to determine whether there is a clinical problem associated with the use of these agents and to rank them in order of potency.

Selected Publications

Paule MG, Li M, Allen RR, Liu F, Zou X, Hotchkiss C, Hanig JP, Patterson TA, Slikker W Jr, Wang C. Ketamine anesthesia during the first week of life can cause long-lasting cognitive deficits in rhesus monkeys. Neurotoxicol Teratol 2011 Jan 15.

Patterson YA, Li M, Hotchkiss CE, Mauz A, Eddie M, Greischel A, Stierstorfer B, Deschl U, Paule MG. Toxicity assessment of pramipexole in juvenile rhesus monkeys. Toxicology 2010;276(3):164-71.

Zou X, Patterson TA, Sadovova N, Twaddle NC, Doerge DR, Zhang X, Fu X, Hanig JP, Paule MG, Slikker W, Wang C. Potential neurotoxicity of ketamine in the developing rat brain. Toxicol Sci 2009;108(1):149-58.

Wang C, Sadovova N, Patterson TA, Zou X, Fu X, Hanig JP, Paule MG, Ali SF, Zhang X, Slikker W. Protective effects of 7-nitroindazole on ketamine-induced neurotoxicity in rat forebrain culture. Neurotoxicology 2008;29(4):613-20.

Zou X, Sadovova N, Patterson TA, Divine RL, Hotchkiss CE, Ali SF, Hanig JP, Paule MG, Slikker W, Wang C. The effects of L-carnitine on the combination of, inhalation anesthetic-induced developmental, neuronal apoptosis in the rat frontal cortex. Neuroscience 2008;151(4):1053-65.

Slikker W, Zou X, Hotchkiss CE, Divine RL, Sadovova N, Twaddle NC, Doerge DR, Scallet AC, Patterson TA, Hanig JP, Paule MG, Wang C. Ketamine-induced neuronal cell death in the perinatal rhesus monkey. Toxicol Sci 2007;98(1):145-58.

Wang C, Sadovova N, Ali HK, Duhart HM, Fu X, Zou X, Patterson TA, Binienda ZK, Virmani A, Paule MG, Slikker W, Ali SF. L-carnitine protects neurons from 1-methyl-4-phenylpyridinium-induced neuronal apoptosis in rat forebrain culture.Neuroscience 2007;144(1):46-55.

Haberny KA, Paule MG, Scallet AC, Sistare FD, Lester DS, Hanig JP, Slikker W.Ontogeny of the N-methyl-D-aspartate (NMDA) receptor system and susceptibility to neurotoxicity. Toxicol Sci 2002;68(1):9-17.

Popke EJ, Patton R, Newport GD, Rushing LG, Fogle CM, Allen RR, Pearson EC, Hammond TG, Paule MG. Assessing the potential toxicity of MK-801 and remacemide: chronic exposure in juvenile rhesus monkeys. Neurotox teratol 2002;24(2):193-207.

Mayorga AJ, Popke EJ, Fogle CM, Paule MG. Similar effects of amphetamine and methylphenidate on the performance of complex operant tasks in rats. Behav Brain Res 2000;109(1):59-68.

Buffalo EA, Gillam MP, Allen RR, Paule MG. Acute behavioral effects of MK-801 in rhesus monkeys: assessment using an operant test battery. Pharmacol Biochem Behav 1994;48(4):935-40.