Epidemiology & Public Health
Director of the Division of Translational Toxicology
Education and Training
In 1987, Dr. Pereira graduated from the School of Pharmacy at the Universidade Federal do Rio de Janeiro, in Brazil. In 1989, she earned an M.Sc. degree from the Departmento de Farmacologia Basica e Clinica at the same University. During her training, Dr. Pereira received an in-depth education in classical pharmacology, and conducted experimental research aimed at evaluating the antiinflamatory and analgesic properties of novel compounds designed and synthesized at the Departamento de Tecnologia Farmacêutica at the Universidade Federal do Rio de Janeiro. In 1989, Dr. Pereira started her pre-doctoral training in electrophysiological techniques applied to the CNS at the Instituto de Biofisica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro. In 1993, Dr. Pereira began her doctoral studies at the University of Maryland School of Medicine. Under the advisorship of Dr. Edson Albuquerque at the University of Maryland School of Medicine and Dr. Alfred Maelicke at the University of Mainz in Germany, Dr. Pereira studied the modulation of neuronal nicotinic receptors by compounds now referred to as "nicotinic allosteric potentiating ligands" and approved to treat Alzheimer's disease. After completing her Ph.D. in 1996, Dr. Pereira received post-doctoral training from Drs. Albuquerque and Maelicke, and, in 2001, she joined the faculty of the Department of Pharmacology and Experimental Therapeutics at the University of Maryland School of Medicine. Currently, Dr. Pereira is pursuing a scientific career as an Associate Professor in the Division of Translational Toxicology of the Department of Epidemiology and Public Health.
NAME: Pereira, Edna F.R.
eRA COMMONS USER NAME (credential, e.g., agency login): EPEREIRA
POSITION TITLE: Associate Professor
|INSTITUTION AND LOCATION||DEGREE/TRAINING||Completion Date||FIELD OF STUDY|
|Universidade Federal do Rio de Janeiro||equiv. Pharm.D||1987||Pharmacy|
|Universidade Federal do Rio de Janeiro||M.Sc.||1989||Pharmacology|
|University of Maryland at Baltimore||Ph.D.||1996||Neuropharmacology|
|University of Maryland at Baltimore||Postdoctoral||1998||Neuropharmacology|
A. Personal Statement
I have extensive experience in the fields of molecular, cellular, and system pharmacology and toxicology. At the beginning of my career I worked on animal models of inflammation and pain. My research was aimed at evaluating the anti-inflammatory and analgesic actions of natural products and synthetic compounds. These studies, which were carried out in collaboration between the Medicinal Chemistry laboratory directed by Dr. Eliezer Barreiro and the Pharmacology laboratory directed by Dr. Nuno A. Pereira, revealed the anti-inflammatory properties of bioisosters of indomethacin synthesized from safrole. Subsequently, I moved to Dr. Albuquerque’s laboratory, where I received training in neuropharmacology. We discovered that pyrazole - the backbone of a number of anti-inflammatory drugs - has centrally active properties. We demonstrated that pyrazole, although unable to activate neuronal nicotinic receptors, could bind to the receptors and increase their activation by classical agonists. My PhD thesis was focused on identifying mechanisms by which nicotinic receptor activity could be allosterically potentiated in neurons. The work I carried out under the advisorship of Drs. Albuquerque and Maelicke led to the characterization of a binding region on the nicotinic receptor α subunits that recognizes galantamine as a prototypic ligand. Binding of galantamine to this site on the nicotinic receptors reduces agonist-induced receptor desensitization and, thereby, increases receptor activity.
After joining the faculty of the University of Maryland School of Medicine in 1999, I continued to collaborate with Dr. Albuquerque in testing the effectiveness of galantamine in reducing neurodegeneration triggered by different insults. Using a variety of technical approaches that included electrophysiology, immunohistochemistry, and histochemistry, we demonstrated that galantamine, acting in part as a nicotinic allosteric potentiating ligand, can prevent the neurodegeneration induced by organophosphorus pesticides and nerve agents both in vitro and in vivo.
During the past 10 years, while continuing to work on studies addressing the mechanisms by which nicotinic receptors and other receptors modulate synaptic transmission and neurodevelopment in the mammalian central nervous system, I became a member of a multidisciplinary research program. Drawing from the varied expertise within the research team, we have examined the effects of acute exposure of the mature brain to organophosphorus nerve agents and pesticides. In 2006, we published the first paper demonstrating that galantamine, currently approved to treat Alzheimer’s disease, effectively counters the acute and delayed toxicity of organophosphorus compounds in guinea pigs. Since then we have published numerous articles that have helped advance the field for development of medical countermeasures to treat the acute and chronic toxicity induced by organophosphorus pesticides and nerve agents.
B. Positions and Honors
1986-1989 Pharmacist. Municipal Secretary of Health of Rio de Janeiro, Rio de Janeiro, RJ Brazil.
1989-1990 Assistant Professor. Depto. Fisiol. Farmacol., Escola de Medicina de Campos, Campos, RJ, Brazil.
1990-1993 Assistant Professor. Depto. Farmacol. Bás. Clín., Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
1999-2003 Research Associate. Dept. Pharmacol. Exp. Ther., University of Maryland School of Medicine, Baltimore, MD, USA.
2003-2010 Assistant Professor, Dept. Pharmacol. Exp. Ther., University of Maryland School of Medicine, Baltimore, MD, USA.
2010-2014 Assistant Professor, Dept. Epidemiol. Public Health, University of Maryland School of Medicine, Baltimore, MD, USA.
2014-present Associate Professor, Dept. Epidemiol. Public Health, University of Maryland School of Medicine, Baltimore, MD, USA.
2018-present Director of Division, Division Translational Toxicology, Dept. Epidemiol. Public Health, University of Maryland School of Medicine, Baltimore, MD, USA.
Honors, Awards, and Professional Memberships
Fellowships from Conselho Nacional de Pesquisa e Desenvolvimento (CNPq, 1990-1992) and Coordenação de Aperfeiçomaento de Pessoal de Nível Superior (CAPES, 1989-1990), Brazil.
Member, Editorial Board of Revista Brasileira de Farmácia (1990-2010)
Member of Society for Neuroscience (1990-present), American Association for the Advancement of Science (1996-present), American Society of Pharmacology and Experimental Therapeutics (2008-present)
Reviewer, VA Study Section ZRD1 SPLD-B (01) Gulf War Review Panel (2018-2020)
Reviewer, NIH Study Sessions ZRG1 MDCN-B50R, ZRG1 MDCN-B54R (Adhoc member, 2018, 2020)
Reviewer, NIH study section NAL (Adhoc member, 2019)
Member of the CDMRP's Combat Readiness - Medical Research Program Stakeholders Panel (2019)
Reviewer, Toxicological Profile for the Agency for Toxic Substances and Disease Registry and the Centers for Disease Control & Prevention (CDC, 2016)
Reviewer, Comitato Telethon Fondazione Onlus, Italy (2012 grant cycle)
Member, International Advisory Board of the International Symposium on Cholinergic Mechanisms (2008-present) and local organizer of the XIII International Symposium on Cholinergic Mechanisms (2008)
Reviewer, Philip Morris External Research Program (2007 grant cycle)
Reviewer, NCI/NIH special emphasis panel ZCA1 GRB-I (Adhoc member, 2004)
Reviewer for PLOS One, Journal of Neurochemistry, Journal of Pharmacology and Experimental Therapeutics, Journal of Alzheimer's Disease, Biochemical Pharmacology, Brain Research, Journal of Neuroscience, Neuroscience Letters, Journal of Toxicology and Applied Pharmacology
C. Contributions to Science
1. Studies of nicotinic allosteric potentiating ligands
In the early 1990’s, very little information was available regarding the actions of ligands capable of interacting directly with nicotinic receptors in the central nervous system and increase their activity. Research that I conducted in Dr. Albuquerque’s and Dr. Maelicke’s laboratories led to the identification of galantamine, a drug used for treatment of Alzheimer’s disease, as a nicotinic allosteric potentiating ligand. With the electrophysiological experiments that I performed, we were able to demonstrate that, by binding to a site close to, but distinct from the acetylcholine-binding site on nicotinic receptors, galantamine was a weak nicotinic receptor agonist. We also demonstrated that, by binding to this site, galantamine can reduce agonist-induced receptor desensitization and increase nicotinic receptor activity induced by classical agonists.
Pereira EFR, Reinhardt-Maelicke S, Schrattenholz A, Maelicke A, Albuquerque EX. Identification and functional characterization of a new agonist site on nicotinic acetylcholine receptors of cultured hippocampal neurons. J Pharmacol Exp Ther 265:1474-1491, 1993. PMID: 8510023
Pereira EFR, Alkondon M, Tano T, Castro NG, Fróes-Ferrão MM, Rozental R, Aronstam RS, Schrattenholz A, Maelicke A, Albuquerque EX. A novel agonist binding site on nicotinic acetylcholine receptors. J Recept Res. 13:413-436, 1993. PMID: 8450498
Schrattenholz A, Pereira EFR, Roth U, Weber KH, Albuquerque EX, Maelicke A. Agonist responses of neuronal nicotinic acetylcholine receptors are potentiated by a novel class of allosterically acting ligands. Mol Pharmacol 49:1-6, 1996. PMID: 8569694
Pereira EFR, Hilmas C, Santos MD, Alkondon M, Maelicke A, Albuquerque EX. Unconventional ligands and modulators of nicotinic receptors. J Neurobiol 53:479-500, 2002. PMID: 12436414
2. Studies on the neuroprotective actions of galantamine
Using in vivo and in vitro models of neurodegeneration and histochemical and immunohistochemical methods similar to those delineated in this application, our research group has provided evidence of the neuroprotective effectiveness of galantamine. This effect of galantamine is a major determinant of its ability to mitigate the neurotoxicity of organophosphorus nerve agents and pesticides. The use of galantamine to counter the acute and delayed neurotoxicity of nerve agents and pesticides is currently protected under the international patent application PCT/US05/33789.
Albuquerque EX, Pereira EFR, Aracava Y, Fawcett WP, Oliveira M, Randall WR, Hamilton TA, Kan RK, Romano JA Jr, Adler M. Effective countermeasure against poisoning by organophosphorus insecticides and nerve agents. Proc Natl Acad Sci USA 103:13220-13225, 2006. PMID: 16914529; PMCID: PMC1550772
Pereira EFR, Aracava Y, Alkondon M, Akkerman M, Merchenthaler I, Albuquerque EX. Molecular and cellular actions of galantamine: clinical implications for treatment of organophosphorus poisoning. J Mol Neurosci 40:196-203, 2010. PMID: 19690988
Mamczarz J, Kulkarni GS, Pereira EFR, Albuquerque EX. Galantamine counteracts development of learning impairment in guinea pigs exposed to the organophosphorus poison soman: clinical significance. Neurotoxicology 32:785-798, 2011. PMID: 21784098
3. Studies on modulation of synaptic transmission in the brain
Our research group demonstrated that activation of neuronal nicotinic and muscarinic receptors present in the somata, axons, and axon terminals of different neurons increases both glutamatergic and GABAergic synaptic transmission in the rat cerebral cortex and hippocampus and in the human cerebral cortex. We also demonstrated that kynurenic acid, acting via mechanisms that are independent of its inhibitory actions on α7 nicotinic receptors and NMDA receptors, suppresses synaptic transmission hippocampus. This finding led to the hypothesis that the G protein-coupled receptor GPR35 (also known as a molecular target for kynurenic acid) could be present in the brain and mediate the effects of kynurenic acid on synaptic transmission. Our most recent publication provides evidence supporting this hypothesis. This latest finding opens the potential for future development of drugs aimed at treating recurrent seizures, particularly those that are resistant to treatment with currently available anti-epileptic drugs.
Alkondon M, Pereira EFR, Barbosa CT, Albuquerque EX. Neuronal nicotinic acetylcholine receptor activation modulates gamma-aminobutyric acid release from CA1 neurons of rat hippocampal slices. J Pharmacol Exp Ther 283:1396-1411, 1997. PMID: 9400016
Lopes C, Pereira EFR, Wu HQ, Purushottamachar P, Njar V, Schwarcz R, Albuquerque EX. Competitive antagonism between the nicotinic allosteric potentiating ligand galantamine and kynurenic acid at α7* nicotinic receptors. J Pharmacol Exp Ther 322:48-58, 2007. PMID: 17446300
Santos MD, Pereira EFR, Aracava Y, Castro NG, Fawcett WP, Randall WR, Albuquerque EX. Low concentrations of pyridostigmine prevent soman-induced inhibition of GABAergic transmission in the central nervous system: involvement of muscarinic receptors. J Pharmacol Exp Ther 304:254-265, 2003. PMID: 12490599
Alkondon M, Pereira EFR, Todd SW, Randall WR, Lane MV, Albuquerque EX. Functional G-protein-coupled receptor 35 is expressed by neurons in the CA1 field of the hippocampus. Biochem Pharmacol 93:506-518, 2015. PMID: 25542997
4. Studies on the neurotoxic effects of nerve agents and organophosphorus pesticides in the mature and the developing mammalian brain
Our most recent studies demonstrated that exposure of prepubertal guinea pigs to sub-acute doses of the nerve agent soman induces spatial learning deficits and disrupts the structural integrity of the brain. They also provided evidence that pre-treatment of the animals with galantamine effectively countered the neurotoxic effects of soman. Relevant to the work proposed here is our recent publication showing that sub-lethal exposure of pregnant guinea pigs to the organophosphorus pesticide chlorpyrifos causes in the offspring cognitive deficits that are accompanied by marked alterations in the structural integrity of specific brain regions.
Alkondon M, Aracava Y, Pereira EFR, Albuquerque EX. A single in vivo application of cholinesterase inhibitors has neuron type-specific effects on nicotinic receptor activity in guinea pig hippocampus. J Pharmacol Exp Ther 328:69-82, 2009. PMID: 18842705
Fawcett WP, Aracava Y, Adler M, Pereira EFR, Albuquerque EX. Acute toxicity of organophosphorus compounds in guinea pigs is sex- and age-dependent and cannot be solely accounted for by acetylcholinesterase inhibition. J Pharmacol Exp Ther 328:516-524, 2009. PMID: 18984651
Mullins RJ, Xu S, Pereira EFR, Pescrille JD, Todd SW, Mamczarz J, Albuquerque EX, Gullapalli RP. Prenatal exposure of guinea pigs to the organophosphorus pesticide chlorpyrifos disrupts the structural and functional integrity of the brain. Neurotoxicology 48:9-20, 2015. PMID: 25704171
Mamczarz J, Pescrille JD, Gavrushenko L, Burke RD, Fawcett WP, DeTolla Jr. LJ, Chen H, Pereira EFR, Albuquerque EX. Spatial learning impairment in prepubertal guinea pigs prenatally exposed to the organophosphorus pesticide chlorpyrifos: Toxicological implications. Neurotoxicology, 56:17-28, 2016.
Complete List of Published Work in MyBibliography:
Nicotinic receptors, organophosphorus, pesticides, animal models, seizures
Albuquerque EX, Pereira EFR, Aracava Y, Fawcett WP, Oliveira M, Randall WR, Hamilton TA, Kan RK, Romano Jr. JA, Adler M. An effective countermeasure against poisoning by organophosphorus insecticides and nerve agents. Proc Natl Acad Sci USA 103:13220-13225, 2006.
Albuquerque EX, Pereira EFR, Alkondon M, Rogers SW. Mammalian nicotinic acetylcholine receptors: from structure to function. Physiol Rev 89:73-120, 2009.
Banerjee J, Alkondon M, Albuquerque EX, Pereira EFR. Contribution of CA3 and CA1 pyramidal neurons to the tonic α7 nAChR-dependent glutamatergic input to CA1 pyramidal neurons. Neurosci Lett 554:167-171, 2013.
Pereira EFR, Aracava Y, DeTolla LJ Jr, Beecham EJ, Basinger GW Jr, Wakayama EJ, Albuquerque EX. Animal models that best reproduce the clinical manifestations of human intoxication with organophosphorus compounds. J Pharmacol Exp Ther 350:313-321, 2014.
Mamczarz J, Pescrille JD, Gavrushenko L, Burke RD, Fawcett WP, DeTolla Jr LJ, Chen H, Pereira EFR, Albuquerque EX. Spatial learning impairment in prepubertal guinea pigs prenatally exposed to the organophosphorus pesticide chlorpyrifos: Toxicological implications. Neurotoxicology 56:17-28, 2016.
Dr. Pereira's research is focused on understanding mechanisms that regulate synaptic transmission and neuronal viability in the developing and the mature male and female brains with the ultimate goal of developing more effective treatments to halt the immediate and delayed neurotoxic effects of organophosphorus pesticides.