Active Grant Support, Collaborations, and Recent Publications
Active Grant Support
Title: “Targeting M1/M3 Muscarinic Receptors to Treat Gestational Pesticide Poisoning”
Principal Investigator: Edna F.R Pereira, Rao Gullapalli
Agency: National Institutes of Health/National Institute of Environmental Health
Grant Number: R01 ES027822
Funding Period: 01/01/2018 – 12/31/2022
The major goal of this project is to examine in the guinea pig model the effectiveness of the M1/M3 muscarinic receptor antagonist R,S-trihexyphenidyl as a treatment to mitigate the morbidity and mortality induced by gestational organophosphate poisoning.
Title: “Effect of Prenatal Exposure to Acetaminophen During Critical Period of Brain Growth Spurt on Exploratory and Cognitive Behavior: Guinea Pig Model”
Principal Investigator: Jacek Mamczarz
Agency: National Institutes of Health/National Institute of Child and Human Development
Grant Number: R21 HD095429
Funding Period: 09/01/2020 – 08/31/2022
The primary objective of this study is to use the guinea pig as the animal model of choice to test the central hypothesis that prenatal exposure to APAP during the period of brain growth spurt has long-term, sex-dependent effects on emotional and cognitive behavior that correlate with disruption of the electrical activity and/or structural integrity of the brain.
Title: “Brain-Selective Estrogen Therapy for Menopausal Hot Flushes in an Advanced Translational Animal Model” (under review)
Principal Investigator: Istvan Merchenthaler
Agency: National Institutes of Health/National Institute of Aging
Grant Number: R01 AG070072
Funding Period: 01/01/2021 – 12/31/2026
The major goal of this project is to examine in a non-human primate model the effectiveness of the pro-estrogen (paraquinol of estradiol) to counter hot flushes. Since the pro-estrogen is converted to estradiol only in the brain, the pro-drug approach could become a safe and efficacious estrogen replacement therapy to mitigate CNS-based effects of menopause.
Title: “Targeting Therapeutic Efficacy of Ketamine Metabolites for Depression Treatment”
Principal Investigator: Todd Gould (Department of Psychiatry)
Agency: National Institutes of Health/National Institute of Mental Health
Grant Number: R01 MH107615
Funding Period: 01/01/2018 – 12/31/2027
The primary objective of this study is to examine the antidepressant-like effects of ketamine metabolites, particularly the hydroxynorketamines, and to determine whether NMDA receptor inhibition accounts for the antidepressant effectiveness of these metabolites.
Title: “Viral Protein (VPR) in HIV-Associated Brain Neuroinflammation and Neurotoxicity”
Principal Investigator: Richard Zhao (Department of Pathology, J. Marc Simard (Department of Neurosurgery)
Agency: Veteran Affairs
Grant Number: I01 BX004652
Funding Period: 01/01/2020 – 06/30/2024
The goals of this project are to examine whether Vpr contributes to HIV-associated neurocognitive disorders (HAND) via TLR4/MyD88- and/or TNFα-mediated NF-κB activation, which in turn upregulates the Sur1-Trpm4 channel leading to neuroinflammation and neurotoxicity and to determine whether inhibition of the Sur1-Trpm4 channel mitigates Vpr-induced HAND.
On the Effects and Models of Organophosphorus-Induced Neurotoxicity
Todd SW, Lumsden EW, Aracava Y, Mamczarz J, Albuquerque EX, Pereira EFR. Gestational exposures to organophosphorus insecticides: From acute poisoning to developmental neurotoxicity. Neuropharmacology 180:108271, 2020. https://doi.org/10.1016/j.neuropharm.2020.108271
Lane M, Carter D, Pescrille JD, Aracava Y, Fawcett WP, Basinger GW, Pereira EFR, Albuquerque EX. Oral pretreatment with galantamine effectively mitigates the acute toxicity of a supralethal dose of soman in Cynomolgus monkeys posttreated with conventional antidotes. J Pharmacol Exp Ther 375:115-126, 2020. https://doi.org/10.1124/jpet.120.265843.
Lumsden EW, McCowan L, Pescrille JD, Fawcett WP, Chen H, Albuquerque EX, Mamczarz J, Pereira EFR. Learning and memory retention deficits in prepubertal guinea pigs prenatally exposed to low levels of the organophosphorus insecticide malathion. Neurotoxicol Teratol 81:106914, 2020. https://doi.org/10.1016/j.ntt.2020.106914.
On the Mechanisms Underlying the Antidepressant Effectiveness of Ketamine Metabolites
Riggs LM, Aracava Y, Zanos P, Fischell J, Albuquerque EX, Pereira EFR, Thompson SM, Gould TD. (2R,6R)-hydroxynorketamine rapidly potentiates hippocampal glutamatergic transmission through a synapse-specific presynaptic mechanism. Neuropsychopharmacology 45:426-436, 2020. https://doi.org/10.1038/s41386-019-0443-3.
Lumsden EW, Troppoli TA, Myers SJ, Zanos P, Aracava Y, Kehr J, Lovett J, Kim S, Wang FH, Schmidt S, Jenne CE, Yuan P, Morris PJ, Thomas CJ, Zarate CA Jr, Moaddel R, Traynelis SF, Pereira EFR, Thompson SM, Albuquerque EX, Gould TD. Antidepressant-relevant concentrations of the ketamine metabolite (2R,6R)-hydroxynorketamine do not block NMDA receptor function. Proc Natl Acad Sci U S A 116:5160-5169, 2019. https://doi.org/10.1073/pnas.1816071116.
On the Neurotoxic Effects of the HIV-1 Viral Protein R (Vpr)
Li G, Makar T, Gerzanich V, Kalakonda S, Ivanova S, Pereira EFR, Andharvarapu S, Zhang J, Simard JM, Zhao RY. HIV-1 Vpr-Induced Proinflammatory Response and Apoptosis Are Mediated through the Sur1-Trpm4 Channel in Astrocytes. mBio 11:e02939-20, 2020. https://doi.org/10.1128/mBio.02939-20.
On the Brain-Selective Pro-Estrogen Therapy and Other Neuroactive Hormones
Merchenthaler I, Lane M, Stennett C, Zhan M, Nguyen V, Prokai-Tatrai K, Prokai L. Brain-selective estrogen therapy prevents androgen deprivation-associated hot flushes in a rat model. Pharmaceuticals (Basel) 13:119, 2020. https://doi.org/10.3390/ph13060119.
Dudas B, Merchenthaler I. Thyrotropin-releasing hormone axonal varicosities appear to innervate dopaminergic neurons in the human hypothalamus. Brain Struct Funct 225:2193-2201, 2020. https://doi.org/10.1007/s00429-020-02120-8.
Luu A, Oberdoerster Z, Grignol G, Merchenthaler I, Dudas B. Presence of substance P positive terminals on hypothalamic somatostatinergic neurons in humans: the possible morphological substrate of the substance P-modulated growth hormone secretion. Brain Struct Funct 225:241-248, 2020. https://doi.org/10.1007/s00429-019-01990-x.