Active Grant Support
Title: Brain-Selective Therapy to Alleviate Hot Flushes of Prostate Cancer Patients (Subcontract)
Principal Investigator: Istvan Merchenthaler
Agency: University of North Texas Health Science Library (NIH passthrough)
Grant Number: 1R01CA2155550 (Prokai)
Funding Period: 4/1/17 – 3/31/20
Total Costs: $529,701
Synthetic estrogens are used in the clinic to Alleviate debilitating neurological Symptoms associated with androgen deprivation Therapy (ADT), an effective treatment improving survival in Prostate Cancer Patients when administered timely in the course of Carcinoma. However, this remedy to relieve the Symptoms, most commonly manifested as Hot Flushes, causes feminizations (most prominently gynecomastia) that significantly diminishes patients' compliance because of physical and psychological discomfort. Because only estrogens can provide adequate remedy of Hot Flushes based on current clinical practices, there is an unmet medical need for an effective, side effect-free and, consequently, compliance-gaining intervention to Alleviate these vasomotor Symptoms distressing Prostate Cancer Patients on ADT. The scientific premise of this grant application is based on it central hypotheses that treatment with 10β,17β-dihydroxyestra-1,4-dien-3-one (DHED), an innovative Brain-Selective bioprecursor prodrug of 17b-estradiol, will ease ADT-associated hot flushes without feminizing side-effects. In the first specific aim, we will perform preclinical pharmacokinetics, distribution and bioavailability studies in orchidectomized male rats to support our particular hypotheses that DHED treatment confines the formation of17b-estradiol from the prodrug into the brain. In the second specific aim, we will assess DHED treatments through measuring effects elicited by the estrogen delivered selectively in the brain and, consequently, avoiding exposure of peripheral tissues to the hormone through multiple methodologies. One of our specific hypotheses is that oral treatment with DHED will abate orchidectomy- induced tail skin temperature elevation in a pharmacological model, and will restore diurnal changes lost after orchidectomy in a physiological paradigm, in two well-established and complementary rat models of hot flushes. Since our hypothesis is that Hot Flushes are due to an imbalance of neurotransmitters/neuromodulators innervating thermosensitive neurons in the preoptic area of the hypothalamus, we will Monitor norepinephrine, serotonin, and neurokinin B involved in thermoregulatory responses with in vivo microdialysis to provide additional, mechanism-focused approach for assessment. As the synthesis and release of these neurotransmitters and their cognate receptors are regulated by estrogen, we hypothesize that the major action of estrogen is to re-establish the physiological balance among these neurotransmitters to stabilize neuronal activity on the thermoregulatory center; i.e., to prevent heat dissipation (Hot flush). Finally, we will seek supporting evidence for the brain-specific action of DHED-derived 17b-estradiol by evaluating estrogen- induced gene expression in the brain, and its lack in the breast, pituitary, Prostate and Prostate Cancer cells. The overall goal of our aims is to support subsequent translational research focusing on DHED’s therapeutic use toremedy Hot Flushes and potentially other neurological Symptoms in Prostate Cancer Patients undergoing ADT to manage their malignancy.
Title: “Neurotoxicity of Organophosphorus Pesticides in Developing Guinea Pigs”
PIs: Edson X. Albuquerque, Rao Gullapalli, Jacek Mamczarz, William Randall
Funding Agency: National Institutes of Health/National Institute of Environmental Health
Funding Period: 7/1/2010 – 6/30/2014
This project will use a multi-disciplinary approach to: (i) identify the structural and functional brain damage induced by the developmental exposure of guinea pigs to the organophosphorus pesticides chlorpyrifos and malathion, (ii) identify potential epigenetic mechanisms underlying the developmental toxicity of these pesticides, and (iii) examine the potential effectiveness of galantamine as an antidotal therapy to treat the neurotoxic effects of the pesticides in the developing guinea pigs.
Title: “Nicotinic Receptor and Hippocampal Synaptic Function”
PI: Edson X. Albuquerque
Funding Agency: National Institutes of Health/National Institute of Neurological Disorders and Stroke
Funding Period: 5/15/08-4/30/13
The aim of this project is to characterize the neuronal nicotinic receptors located in the hippocampal region of the brain, identifying their physiological roles in neuronal function and in synaptic transmission.
Title: “Galantamine and Anticonvulsants in the Treatment of Nerve Agent Toxicity”
PI: Edson X. Albuquerque
Funding Agency: Defense Threat Reduction Agency/Department of Defense
Funding Period: 7/1/2010 – 6/30/2012
This research contract is aimed at determining the effectiveness of a combination of galantamine (or its derivatives) and anticonvulsants to treat convulsions and behavioral impairments caused by the exposure of adult male guinea pigs to the nerve agents soman and sarin.
Title: “Novel Treatment of Menopausal Hot Flushes with Paraquinol of Estrogen”
PI: Istvan Merchenthaler
Funding Agency: National Institute of Aging, National Institutes of Health
Funding Period: 1/3/09 – 28/2/13
This research grant is aimed at evaluating pro-estrogen (paraquinol of estradiol) in animal models of depression/anxiety and sleep disturbances. The hypoestrogenic status during the peri-menopause and menopause is associated with increased incidence of depression and anxiety and sleep disorders. Since the pro-estrogen is converted to estradiol only in the brain, the pro-drug approach seems to be a safe and efficacious estrogen replacement therapy without any side effects in the periphery.