A5101815684- Neuroscience and Neuropharmacology Research
- Receptor Mechanisms and Signaling
- Neurotransmitter Receptor Influence on Behavior
- Ion channel regulation and function
- Alzheimer's disease research and treatments
- Epilepsy research and treatment
- Neuroinflammation and Neurodegeneration Mechanisms
- Neuropeptides and Animal Physiology
- Memory and Neural Mechanisms
- Pharmacological Receptor Mechanisms and Effects
- Adenosine and Purinergic Signaling
- Tryptophan and brain disorders
- Stress Responses and Cortisol
- Synthesis and pharmacology of benzodiazepine derivatives
- Cholesterol and Lipid Metabolism
- Sleep and Wakefulness Research
- Synthesis and bioactivity of alkaloids
- Nicotinic Acetylcholine Receptors Study
- Cholinesterase and Neurodegenerative Diseases
- Neuroendocrine regulation and behavior
- Neurogenesis and neuroplasticity mechanisms
- Mitochondrial Function and Pathology
- Amino Acid Enzymes and Metabolism
- RNA regulation and disease
- Biochemical effects in animals
Washington University in St. Louis
2018-2024
Taylor Family Institute for Innovative Psychiatric Research
2018-2024
University of Miami
2024
Bristol-Myers Squibb (Germany)
2024
Duke University
2024
University of South Florida
2023
USF Health Byrd Alzheimer's Institute
2023
Voyager Therapeutics (United States)
2014-2022
Sage Therapeutics (United States)
2013-2020
MIND Research Institute
2013-2020
Two metabolites of the steroid hormones progesterone and deoxycorticosterone, 3α-hydroxy-5α-dihydroprogesterone 3α,5α-tetrahydrodeoxycorticosterone, are potent barbiturate-like ligands γ-aminobutyric acid (GABA) receptor-chloride ion channel complex. At concentrations between 10 -7 -5 M both steroids inhibited binding convulsant t-butylbicyclophosphorothionate to GABA-receptor complex increased benzodiazepine flunitrazepam; they also stimulated chloride uptake (as measured by 36 Cl - ) into...
Neuroactive steroids are natural or synthetic that rapidly alter the excitability of neurons by binding to membrane-bound receptors such as those for inhibitory and (or) excitatory neurotransmitters. The best-studied neuroactive a series sedative-hypnotic 3α-hydroxy ring A-reduced pregnane include major metabolites progesterone deoxycorticosterone, 3α-hydroxy-5α-pregnan-20-one (allopregnanolone) 3α,21-dihydroxy-5α-pregnan-20-one (allotetrahydroDOC), respectively. These 3α-hydroxysteroids do...
Parkinson's disease is a chronic neurodegenerative disorder characterized by the loss of dopamine neurons in substantia nigra, decreased striatal levels, and consequent extrapyramidal motor dysfunction. We now report that minocycline, semisynthetic tetracycline, recently shown to have neuroprotective effects animal models stroke/ischemic injury Huntington's disease, prevents nigrostriatal dopaminergic neurodegeneration 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model disease....
The effects of ethanol on Cl- uptake were studied using a cell-free subcellular preparation from brain that contains gamma-aminobutyric acid (GABA)/barbiturate receptor-sensitive transport system. In isolated vesicles prepared rat cerebral cortex, ethanol, at concentrations are present during acute intoxication (20-50 mM), stimulated 36Cl- in concentration-dependent and biphasic manner. ethanol-stimulated was markedly inhibited by the GABA antagonists picrotoxin bicuculline but not variety...
Ethanol, at pharmacologically relevant concentrations of 20 to 100 mM, stimulates gamma-aminobutyric (GABA) receptor-mediated uptake 36Cl-labeled chlorine into isolated brain vesicles. One drug that acts GABA-benzodiazepine receptors, the imidazobenzodiazepine Ro15-4513, has been found be a potent antagonist ethanol-stimulated 36Cl- vesicles, but it fails antagonize either pentobarbital- or muscimol-stimulated uptake. Pretreatment rats with Ro15-4513 blocks anticonflict activity low doses...
The high-affinity tritiated (3H) imipramine binding sites are functionally (and perhaps structurally) associated with the presynaptic neuronal and platelet uptake for serotonin. Since there is an excellent correlation between relative potencies of a series antidepressants in displacing 3H-imipramine from human brain platelet, we have examined to platelets 14 depressed patients 28 age- sex-matched controls. A highly significant decrease number sites, no change apparent affinity constants, was...
The ethyl ester of beta-carboline-3-carboxylic acid has a high affinity for benzodiazepine receptors in the brain. In rhesus monkey this substance produces an acute behavioral syndrome characterized by dramatic elevations heart rate, blood pressure, plasma cortisol, and catecholamines. effects are blocked benzodiazepines specific receptor antagonist Ro 15-1788. may consist several subsites or functional domains that independently recognize agonist, antagonists, "active" antagonists such as...
There is considerable debate whether Alzheimer's disease (AD) originates in basal forebrain or entorhinal cortex. Here we examined longitudinal decreases and cortex grey matter volume were interdependent sequential. In a large cohort of age-matched older adults ranging from cognitively normal to AD, demonstrate that predicts degeneration. Models parallel degeneration origin received negligible support. We then integrated volumetric measures with an amyloid biomarker sensitive pre-symptomatic...
The recent FDA approval of the neurosteroid, brexanolone (allopregnanolone), as a treatment for women with postpartum depression, and successful trials related neuroactive steroid, SGE-217, men major depressive disorder offer hope new era in treating mood anxiety disorders based on potential neurosteroids modulators brain function. This review considers mechanisms contributing to antidepressant anxiolytic effects allopregnanolone other GABAergic focusing their actions positive allosteric...
The muscarinic receptor agonist xanomeline has antipsychotic properties and is devoid of dopamine receptor–blocking activity but causes cholinergic adverse events. Trospium a peripherally restricted antagonist that reduces peripheral effects xanomeline. efficacy safety combined trospium in patients with schizophrenia are unknown.
N -methyl- d -aspartate receptors (NMDARs) are glutamate-gated ion channels that critical to the regulation of excitatory synaptic function in CNS. NMDARs govern experience-dependent plasticity and have been implicated pathophysiology various neuropsychiatric disorders including cognitive deficits schizophrenia certain forms autism. Certain neurosteroids modulate experimentally but their low potency, poor selectivity, very brain concentrations make them candidates as endogenous ligands or...
Altered neurotransmission of γ-aminobutyric acid (GABA) has been implicated in the pathogenesis depression. Whether SAGE-217, an oral, positive allosteric modulator GABA type A receptors, is effective and safe for treatment major depressive disorder unknown.In this double-blind, phase 2 trial, we enrolled patients with depression randomly assigned them a 1:1 ratio to receive 30 mg SAGE-217 or placebo once daily. The primary end point was change from baseline day 15 score on 17-item Hamilton...
Importance A significant need exists for new antipsychotic medications with different mechanisms of action, greater efficacy, and better tolerability than existing agents. Xanomeline is a dual M 1 /M 4 preferring muscarinic receptor agonist no direct D 2 dopamine blocking activity. KarXT combines xanomeline the peripheral antagonist trospium chloride goal reducing adverse events due to xanomeline-related activation. In prior trials, xanomeline-trospium was effective in symptoms psychosis...
Anandamide (arachidonylethanolamide) is a novel lipid neurotransmitter first isolated from porcine brain which has been shown to be functional agonist for the cannabinoid CB1 and CB2 receptors. never human or peripheral tissues its role in physiology not examined. was measured by LC/MS/MS found rat hippocampus (and parahippocampal cortex), striatum, cerebellum, areas known express high levels of Significant anandamide were also thalamus expresses low spleen receptor. Small amounts detected...
We have isolated a brain-specific cDNA that encodes Na(+)-dependent inorganic phosphate (Pi) cotransporter (BNPI). The nucleotide sequence of BNPI predicts protein 560 amino acids with 6-8 putative transmembrane-spanning segments is approximately 32% identical to the rabbit kidney Pi cotransporter. Expression mRNA in Xenopus oocytes results transport similar reported for recombinantly expressed or native RNA blot analysis reveals predominantly (if not exclusively) brain, and situ...
Lithium is one of the most widely used mood-stabilizing agents for treatment bipolar disorder. Although underlying mechanism(s) this mood stabilizer remains controversial, recent evidence linking lithium to neurotrophic/neuroprotective effects (Choi and Sung (2000) 1475, 225-230; Davies et al. 351, 95-105) suggests novel benefits drug in addition stabilization. Here, we report that both as well valproic acid (VPA) inhibit beta-amyloid peptide (Abeta) production HEK293 cells stably...
Neurotoxicity induced by overstimulation of N -methyl- d -aspartate (NMDA) receptors is due, in part, to a sustained rise intracellular Ca 2+ ; however, little known about the ensuing events that ultimately result cell death. Here we show NMDA relatively low concentrations glutamate induces apoptosis cultured cerebellar granule neurons (CGNs) and CGNs do not require new RNA or protein synthesis. Glutamate-induced is, associated with concentration- time-dependent activation interleukin...