A5016974839- Neuroscience and Neuropharmacology Research
- Adenosine and Purinergic Signaling
- Receptor Mechanisms and Signaling
- Pharmacological Receptor Mechanisms and Effects
- Ion channel regulation and function
- Neurotransmitter Receptor Influence on Behavior
- Synthesis and pharmacology of benzodiazepine derivatives
- Epilepsy research and treatment
- Chemical Synthesis and Analysis
- Pain Management and Opioid Use
- Neuropeptides and Animal Physiology
- Diet and metabolism studies
- Glycosylation and Glycoproteins Research
- Lung Cancer Treatments and Mutations
- Atherosclerosis and Cardiovascular Diseases
- Click Chemistry and Applications
- Microfluidic and Bio-sensing Technologies
- Sleep and Wakefulness Research
- Peptidase Inhibition and Analysis
- Monoclonal and Polyclonal Antibodies Research
- Cholinesterase and Neurodegenerative Diseases
- Cancer Treatment and Pharmacology
- Medical Imaging Techniques and Applications
- Extracellular vesicles in disease
- Advanced MRI Techniques and Applications
University of Virginia
2020-2023
National Institutes of Health
1981-2020
National Institute of Mental Health
1978-2020
University of Manitoba
2016
Health Sciences Centre
2016
University Medical Center Groningen
2011-2014
University of Groningen
2011-2014
University of California, San Francisco
2011-2013
Eli Lilly (United States)
1993-2004
Institute of Neurobiology
1987
The potentiation of gamma-aminobutyric acid (GABA) receptor-mediated 36Cl- uptake by various steroids has been characterized in rat cerebral cortical synaptoneurosomes. Several these steroids, including 3 alpha-hydroxy-5 alpha-pregnan-20-one (3 alpha-OH-DHP) and alpha,21-dihydroxy-5 (THDOC), increase the potency muscimol to stimulate a concentration-dependent stereospecific manner. Concentration-response curves for alpha-OH-DHP, THDOC, alpha-hydroxy-pregn-4-en-20-one, pentobarbital...
Substantial in vitro and animal data suggest that methylxanthines, such as caffeine theophylline, act adenosine receptor antagonists. To test this hypothesis humans, we first determined if theophylline would antagonize the effects of adenosine. Intravenous administration adenosine, 80 micrograms/kg/min, increased heart rate 28 +/- 6 bpm, systolic blood pressure 19 5 mm Hg minute ventilation 6.1 2.2 liters/min. All these changes were significantly attenuated during (17 3 bpm 1 2 1.6 0.6...
The effect of chronic ethanol exposure on the function gamma-aminobutyric acid (GABA) receptor-coupled chloride ion channel was studied in synaptoneurosomes from rat cerebral cortex. Ethanol administered to rats by inhalation resulting high blood levels which have previously been shown produce tolerance and dependence. After 14 days exposure, stimulation (apparent Vmax) 36Cl- uptake GABA agonist muscimol decreased approximately 26%. Similarly, barbiturate pentobarbital also reduced same...
"Desensitization" of the gamma-aminobutyric acid (GABA) receptor-coupled chloride ion channel was studied using an in vitro method for measuring (Cl-) permeability brain vesicles (synaptoneurosomes). Muscimol, a GABA agonist, stimulated 36Cl- uptake rat cerebral cortical synaptoneurosomes concentration-dependent manner (EC50 7.3 +/- 0.5 microM), whereas pentobarbital biphasic manner, indicated by bell-shaped concentration-response relationship, with maximal response at 500 microM 271 17...
The binding of [3H]diazepam to benzodiazepine receptors was studied in extensively washed membranes rat cerebral cortex the presence depressant barbiturate, pentobarbital. Pentobarbital, like endogenous neurotransmitter gamma-aminobutyric acid (GABA), increased basal and also potentiated GABA-enhanced by increasing apparent affinity for receptor. concentrations pentobarbital necessary elicit these effects vitro are same as those observed after treatment with pharmacologically relevant doses,...
Rapid and robust changes in the chloride ionophore component of benzodiazepine/gamma-aminobutyric acid receptor complex ("supramolecular complex") were observed central nervous system rats exposed to a brief, ambient temperature swim stress. Stress-induced modification was manifest as an increase efficacy halides (Cl-, Br- I-) enhance [3H]flunitrazepam binding. In contrast, neither gamma-aminobutyric acid-enhanced binding nor [3H] flunitrazepam assayed absence halide ions altered by...
Accumulation of hyperphosphorylated tau, a microtubule-associated protein, plays an important role in the progression Alzheimer disease. Animal studies suggest that one strategy for treating disease and related tauopathies may be inhibition <i>O</i>-GlcNAcase (OGA), which subsequently decrease pathologic tau phosphorylation. Here, we report pharmacokinetics novel PET radioligand, <sup>18</sup>F-LSN3316612, binds with high affinity selectivity to OGA. <b>Methods:</b> imaging was performed on...
We aimed to develop effective radioligands for quantifying brain O-linked-β-N-acetyl-glucosamine (O-GlcNAc) hydrolase (OGA) using positron emission tomography in living subjects as tools evaluating drug target engagement. Posttranslational modifications of tau, a biomarker Alzheimer's disease, by O-GlcNAc through the enzyme pair OGA and transferase (OGT) are inversely related amounts its insoluble hyperphosphorylated form. Increase tau O-GlcNAcylation inhibition is believed reduce...
The "cage" convulsant t-butylbicyclophosphoro[35S]thionate ([35S]TBPS) binds with high affinity to sites at or near a gamma-aminobutyric acid (GABA)-gated chloride channel according current hypothesis. We now report that the potencies of series anions in enhancing [35S]TBPS binding correlated highly their relative permeabilities through GABA-gated channels. Furthermore, statistically significant correlations are obtained between apparent (Kd) estimated presence these and latter relationships...
Cerebral adenosine A2A receptors (A2ARs) are attractive therapeutic targets for the treatment of neurodegenerative and psychiatric disorders. We developed high affinity selective compound 8 (SCH442416) analogs as in vivo probes A2ARs using PET. observed A2AR-mediated accumulation [18F]fluoropropyl ([18F]-10b) [18F]fluoroethyl ([18F]-10a) derivatives brain. The striatum was clearly visualized PET vitro autoradiography images control animals no longer visible after pretreatment with A2AR...
Previous studies found that [18F]LSN3316612 was a promising positron emission tomography (PET) radioligand for imaging O-GlcNAcase in nonhuman primates and human volunteers. This study sought to further evaluate the suitability of clinical research.Kinetic evaluation conducted combined set baseline brain scans from 17 healthy volunteers test-retest 10 these volunteers; another 6 had whole-body measure radiation exposure body organs. Total distribution volume (VT) estimates were compared one-...
Background In spontaneously hypertensive rats ( SHR ) we observed profound myocardial metabolic changes during early hypertension before development of cardiac dysfunction and left ventricular hypertrophy. this study, evaluated whether metformin improved abnormalities simultaneously prevented contractile hypertrophy in . Methods Results control Wistar–Kyoto were treated with from 2 to 5 months age, when hearts exhibit develop We the effect on glucose uptake rates dynamic 2‐[ 18 F]...