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Anthony J. Trevor

Bio: Anthony J. Trevor is an academic researcher from University of California, San Francisco. The author has contributed to research in topics: MPTP & Metabolite. The author has an hindex of 32, co-authored 70 publications receiving 4796 citations. Previous affiliations of Anthony J. Trevor include United States Department of Veterans Affairs.


Papers
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Journal ArticleDOI
TL;DR: The neurotoxic chemical MPTP is metabolized by rat brain mitochondrial fractions at a rate of 0.91 +/- 0.02 nmoles/mg protein/min, and the major metabolite has been identified as the 1-methyl-4- phenylpyridinium species.

1,111 citations

Journal ArticleDOI
TL;DR: It is concluded that the more potent S(+) isomer of ketamine was associated with a more rapid recovery of psychomotor skills than the currently used racemic mixture.
Abstract: The clinical and electroencephalographic (EEG) effects of the individual ketamine isomers were compared with the racemic mixture in five volunteers who received each drug on a separate occasion. Racemic ketamine 275 ± 25 mg, s(+) ketamine 140 ± 21 mg or R(−) ketamine 429 ± 37 mg produced an anaesthetic state lasting 6 ± 2 min (mean ± SD). However, the EEG evaluation of the R(−) isomer revealed less overall slowing, and an absence of the large slow wave complexes produced by the s(+) isomer and the racemic mixture. The pharmacokinetic profiles for the individual isomers of ketamine did not differ significantly from the racemic mixture. Even though the apparent anaesthetic state produced in these healthy volunteers did not differ qualitatively between the three drug groups, recovery times (assessed using a standardized battery of psychometric tests) were consistently shorter following the individual isomers compared with the racemic mixture. The serum ketamine concentrations associated with regaining consciousness and orientation were consistent with an s(+):R(−) isomer potency ratio of 4:1. In terms of their ability to impair psychomotor function, the s(+):R(−) potency ratio varied from 3:1 to 5:1. After comparable degrees of CNS depression, we conclude that the more potent s(+) isomer of ketamine was associated with a more rapid recovery of psychomotor skills than the currently used racemic mixture.

352 citations

Journal ArticleDOI
TL;DR: Mouse brain synaptosomal preparations were used to study uptake of N-methyl-4-phenylpyridine (MPP+), a metabolite of the neurotoxin MPTP, and this selective uptake may contribute to the specificity of the toxic effects of MPTP on nigrostriatal dopaminergic neurons.

277 citations

Journal ArticleDOI
TL;DR: Rapid progress in clarifying the individual steps leading to the neuropathological symptoms has been remarkable and a plausible mechanistic picture has emerged so that the time seems right to review current knowledge of the individual biochemical events involved in the expression of the selective neurotoxicity of MPTP.
Abstract: Although only 3 years have passed since the appearance of the first report linking the presence of 1 -methyl-4-phenyl1,2,3,6-tetrahydropyriidine (MPTP) in preparations of an illicitly synthesized meperidine analog to the appearance of parkinsonian symptoms (Langston et al., 1983), progress in clarifying the individual steps leading to the neuropathological symptoms has been remarkable. Although some interesting questions still remain, a plausible mechanistic picture has emerged so that the time seems right to review current knowledge of the individual biochemical events involved in the expression of the selective neurotoxicity of MPTP. One reason for the rapid progress has been the worldwide interest generated by the availability of the first animal model for parkinsonism and the hope that elucidation of the mechanism of the neurotoxicity of MPTP may yield clues to some of the causes of idiopathic Parkinson’s disease. To the extent that this has been achieved, the accidental presence of this potent neurotoxin in some batches of “new heroin” may benefit mankind, despite the tragic consequences to the individuals exposed to it and the alarming social and medical problems of “designer drugs” that it has brought into sharp focus.

251 citations

Journal ArticleDOI
TL;DR: MPTP appears to be a suicide inactivator of MAO, which is oxidized by brain mitochondrial preparations in a process which is blocked by deprenyl and pargyline, implying catalysis by monoamine oxidase B.

203 citations


Cited by
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Journal ArticleDOI
TL;DR: These data indicate that N-methyl-D-aspartate antagonists produce a broad range of symptoms, behaviors, and cognitive deficits that resemble aspects of endogenous psychoses, particularly schizophrenia and dissociative states.
Abstract: Background: To characterize further behavioral, cognitive, neuroendocrine, and physiological effects of subanesthetic doses of ketamine hydrochloride in healthy human subjects. Ketamine, a phencyclidine hydrochloride derivative, is a dissociative anesthetic and a noncompetitive antagonist of the N -methyl-D-aspartate subtype of excitatory amino acid receptor. Methods: Nineteen healthy subjects recruited by advertisements from the community participated in this randomized, double-blind, placebo-controlled study. Subjects completed three test days involving the 40-minute intravenous administration of placebo, ketamine hydrochloride (0.1 mg/kg), or ketamine hydrochloride (0.5 mg/kg). Behaviors associated with the positive and negative symptoms of schizophrenia were assessed by using the Brief Psychiatric Rating Scale. Changes in perception and behaviors associated with dissociative states were assessed by the Perceptual Aberration Subscale of the Wisconsin Psychosis Proneness Scale and the Clinician-Administered Dissociative States Scale. Cognitive function was assessed by using the (1) Mini-Mental State Examination; (2) tests sensitive to frontal cortical dysfunction, including a continuous performance vigilance task, a verbal fluency task, and the Wisconsin Card Sorting Test; and (3) tests of immediate and delayed recall. Plasma levels of cortisol, prolactin, homovanillic acid, and 3-methoxy-4-hydroxyphenethyleneglycol were measured. Results: Ketamine (1) produced behaviors similar to the positive and negative symptoms of schizophrenia; (2) elicited alterations in perception; (3) impaired performance on tests of vigilance, verbal fluency, and the Wisconsin Card Sorting Test; (4) evoked symptoms similar to dissociative states; and (5) preferentially disrupted delayed word recall, sparing immediate recall and postdistraction recall. Ketamine had no significant effect on the Mini-Mental State Examination at the doses studied. Ketamine also had no effect on plasma 3-methoxy-4hydroxyphenethyleneglycol levels, although it blunted a test day decline in plasma homovanillic acid levels at the higher dose. It also dose dependently increased plasma cortisol and prolactin levels. Ketamine produced small dose-dependent increases in blood pressure. Conclusions: These data indicate that N -methyl-Daspartate antagonists produce a broad range of symptoms, behaviors, and cognitive deficits that resemble aspects of endogenous psychoses, particularly schizophrenia and dissociative states.

3,166 citations

Journal ArticleDOI
TL;DR: The nature of antioxidants is discussed, it being suggested that antioxidant enzymes and chelators of transition metal ions may be more generally useful protective agents than chain‐breaking antioxidants.
Abstract: Radicals are species containing one or more unpaired electrons. The oxygen radical superoxide (O 2 - ) and the non-radical oxidants hydrogen peroxide (H2O2) and hypochlorous acid (HOCl) are produced during normal metabolism and perform several useful functions. Excessive production of O 2 - and H2O2 can result in tissue damage, which often involves generation of highly reactive hydroxy 1 radical (· OH) and other oxidants in the presence of “catalytic” iron or copper ions. A major form of antioxidant defence is the storage and transport of iron or copper ions in forms that will not catalyze formation of reactive radicals. Tissue injury, e. g., by ischaemia or trauma, can cause increased iron availability and accelerate free radical reactions. This may be especially important in the brain, since areas of this organ are rich in iron and cerebrospinal fluid cannot bind released iron ions. Oxidative stress upon nervous tissue can produce damage by several interacting mechanisms, including rises in intracellular free Ca2+ and, possibly, release of excitatory amino acids. Recent suggestions that free radical reactions are involved in the neurotoxicity of aluminium and in damage to the substantia nigra in Parkinson’s disease are reviewed. Finally, the nature of antioxidants is discussed, with a suggestion that antioxidant enzymes and chelators of iron ions may be more generally useful protective agents than chain-breaking antioxidants. Careful precautions must be taken in the design of antioxidants for therapeutic use.

2,968 citations

Journal ArticleDOI
TL;DR: Robust and rapid antidepressant effects resulted from a single intravenous dose of an N-methyl-D-aspartate antagonist; onset occurred within 2 hours postinfusion and continued to remain significant for 1 week.
Abstract: Context Existing therapies for major depression have a lag of onset of action of several weeks, resulting in considerable morbidity. Exploring pharmacological strategies that have rapid onset of antidepressant effects within a few days and that are sustained would have an enormous impact on patient care. Converging lines of evidence suggest the role of the glutamatergic system in the pathophysiology and treatment of mood disorders. Objective To determine whether a rapid antidepressant effect can be achieved with an antagonist at theN-methyl-D-aspartate receptor in subjects with major depression. Design A randomized, placebo-controlled, double-blind crossover study from November 2004 to September 2005. Setting Mood Disorders Research Unit at the National Institute of Mental Health. Patients Eighteen subjects withDSM-IVmajor depression (treatment resistant). Interventions After a 2-week drug-free period, subjects were given an intravenous infusion of either ketamine hydrochloride (0.5 mg/kg) or placebo on 2 test days, a week apart. Subjects were rated at baseline and at 40, 80, 110, and 230 minutes and 1, 2, 3, and 7 days postinfusion. Main Outcome Measure Changes in scores on the primary efficacy measure, the 21-item Hamilton Depression Rating Scale. Results Subjects receiving ketamine showed significant improvement in depression compared with subjects receiving placebo within 110 minutes after injection, which remained significant throughout the following week. The effect size for the drug difference was very large (d = 1.46 [95% confidence interval, 0.91-2.01]) after 24 hours and moderate to large (d = 0.68 [95% confidence interval, 0.13-1.23]) after 1 week. Of the 17 subjects treated with ketamine, 71% met response and 29% met remission criteria the day following ketamine infusion. Thirty-five percent of subjects maintained response for at least 1 week. Conclusions Robust and rapid antidepressant effects resulted from a single intravenous dose of anN-methyl-D-aspartate antagonist; onset occurred within 2 hours postinfusion and continued to remain significant for 1 week. Trial Registration clinicaltrials.gov Identifier:NCT00088699.

2,965 citations

Journal ArticleDOI
TL;DR: Results indicated a specific defect of Complex I activity in the substantia nigra of patients with Parkinson's disease, which adds further support to the proposition that Parkinson’s disease may be due to an environmental toxin with action(s) similar to those of MPTP.
Abstract: The structure and function of mitochondrial respiratory-chain enzyme proteins were studied postmortem in the substantia nigra of nine patients with Parkinson's disease and nine matched controls. Total protein and mitochondrial mass were similar in the two groups. NADH-ubiquinone reductase (Complex I) and NADH cytochrome c reductase activities were significantly reduced, whereas succinate cytochrome c reductase activity was normal. These results indicated a specific defect of Complex I activity in the substantia nigra of patients with Parkinson's disease. This biochemical defect is the same as that produced in animal models of parkinsonism by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and adds further support to the proposition that Parkinson's disease may be due to an environmental toxin with action(s) similar to those of MPTP.

2,266 citations

Journal ArticleDOI
01 Jan 1999-Science
TL;DR: Blockade of N-methyl-D-aspartate (NMDA) glutamate receptors for only a few hours during late fetal or early neonatal life triggered widespread apoptotic neurodegeneration in the developing rat brain, suggesting that the excitatory neurotransmitter glutamate, acting at NMDA receptors, controls neuronal survival.
Abstract: Programmed cell death (apoptosis) occurs during normal development of the central nervous system. However, the mechanisms that determine which neurons will succumb to apoptosis are poorly understood. Blockade of N-methyl-D-aspartate (NMDA) glutamate receptors for only a few hours during late fetal or early neonatal life triggered widespread apoptotic neurodegeneration in the developing rat brain, suggesting that the excitatory neurotransmitter glutamate, acting at NMDA receptors, controls neuronal survival. These findings may have relevance to human neurodevelopmental disorders involving prenatal (drug-abusing mothers) or postnatal (pediatric anesthesia) exposure to drugs that block NMDA receptors.

1,964 citations