Biomedical subjects

T L Perry

Publications and source records attributed to T L Perry.

At least 37 records · Page 2Linked to original sources

PubMed1989

Stereoselective disposition of racemic E-10-hydroxynortriptyline in human beings.

The disposition and elimination kinetics of the enantiomers of E-10-hydroxynortriptyline (E-10-OH-NT) were studied in six rapid and four slow hydroxylators of debrisoquin after a single oral dose of 75 mg racemic E-10-OH-NT hydrogen maleate. The plasma levels and the AUC of unconjugated (-)E-10-OH-NT were two to five times higher than those of (+)E-10-OH-NT. The plasma half-lives of both enantiomers were 8 to 9 hours. A significantly higher proportion of the given dose of (+)E-10-OH-NT (64.4% +/- 12.1%) than of (-)E-10-OH-NT (35.3% +/- 9.7%) was recovered in urine as glucuronide conjugate, but more (-)E-10-OH-NT was recovered unchanged in urine. The total oral plasma clearance and the metabolic clearance by glucuronidation were significantly (p less than 0.0001) higher for (+)E-10-OH-NT than for (-)E-10-OH-NT. The findings indicate that first-pass glucuronidation of E-10-OH-NT is enantioselective in human beings in vivo, with preference for (+)E-10-OH-NT. The renal clearance of unbound (-)E-10-OH-NT (0.57 +/- 0.16 L.kg-1.hr-1), on the other hand, exceeded that of (+)E-10-OH-NT (0.44 +/- 0.14 L.kg-1.hr-1) (p less than 0.005), which suggests enantioselective tubular secretion. The debrisoquin hydroxylation status was not associated with any of the investigated kinetic processes that relate to E-10-OH-NT.

Administration, Oral↗

PubMed1988

Tetrahydroisoquinoline lacks dopaminergic nigrostriatal neurotoxicity in mice.

1,2,3,4-Tetrahydroisoquinoline (TIQ) has been reported to occur in human brain, with its content being 10-fold higher in the brain of a patient with Parkinson's disease (PD) than in that of a control subject. This congener of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) could be formed in brain by the condensation of phenylethylamine with metabolically formed formaldehyde. Phenylethylamine contents are greatly increased in the tissues of untreated patients with phenylketonuria. We injected C57 black mice repeatedly with maximal tolerated doses of TIQ, but later found no reduction in the contents of dopamine and its metabolites in their striata. We doubt that TIQ is a cause of PD, especially since the disorder has not been reported to occur in elderly patients with phenylketonuria.

Animals↗

PubMed1988

Brain neurotransmitters in glycine encephalopathy.

We measured neurotransmitter markers in autopsied brain of infants with glycine encephalopathy (GE). Because patients with GE develop intractable seizures, special attention was devoted to those neurotransmitter systems implicated in human epilepsy. Mean levels of glycine in the frontal cortex of GE patients were three times higher than control values. No abnormalities were observed for concentrations of gamma-aminobutyric acid (and related receptors), other major neurotransmitter amino compounds, or activities of cholineacetyltransferase and aspartate aminotransferase. Mean acetylcholinesterase activity was significantly elevated by 46%. As experimental data suggest, glycine markedly potentiates the action of the excitatory neurotransmitter glutamic acid. To the extent that the brain seizures in patients with GE can be explained by this mechanism, pharmacotherapy with excitatory amino acid antagonists may represent a new approach to the treatment of GE.

Amino Acid Metabolism, Inborn Errors↗

PubMed1988

2-Phenylpyridine and 3-phenylpyridine, constituents of tea, are unlikely to cause idiopathic Parkinson's disease.

Idiopathic Parkinson's disease (PD) is likely to be caused by one or more unidentified neurotoxins, present in the environment or formed endogenously, which progressively damage dopaminergic nigrostriatal neurons. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is an experimental neurotoxin which produces biochemical and neuropathological changes in lower primates and mice and in humans inadvertently exposed to it that closely resemble those found in PD. 2-Phenylpyridine (2-PP) and 3-phenylpyridine (3-PP), both of them present in tea, are the only MPTP analogues that are known to be present in the human diet. We exposed C57 black mice, animals very sensitive to the dopaminergic neurotoxicity of MPTP, to prolonged parenteral and oral administration of large doses of 2-PP, and to prolonged parenteral administration of the N-methylated tetrahydro derivatives of 2-PP and 3-PP. The latter are closer chemical analogues of MPTP than are 2-PP and 3-PP themselves. None of these MPTP analogues lowered the contents of dopamine and its metabolites in the striatum of mice. We speculate that the neurotoxins which cause PD are unlikely to resemble MPTP structurally, and we suggest that the search for chemical causes of PD should be directed to a wider variety of compounds encountered by humans.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1988

Cerebrospinal fluid values for monoamine metabolites, gamma-aminobutyric acid, and other amino compounds in Rett syndrome.

We measured concentrations of 3-methoxy-4-hydroxy-phenylglycol, 3,4-dihydroxyphenylacetic acid, homovanillic acid, and 5-hydroxyindoleacetic acid--the metabolites of noradrenaline, dopamine, and serotonin used as central neurotransmitters--in the cerebrospinal fluid (CSF) specimens of five girls with Rett syndrome. These patients met the clinical criteria for both inclusion and exclusion of the diagnosis of Rett syndrome. In contrast to previous reports, cerebral monoamine metabolites were present in normal concentrations in CSF. In addition, concentrations of gamma-aminobutyric acid and of a large number of other amino acids and related compounds were normal in the CSF of patients with the syndrome. We doubt that an underlying biochemical cause for this disorder has yet been discovered.

Adolescent↗

PubMed1988

Brain amino acids and glutathione in progressive supranuclear palsy.

We measured amino acid contents in autopsied brains of seven patients with progressive supranuclear palsy (PSP) and in control subjects dying without brain disease. Glutathione was also quantitated in rapidly frozen brains of PSP patients, Parkinson's disease (PD) patients, and controls. In PSP, we found glutamic acid markedly increased in the nucleus accumbens; taurine significantly increased in nucleus accumbens, substantia nigra, and globus pallidus; and gamma-aminobutyric acid significantly increased in nucleus accumbens and putamen. Glycerophosphoethanolamine contents were significantly increased in most regions. Glutathione, which is significantly decreased in substantia nigra in PD, was increased in this brain region in PSP, suggesting that different mechanisms may be responsible for destruction of dopaminergic nigrostriatal neurons in these two disorders.

Aged↗

PubMed1987

4-phenylpyridine and three other analogues of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine lack dopaminergic nigrostriatal neurotoxicity in mice and marmosets.

C57 black mice were injected repeatedly with maximal tolerated doses of 2 chemical analogues of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP); 4-phenylpyridine and 4-phenyl-1,2,3,6-tetrahydropyridine. Although both compounds were clearly acutely toxic to mice, neither caused any reduction in striatal dopamine content after chronic exposure. Two MPTP analogues which may be formed endogenously during the metabolism of brain monoamines, 2-methyl-1,2,3,4-tetrahydroisoquinoline and 2-methyl-1,2,3,4-tetrahydro-beta-carboline, were injected repeatedly into common marmosets. Again, although both compounds appeared highly toxic, neither caused any reduction in striatal dopamine content. It appears unlikely that any of these 4 MPTP analogues causes idiopathic Parkinson's disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed1987

Tissue culture evidence for a circulating neurotoxin in Huntington's chorea.

We explored with tissue culture techniques the possibility that a circulating neurotoxin might cause the premature loss of certain populations of neurons that characterizes Huntington's chorea (HC). Explants of striatum from newborn rats were grown in culture media containing 30% by volume of serum from drug-free HC patients or from healthy control subjects. Glutamic acid decarboxylase (GAD), the enzyme which synthesizes gamma-aminobutyric acid (GABA), was later assayed in these explants as an indicator of the health of GABAergic striatal neurons. The sera of 7 of 8 HC patients decreased GAD activity markedly when present as 30% of the tissue culture medium. When present in lower concentration (15%), HC sera either decreased or increased GAD activity in explants. Deproteinization of sera with perchloric acid did not abolish these effects on GAD activity. A depressant effect on GAD activity was detected in the cerebrospinal fluid of 1 of 4 HC patients tested. These experiments suggest the presence of a circulating neurotoxin, possibly excitotoxic to GABAergic striatal interneurons, and probably a small molecule. Identification of this substance could lead to an effective preventive treatment for persons genetically at risk for HC.

Adolescent↗

PubMed1987

Alpha-tocopherol and beta-carotene do not protect marmosets against the dopaminergic neurotoxicity of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

Idiopathic Parkinson's disease (PD) may possibly be caused by one or more unidentified neurotoxins present in the environment, or formed endogenously, which progressively damage dopaminergic nigrostriatal neurons. N-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is an experimental neurotoxin which produces biochemical and neuropathological changes in humans, lower primates and mice that closely resemble those found in PD. Because the mechanisms of neuronal damage in both idiopathic PD and in the MPTP model of PD may involve free radical formation in the substantia nigra, antioxidants might protect dopaminergic neurons. Previously, we found that both alpha-tocopherol and beta-carotene partially protected mice against MPTP. However, in the experiments described in this paper, neither alpha-tocopherol nor beta-carotene, each administered in massive doses, had any demonstrable protective effect for dopaminergic nigrostriatal neurons in marmosets injected with low doses of MPTP. Without more knowledge about the identity of the neurotoxin(s) causing idiopathic PD, and their mechanism of action, it is not possible at this time to predict whether these 2 antioxidants might be clinically useful in preventing or ameliorating PD.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed1987

Glucuronidation of the enantiomers of E-10-hydroxynortriptyline in human and rat liver microsomes.

Conjugation of racemic E-10-hydroxynortriptyline (E-10-OH-NT) with glucuronic acid was studied in the liver microsomal fraction of rats and humans. The diastereomeric glucuronides of E-10-OH-NT were resolved and quantitated by HPLC. Only the (+)-enantiomer was glucuronidated in liver microsomes from humans. Rat liver microsomes catalyzed the formation of both glucuronides. Phenobarbital pretreatment of rats increased the glucuronidation of both enantiomers about five-fold. The formation rate of (+)-E-10-OH-NT glucuronide varied from 5.5 to 33.2 pmol/mg x min, in microsomes from 13 humans. High activity was found in individuals previously treated with pentobarbital. Inhibition experiments with human liver microsomes showed that amitriptyline is a potent competitive inhibitor of (+)-E-10-OH-NT glucuronidation. p-Nitrophenol, paracetamol and 2-hydroxydesipramine also inhibited this reaction.

Adult↗

PubMed1987

Brain glutamate deficiency in amyotrophic lateral sclerosis.

Amino acid contents were measured in autopsied brains of eight patients with the sporadic form of amyotrophic lateral sclerosis (ALS) and in brains of control subjects dying without neurologic or psychiatric disease. Glutamic acid content was reduced in most brain regions and in the cervical cord in the ALS patients, while glutamine contents were normal. Taurine contents were increased, and gamma-aminobutyric acid contents were decreased in some brain regions in the ALS patients. The brain glutamate deficiency in ALS is unexplained, but insufficient production or release of this excitatory neurotransmitter might have important secondary effects on motor neurons.

Amino Acids↗

PubMed1986

Chronic organic manganese administration in the rat does not damage dopaminergic nigrostriatal neurons.

In an attempt to produce an animal model of Parkinson's disease, we injected rats repeatedly with high doses of methylcyclopentadienyl manganese tricarbonyl (MMT), a compound which has been reported to lower striatal dopamine content in mice. Chronic MMT administration for up to 5 months, even though it produced a substantial elevation in brain manganese content during the period of exposure, did not destroy dopaminergic nigrostriatal neurons. This was assessed by measurements of tyrosine hydroxylase activity and contents of dopamine and its metabolites in the striatum, and by histological examination of the substantia nigra. Our results differ from those of others who administered manganese chloride in drinking water to rats. This discrepancy is unlikely to be a consequence of differences in duration of exposure or route of administration. It could be due to our having used an organic rather than an inorganic manganese compound, or to a species difference in vulnerability to organic manganese between rats and mice.

Animals↗

PubMed1985

Brain gamma-aminobutyric acid and benzodiazepine receptor binding in dialysis encephalopathy.

We measured gamma-aminobutyric acid (GABA) and benzodiazepine binding in autopsied frontal cortex of 8 patients dying with dialysis encephalopathy (DE). No alteration in [3H] GABA binding was observed. However, a mild reduction (-23%, P less than 0.05) of [3H] flunitrazepam-binding density was found in DE cortex. The magnitude of this reduction was similar to that observed in frontal cortex of amygdala-kindled rats [10]. We suggest that a reduction in benzodiazepine receptor number, in combination with markedly reduced GABA concentration in DE cerebral cortex may contribute to some of the clinical features (especially seizures) characteristically observed in this syndrome.

Benzodiazepinones↗

PubMed1985

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) does not destroy nigrostriatal neurons in the scorbutic guinea pig.

Guinea pigs were injected subcutaneously with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in maximal tolerated doses (8 mg/kg, once daily) for 10 or 15 days. No neurological effects were noted, other than sedation and hypotonia lasting a few hours after each injection, either in animals maintained on normal diet or in animals fed an ascorbate-deficient diet and rendered severely scorbutic. Subsequent chemical analyses of the striatum showed no evidence of lasting damage to nigrostriatal dopaminergic neurons in MPTP treated guinea pigs on normal diet, and minimal evidence of permanent damage to these neurons in scorbutic animals. MPTP was undetectable in the urine of MPTP-treated animals, although a metabolite, presumably 1-methyl-4-phenylpyridinium ion (MPP+) was regularly present in urine. The relative lack of neurotoxicity of MPTP in the guinea pig remains unexplained. This species clearly is not a suitable small animal for MPTP-induced parkinsonism.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed1985

Brain amino acid abnormalities in pyruvate carboxylase deficiency.

Amino acids were measured in several regions of autopsied brain from an infant who died with congenital lactic acidosis due to pyruvate carboxylase deficiency (McKusick 26615), as well as in cerebrospinal fluid (CSF) and plasma of four living infants with this disorder. Glutamine content was greatly reduced in all brain regions, while glutamic acid and proline contents were elevated. The gamma-aminobutyric acid (GABA) content was normal in brain. Glutamine concentrations in CSF and plasma were also decreased in the living patients. Glutamine may serve as a pool to provide glutamate and GABA for use as neurotransmitters, and to provide alpha-ketoglutarate for the tricarboxylic acid cycle when oxaloacetate can no longer be formed directly from pyruvate.

Acidosis, Lactic↗

PubMed1985

Multiple system atrophy with neuronal intranuclear hyaline inclusions. Report of a case and review of the literature.

A 31/2-year-old girl presented with frequent falls. She had an unsteady gait, delayed behavioural development absent tendon reflexes and in the legs decreased strength tone and equivocal plantar responses. She then developed ataxia, nystagmus, choreoathetosis, cranial nerve palsies, diminished strength and tone in the arms, sensory deficit in the limbs and autonomic nervous system dysfunction. She became progressively less responsive and succumbed at the age of 63/4 years. Examination of the central, peripheral and autonomic nervous system showed ubiquitous neuronal intranuclear hyaline inclusions and neuronal loss in several sites.

Amino Acids↗

PubMed1985

Is a circulating neurotoxin involved in the pathogenesis of Huntington's chorea?

We tested the hypothesis that the premature neuronal death which occurs in Huntington's chorea (HC) might be the result of a genetically-determined enzymatic failure in the degradation of a circulating neurotoxin of either endogenous of exogenous origin. Infant rats were given daily subcutaneous injections of large quantities of whole serum (for 24 days), or of a concentrated serum ultrafiltrate (for 37 days), obtained from HC patients or control subjects. Animals were killed 4 months after the end of injections, and their striata were examined neurochemically. There was a significant but small (16%) reduction in the mean striatal content of gamma-aminobutyric acid (GABA) in rats treated with whole serum from HC patients, but no striatal GABA deficiency was observed in rats treated with ultrafiltrates of serum from HC patients. Nor did these rats have any reduction in their striatal choline acetyltransferase activity. We conclude that if a circulating neurotoxin does contribute to the pathogenesis of HC, it must either be a small molecule which is tightly bound to serum proteins, or less likely a large compound with a molecular weight greater than 10 000.

Animals↗

PubMed1985

Chronic treatment with ACTH1-24 does not produce permanent damage to the developing rat brain.

Permanent effects of ACTH1-24 on the developing rat brain were investigated. Rats were injected with 20 IU/kg of ACTH1-24 daily for 4 weeks starting at two days of age. Brain weight, protein, DNA and RNA contents, contents of monoamines and their metabolites, 2',3'-cyclic nucleotide 3'-phosphohydrolase and glutamic acid decarboxylase activities were measured at 24 h and 8 weeks after the last injection. There were no significant changes in these indicators compared to saline-injected controls. These results suggest that chronic treatment with ACTH1-24 does not permanently damage the developing rat brain.

Adrenocorticotropic Hormone↗