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Alterations in brain dipeptide and amino acid content in neurological and psychiatric disorders

University of British Columbia

My thesis is divided into 4 major sections. The first section is devoted in part to a description of the biochemical abnormalities in the metabolism of homocarnosine (y-aminobutyryl-L-histidine, HCarn) occurring in a patient with homocarnosinosis. The patient studied and two of her siblings have a progressive neurological disorder with grossly elevated concentrations of HCarn in their CSF. HCarn content was four times higher in a biopsy from the patient's frontal cortex than in biopsied cortex from a large group of control subjects. Using new techniques for the measurement of the HCarn synthesizing and catabolizing enzymes, it was found that the activity of HCarn-Carn synthetase was not increased in the patient's biopsy whereas homocarnosinase activity was undetectable. It is concluded that the elevated HCarn in brain and CSF in the homocarnosinosis patient is due to a deficiency of brain homocarnosinase activity. The first description of the regional distribution of the two HCarn metabolizing enzymes in human brain was also obtained. The remainder of the first section deals with a description of the neuropharmacological properties of HCarn. Intraventricular injection of HCarn in the rat produced hyperexcitability and in high doses, convulsions, whereas unilateral intra-striatal injection of HCarn resulted in contralateral myoclonus. The results of these experiments are consistent with the possibility that HCarn may be involved in the neuronal excitability of brain. The second section describes experiments which test the hypothesis that the content of the inhibitory neurotransmitter GABA is altered in the autopsied brains of some patients dying with schizophrenia. The mean content of GABA was reduced by 20-25% in nucleus accumbens, caudate nucleus, frontal cortex and thalamus of the schizophrenic patients as compared to a control group. However, the differences were found to be statistically significant for only the caudate and thalamus. Extraneous factors such as age of patient at death and prolonged drug treatment did not readily explain the observed reduction in GABA content. The results of the investigation suggest an association between a deficiency of GABAergic function in certain brain areas with some forms of schizophrenia. The third section describes experiments which test the hypothesis that a deficiency of aspartate found in the cerebellar cortex of some patients with dominantly inherited cerebellar disorders might be due to reduced activity of two enzymes involved in the synthesis of aspartate, namely, aspartate aminotransferase and pyruvate carboxylase. No deficiency of either enzyme was observed in the cerebellar specimens studied. The results of this investigation suggest that the aspartate deficiency in cerebellar cortex found in some dominantly inherited cerebellar disorders does not result from a deficiency of either of these two brain enzymes. In the final section, experiments are described which study the effects of chronic administration of Y-vinyl GABA and of hydrazine on the contents of GABA and other amino compounds in rat brain. Both of these compounds are presently under consideration for use in clinical trials on patients with disorders involving a brain GABA deficiency. Chronic administration of either y-vinyl GABA or of hydrazine markedly increased brain GABA content in the rat. Prolonged treatment with y-vinyl GABA, but not hydrazine, produced a decrease in the activity of glutamic acid decarboxylase (GAD) in rat brain. Since GAD is localized to a large extent in nerve endings, the possibility exists that y-vinyl GABA might reduce the amount of GABA available for release at synapses, a potentially undesirable effect. The contents of many brain amino compounds other than GABA were markedly altered by both drugs. Since the potential harmful effects of these unexpected biochemical alterations in brain are unknown, the nonspecific effects of Y-vinyl GABA and hydrazine are disturbing.

Text

2010-03-26

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http://hdl.handle.net/2429/22584

Pharmacology

University of British Columbia

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