Ahmed, Mahmood Taleb; (1994) Adult hypothyroidism and brain functions: A biochemical, enzymic, metabolic and molecular biological investigation. Doctoral thesis (Ph.D.), University College London (United Kingdom).

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Abstract

The role of thyroid hormones in the development and maintainance of normal CNS functions has been extensively studied and is well established. In the developing brain, hypothyroidism adversely affects most specific parameters of brain cell development which, if not corrected, results in irreversible damage. However, the effect of thyroid hormones on adult brain remains a contentious and relatively neglected area of research. Nevertheless, the clinical findings and symptoms of adult onset dysthyroid states suggest profound changes in brain function. For example, hypothyroidism is associated with psychotic behaviour, delusions, hallucinations, memory impairment, cerebellar ataxia, confusion, slower motor-coordination and loss of the α-rhythm on EEG, whereas hyperthyroidism is accompanied by an increased frequency of the α-rhythm, nervousness, irritability, tremulousness and, in extreme cases, delirium, stupour and coma. Apart from behavioural abnormalities observed in adult hypothyroidism, the putative biochemical and cellular disorders leading to these abnormalities have not been studied in detail. The aim of this study was to evaluate the biochemical and molecular biological changes in different brain regions due to adult hypothyroidism in an animal model. Hypothyroidism was either chemically induced (methimazole; 0.1%, w/v in drinking water) in male rats (6 month of age) or by partial thyroidectomy coupled with the administration of 6-n-propyl-2-thiouracil (0.005%, w/v) in the drinking water. Age-matched euthyroid males served as the controls. Total protein, protein profiles (cytosolic, particulate and synaptosomal), DNA, RNA, inorganic phosphate, acid and alkaline hydrolases (including cell markers), enzymes of energy metabolism, neurotransmitter associated enzymes, metabolism of several metabolic substrates (glucose, glutamate and acetate) and expression of thyroid hormone nuclear receptors (THNRs) isoforms in different brain regions were investigated. Our results show that the body weight, brain weight, total protein, protein profiles of different subcellular fractions, DNA, RNA and inorganic phosphate remained apparently unchanged as a consequence of adult hypothyroidism. Hypothyroidism resulted in brain region-specific changes in certain catabolic enzymes activities. In conclusion, it is postulated that the compromise of these functional enzymes, glutamate metabolism (a major excitatory amino acid neurotransmitter) along with THNRs isoforms and 5'-DII may place severe restrictions on normal brain functions. The biochemical vulnerability of the adult rat cerebellum to the effects of thyroidectomy may correlate with the known clinical manifestations of CNS dysfunction in adult hypothyroid man. These findings raise the possibility of an important role for the thyroid hormones in the maintainance of biochemical and behavioural normality.

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