Abstract
Although hypothyroidism appears to be an important factor in the pathogenesis of depression, the impact of thyroid hormones on the bioenergetics of the adult brain is still poorly known. Since metabolic changes are reported to be a key player in the manifestation of depressive disorder, we investigated whether there are differences in selected metabolic markers in the frontal cortex and hippocampus of Wistar Kyoto rats (WKY; an animal model of depression) compared to those of control Wistar rats and whether the induction of hypothyroidism by propylthiouracil (PTU) elicits similar effects in these animals or intensifies some parameters in the WKY rats. In our study, we used WKY rats as a model of depression since this strain exhibits lower levels of monoamines in the brain than control rats and exhibits behavioral and hormonal alterations resembling those of depression, including increased reactivity to stress. The findings indicate a decrease in glycolysis intensity in both brain structures in the WKY rats as well as in both strains under hypothyroidism conditions. Furthermore, hypothyroidism disrupted the connection between glycolysis and the Krebs cycle in the frontal cortex and hippocampus in the depression model used in this study. Decreased thyroid hormone action was also shown to attenuate oxidative phosphorylation, and this change was greater in the WKY rats. Our results suggest that both the depression and hypothyroidism models are characterized by similar impairments in brain energy metabolism and mitochondrial function and, additionally, that the co-occurrence of hypothyroidism and depression may exacerbate some of the metabolic changes observed in depression.
Highlights
Depression affects more people than all other mental illnesses combined, and the currently available pharmacotherapies and behavioral therapies are not effective in many patients
We found that there were changes in glucose metabolism in the frontal cortex and/or hippocampus in an animal model of depression (WKY rats) and in a model of the co-occurrence of depression and hypothyroidism (WKY rats receiving PTU) compared to the control Wistar rats
The decreased metabolism in the frontal cortex in depression may result from decreases in the levels of T3 and TRα1 and in the expression of Deiodinase 2 (DIO2), an enzyme that catalyzes the conversion of T4 to the active T3 hormone
Summary
Depression affects more people than all other mental illnesses combined, and the currently available pharmacotherapies and behavioral therapies are not effective in many patients. The low efficacy of pharmacotherapy is probably because the antidepressant drugs currently in use mainly affect noradrenergic and serotonergic neurotransmission, while many studies have shown that this disease involves disturbances in neurotransmission and changes in hormonal systems, immune systems, and energy processes that together impair synaptic plasticity, leading to numerous functional changes, including depressed mood (Horowitz and Zunszain, 2015). The. Depression and Hypothyroidism participation of thyroid hormones in the pathogenesis of depression is evidenced by epidemiologic data that indicate that thyroid dysfunction often leads to the development of mental diseases; among patients with affective disorders, 1–4% have hypothyroidism, and 4–40% present subclinical hypothyroidism (Duntas and Maillis, 2013; Loh et al, 2019). The relationship of thyroid dysfunction with mood disorders and cognitive function has been observed clinically for a long time, the effects of thyroid hormones on processes occurring in the brain after the developmental period are unclear. Understanding the role of thyroid hormones in the pathogenesis of depression is hampered by the fact that prodepressive effects are observed in hypothyroidism and sometimes in hyperthyroidism and because these hormones can, in addition to exerting genomic effects, make an impact on the membranes of brain cells
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