Venlafaxine and L-Thyroxine Treatment Combination: Impact on Metabolic and Synaptic Plasticity Changes in an Animal Model of Coexisting Depression and Hypothyroidism.

Katarzyna Głombik,Jan Detka,Bogusława Budziszewska

doi:10.3390/cells10061394

Abstract

The clinical effectiveness of supportive therapy with thyroid hormones in drug-resistant depression is well-known; however, the mechanisms of action of these hormones in the adult brain have not been fully elucidated to date. We determined the effects of venlafaxine and/or L-thyroxine on metabolic parameters and markers involved in the regulation of synaptic plasticity and cell damage in an animal model of coexisting depression and hypothyroidism, namely, Wistar Kyoto rats treated with propylthiouracil. In this model, in relation to the depression model itself, the glycolysis process in the brain was weakened, and a reduction in pyruvate dehydrogenase in the frontal cortex was normalized only by the combined treatment with L-thyroxine and venlafaxine, whereas changes in pyruvate and lactate levels were affected by all applied therapies. None of the drugs improved the decrease in the expression of mitochondrial respiratory chain enzymes. No intensification of glucocorticoid action was shown, while an unfavorable change caused by the lack of thyroid hormones was an increase in the caspase-1 level, which was not reversed by venlafaxine alone. The results indicated that the combined administration of drugs was more effective in normalizing glycolysis and the transition to the Krebs cycle than the use of venlafaxine or L-thyroxine alone.

Highlights

Published: 5 June 2021Major depression, one of the most common mental illnesses, affects more individuals than all other psychiatric illnesses combined, and a significant number of patients do not remit after pharmacological or behavioral treatment
The existence of differences in the levels of the active thyroid hormone triiodothyronine (T3) between the brain and blood is likely to occur because the T3 concentration in the brain depends on thyroid hormone synthesis in the thyroid gland and, to a great extent, the expression of transporters and deiodinase enzymes in particular brain structures [22]. In line with this idea, in previous studies, we have shown a lower concentration of T3 in the frontal cortex of Wistar Kyoto rats (WKY), which are a model of endogenous depression, than in control Wistar rats, the levels of this hormone in the blood did not differ significantly between the studied strains, and even in WKY rats, T3 levels in the serum showed a rising trend [23]
Kyoto rats treated with 0.05% w/v PTU in their drinking water for six weeks and with venlafaxine (VEN, 20 mg/kg/mL dissolved in 0.9% NaCl i.p.) for the last three weeks of the experiment, group IV: Wistar Kyoto rats treated with 0.05% w/v PTU in their drinking water for six weeks and with levothyroxine (L-T4, 1.5 mg/kg/mL dissolved in 0.9% NaCl i.p.) for the last three weeks of the experiment, group V: Wistar Kyoto rats treated with

Summary

Introduction

Published: 5 June 2021Major depression, one of the most common mental illnesses, affects more individuals than all other psychiatric illnesses combined, and a significant number of patients do not remit after pharmacological or behavioral treatment. The low efficiency of the treatment of depression may be due to the poorly understood pathogenesis of this disease and the fact that most of the currently used drugs mainly affect serotonergic and noradrenergic transmission; while it is known that in this disease, metabolic, endocrine, and immune changes occur [1,2,3,4]. As indicated by current studies, the disturbances of neurotransmission observed in depression may not be the primary cause but rather the consequence of metabolic alternations related mainly to the dysfunction of astrocytes, excessive action of pro-inflammatory cytokines released primarily from microglial cells [6,7], and the strong action of glutamate and glucocorticoids [8,9]. An increasing number of studies indicate that metabolic dysfunction and insufficient energy supply to neurons may be important in the pathogenesis of depression [10,11,12]. Glucose is the main source of energy for brain cells, and its metabolism

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