Concurrent administration of thyroxine and donepezil induces plastic changes in the prefrontal cortex of adult hypothyroid rats

Abstract

The aim of the present study was to observe the effects of the concurrent administration of thyroxine (T4) and an acetylcholinesterase (AChE) inhibitor, donepezil (DON), on the hypothyroidism-induced ultrastructural changes of the prefrontal cortex (PFC) in adult rats. The acetylcholine (ACh) content and AChE activity was assessed, as well as the expressions of synaptotagmin-1 (syt-1) and SNAP-25 were analyzed in the rats. Adding 0.05% propylthiouracil to rats' drinking water induced a hypothyroid rat model. The animals were treated with T4 and DON administered separately or in combination from the fifth week. Transmission electron microscope analysis revealed that hypothyroidism induced marked ultrastructural changes, including the neurons, the synapses and the myelin sheath in the PFC. T4 or DON treatment improved the morphologic features of the PFC, and the performance of the T4 combined DON group was the closest to the control group. Moreover, hypothyroidism significantly decreased the content of ACh (29.8%) and activity of AChE (27.8%), which were restored to control values by T4 administration. In addition, DON treatment restored ACh content to normal. At the protein level, hypothyroidism increased the levels of syt-1 and SNAP-25 in the PFC, both of which were not restored to control values following T4 administration, while concurrent administration of T4 and DON was able to induce this effect. These results suggested that adult-onset hypothyroidism induce morphological, biochemical and molecular alterations in the PFC, combined administration of T4 and DON induce plastic changes in the PFC, different from that of the standard T4 therapy, and that the DON treatment may facilitate the recovery of synaptic protein impairments induced by hypothyroidism.

Hashimoto's Thyroiditis Induces Hippocampus-Dependent Cognitive Alterations by Impairing Astrocytes in Euthyroid Mice

“…Thyroid dysfunction can lead to structural damage to synapses, and our previous studies have highlighted that experimental hypothyroidism induces synaptic deficit in the hippocampus (8) and prefrontal lobe (28). However, in this study, there was no statistically significant difference in thyroid hormone levels in serum and hippocampal tissues in the HT group compared with the Con group, so we believe that the synaptic damage is independent of thyroid hormone levels.…”

“…TEM was performed to evaluate the alterations in synaptic density and morphology in mice. TEM procedures were performed as previously described (28). Synapses were imaged at • 20,000 and • 50,000 magnifications.…”

Donepezil Improves Histological and Biochemical Changes in the Hippocampus of Adult Hypothyroid Male Rats

“…Another study reported that following the T4 + DON treatment, the morphological alterations, including the neurons, the synapses and the myelin sheath were similar to that of the control group [55] . The reversible changes of the acetyl cholin (Ach) concentration and acetyl cholinesterase (AChE) activity by T4 supplementation were also observed in other brain regions, such as the hippocampus of the adult hypothyroid rats [56] . The results above indicated that ACh and AChE may be under direct thyroid hormone control.…”

Hashimoto’s thyroiditis induces neuroinflammation and emotional alterations in euthyroid mice

“…For ultrastructure studies of microglia, astrocytes, and neurons, the frontal cortex in HT mice and the equivalent area in Con mice were obtained according to the mouse brain atlas. The entire TEM procedure was well described in our previous study [ 40 ]. Observations of neuroglia and neurons were made using magnifications ranging from 8000 to 12,000×.…”