piperidines and Hypothyroidism

Treatment with tyrosine kinase inhibitors (TKIs) has been associated with alterations in circulating thyroid hormone levels, possibly related to perturbations in peripheral thyroid hormone metabolism. In this study, we evaluated the effect of the multi-kinase inhibitor vandetanib on the expression of the three deiodinase selenoenzymes, responsible for the thyroid hormone activation (type 1 and type 2 deiodinases) or for its inactivation (type 3 deiodinase). Here, we show that the multi-kinase inhibitor vandetanib determines a strong cell-specific downregulation of type 2 deiodinase (D2) expression and a significant reduction in D2 enzymatic activity. This occurs in the diffused population of fibro/adipogenic progenitors, which reside in different tissues - including the muscles - and normally express D2. Given the widespread diffusion of mesenchymal cells within the body, our results may explain at least partially the alterations in thyroid hormone levels that occur in vandetanib-treated patients. Our findings represent a step forward into the understanding of the mechanisms by which TKIs induce hypothyroidism and identify a resident cell population in which such an effect takes place.

Topics: Humans; Hypothyroidism; Iodide Peroxidase; Piperidines; Thyroid Hormones

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 admi-nistration. 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.

Topics: Aging; Animals; Donepezil; Hypothyroidism; Indans; Male; Neuronal Plasticity; Piperidines; Prefrontal Cortex; Rats, Sprague-Dawley; Synaptosomal-Associated Protein 25; Synaptotagmin I; Thyroid Hormones; Thyroxine

A growing number of studies have revealed that neurocognitive impairment, induced by adult-onset hypothyroidism, may not be fully restored by traditional hormone substitution therapies, including thyroxine (T4). The present study has investigated the effect of T4 and donepezil (DON; an acetylcholinesterase (AChE) inhibitor) treatment on the hypothyroidism-induced alterations of acetylcholine (ACh) content and AChE activity. Furthermore, we examined synaptotagmin-1 (syt-1) and SNAP-25 expression in the hippocampus of adult rats. Adding 0.05% propylthiouracil to their drinking water for five weeks induced hypothyroidism in the rat models. From the fourth week, the rats were treated with T4, DON or a combination of both. Concentration of ACh and the activity of AChE was determined colorimetrically. The results demonstrated that hypothyroidism induced a significant decrease of Ach content and AChE activity (by 17 and 34%, respectively), which were restored to control values by T4 administration. DON treatment also restored Ach to the normal level. Protein levels of syt-1 and SNAP-25 were determined by immunohistochemistry. The results demonstrated that syt-1 was expressed at significantly lower levels in hypothyroid rats, while SNAP-25 levels were notably higher compared with the controls. Two-week treatment with T4 alone failed to normalize the expression levels of these two proteins, while co-administration of T4 and DON was able to induce this effect. These data suggested that the thyroid hormone, T4, may have a direct effect on the metabolism of hippocampal ACh in adult rats, and that the DON treatment may facilitate the recovery of synaptic protein impairments induced by hypothyroidism.

Topics: Acetylcholine; Acetylcholinesterase; Animals; Antithyroid Agents; Cholinesterase Inhibitors; Donepezil; Hippocampus; Hypothyroidism; Immunohistochemistry; Indans; Luminescent Measurements; Male; Piperidines; Propylthiouracil; Rats; Rats, Sprague-Dawley; Synaptosomal-Associated Protein 25; Synaptotagmin I; Thyrotropin; Thyroxine; Triiodothyronine

We examined the acute effects of endocannabinoid, anandamide, and of synthetic cannabinoid receptor antagonist, AM251[N-(piperidin-1-yl)-1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide], on TSH, thyroxine (T(4)), and triiodothyronine (T(3)) secretions. Euthyroid male rats showed a 42% decrease in serum TSH, 2 h after a single i.p. injection of 0.02, but not 0.2 mg/kg body weight (BW), anandamide, accompanied by a 39% reduction in serum T(4), without alteration in serum T(3). At 0.5 and 1 h, these serum hormones showed no significant change. Hypothyroid rats showed a 35% reduction in serum TSH (P<0.01), 2 h after anandamide injection, which had no effect on hyperthyroid rats. In both thyroid states, no modification of serum thyroid hormones was observed. Intraperitoneal injection of 0.17 or 1.7 mg/kg BW AM251 in euthyroid rats caused, 1.5 h later, 1.7-fold or 4.3-fold increase in serum TSH respectively, without changing thyroid hormones. Stimulatory effect of 0.17 mg/kg BW AM251 and inhibitory effect of anandamide was abolished in the group injected with AM251 followed by an anandamide injection, 30 min later. Intracerebroventricular injection of 20 ng (but not 200 ng) anandamide induced a decrease in serum TSH at 60 min after injection, which tended to disappear at 120 min. Anterior pituitary explants presented significant reduction in TSH release in the presence of 10(-7) M anandamide in incubation medium, which was blocked by 10(-7) M AM251. In conclusion, anandamide has the ability to acutely inhibit TSH release in eu- and hypothyroid rats, acting at the hypothalamus-pituitary axis. Since, in addition, the cannabinoid receptor antagonist AM251 increased TSH release, we suggest that endocannabinoid system has a role as negative regulator of TSH secretion.

Topics: Animals; Arachidonic Acids; Cannabinoid Receptor Modulators; Endocannabinoids; Hyperthyroidism; Hypothyroidism; In Vitro Techniques; Male; Piperidines; Pituitary Gland; Polyunsaturated Alkamides; Pyrazoles; Radioimmunoassay; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Thyrotropin; Thyroxine; Triiodothyronine

The thyrotrophin (TSH) and prolactin (Prl) releasing effects of domperidone, a recently developed antidopaminergic drug which does not cross the blood-brain barrier, were investigated in 8 women affected by primary hypothyroidism, and were compared to those elicited by another antidopaminergic drug, sulpiride. Domperidone (4 mg iv) induced a clear-cut and sustained rise in both plasma TSH and Prl, with peak levels occurring 15 and 30 min post-injection, respectively. The increments in plasma Prl after domperidone were significantly higher than those in plasma TSH. The TSH and Prl responses induced by domperidone were almost superimposable to those provoked in the same subjects by sulpiride (100 mg im). In view of the inability of domperidone to penetrate into the central nervous system (CNS), these findings imply a 'peripheral' site(s) of action (i.e. anterior pituitary and/or median eminence) for the effect of antidopaminergic drugs on TSH secretion, and, re-iterate the notion that the same 'peripheral' sites are involved in the Prl-releasing effect of these compounds.

Topics: Adolescent; Adult; Aged; Benzimidazoles; Domperidone; Female; Humans; Hypothyroidism; Middle Aged; Piperidines; Prolactin; Receptors, Dopamine; Thyrotropin

Domperidone, an extracerebral dopamine receptor antagonist, was given im to 12 normal subjects and to a group of patients with subclinical hypothyroidism to study its effect on PRL and TSH secretion. Domperidone induced in all subjects a quick and marked increment of serum PRL. At 180 min, the levels remained high. A small but significant increase of TSH was also observed in normal as well as in hypothyroid subjects. Since domperidone does not cross the blood-brain barrier, the hormonal changes observed may be mediated through the pituitary and median eminence, tissues which lie outside of the blood-brain barrier.

Topics: Adult; Benzimidazoles; Domperidone; Female; Humans; Hypothyroidism; Kinetics; Male; Piperidines; Prolactin; Receptors, Dopamine; Reference Values; Sex Factors; Thyrotropin

Administration of the novel agent domperidone (10 mg iv), which combines the properties of specific dopamine receptor blockade and inability to cross the blood-brain barrier, leads to acute and significant TSH and PRL release in man. This suggests that the in vivo site of action of endogenous dopamine in the inhibitory control of these two hormones is either the anterior pituitary or median eminence, since these tissues lie outside the blood-brain barrier. This class of drug is of potential value both clinically and experimentally in the investigation of anterior pituitary control mechanisms.

Topics: Autoimmune Diseases; Benzimidazoles; Domperidone; Dopamine Antagonists; Hypothyroidism; Piperidines; Pituitary Function Tests; Pituitary Gland, Anterior; Prolactin; Secretory Rate; Thyrotropin