Dopamine neuron induction and the neuroprotective effects of thyroid hormone derivatives.

Parkinson's disease (PD) is a neurodegenerative disease characterized by progressive movement disturbances caused by the selective loss of dopamine (DA) neurons in the substantia nigra. Despite the identification of the causal mechanisms underlying the pathogenesis of PD, effective treatments remain elusive. In this study, we observed that a low level of fetal bovine serum (FBS) effectively induced DA neurons in rat neural precursor cells (NPCs) by enhancing nuclear receptor-related 1 protein (NURR1) expression. Among the various components of FBS, the thyroid hormones triiodothyronine (T3) and thyroxine (T4) were identified as key factors for the induction of DA neurons. Since an overdose of thyroid hormones can cause hyperthyroidism, we synthesized several thyroid hormone derivatives that can partially activate thyroid hormone receptors and induce the complete differentiation of NPCs into DA neurons. Two derivatives (#3 and #9) showed positive effects on the induction and maturation of DA neurons without showing significant affinity for the thyroid hormone receptor. They also effectively protected and restored DA neurons from neurotoxic insults. Taken together, these observations demonstrate that thyroid hormone derivatives can strongly induce DA neuron differentiation while avoiding excessive thyroid stimulation and might therefore be useful candidates for PD treatment.

Lipid lowering with thyroid hormone and thyromimetics.

PURPOSE OF REVIEW: To summarize how thyroid hormones exert their effects on lipid metabolism through specific interaction with their nuclear receptors, to review studies of the effects of new and selective thyromimetic drugs in animals and humans and to identify important questions for future research. RECENT FINDINGS: Thyroid hormones exert their effects by stimulation of thyroid hormone receptors that have different tissue distribution and metabolic targets. TRß is predominant in liver and mainly responsible for effects on cholesterol and lipoprotein metabolism, whereas TRα is most important in fat, muscle, and heart. Thyroid hormone analogs (thyromimetics, tiromes) have been developed that activate TRß and are selectively taken up and/or activated by the liver. Such compounds stimulate hepatic LDL receptors, cholesterol elimination as bile acids and cholesterol, and presumably promote reverse cholesterol transport. In animals, they retard atherosclerosis progression. In humans, eprotirome exerts favorable lipid-modulating effects while lacking thyroid hormone-related side-effects and maintaining normal hypothalamic-pituitary-thyroid feedback. When added to statins, it reduces LDL and non-HDL cholesterol, apolipoprotein B, and triglycerides as well as lipoprotein (a). SUMMARY: Liver-specific and ß-selective thyroid hormone analogs activate a spectrum of favorable thyroid hormone actions that optimize lipid metabolism and promote cholesterol elimination. Further studies should establish long-term safety and potential clinical usefulness of thyromimetics.

Relación hepatosomática y depósito de hierro en hígado durante la instauración de anemia ferropénica nutricional / Hepatosomatic index and iron liver stores during the instauration of nutritional ferropenic anaemia

El hígado es el principal órgano de almacén de hierro en el organismo y juega un papel crucial en la homeostasis de dicho mineral. Los niveles de hierro en se consideran un fiel reflejo del estatus de hierro en el organismo, hecho que nos indujo a determinar la relación hepatosomática y el contenido de hierro en hígado durante la instauración de la anemia ferropénica nutricional inducida experimentalmente en ratas en crecimiento. Los depósitos de hierro estaban profundamente deplecionados, el peso corporal y el peso hepático fue menor en animales anémicos. Como consecuencia, la relación hepatosomática se incrementó en animales ferrodeficientes. Durante la ferrodeficiencia, varios factores reguladores de la hepcidina se alteran, aumenta la demanda eritropoyética por disminución de los parámetros hematológicos, hay un menor aporte de oxígeno a los tejidos y se deplecionan los depósitos corporales, alterándose el metabolismo de hierro, hechos que conducen a una disminución de dicha hormona, lo cual se traducirá en una menor interacción con la ferroportina 1, evitando su internalización y degradación, de manera que aumenta el flujo de salida de hierro ferroso desde los hepatocitos y consecuentemente se reduce su depósito. Por otra parte, la ferrodeficiencia afectó el peso corporal, hecho que se puede atribuir a los menores niveles de hormonas tiroideas encontrados en esta patología. Puesto que hay una clara reducción de la hemoglobina y recuento de hematíes, el suministro de oxígeno a las células se limita considerablemente e incide negativamente en la síntesis de ATP e incremento de peso(AU)

Liver is main storage organ of iron in the organism and plays a crucial role in the homeostasis of this mineral. The levels of iron are considered a routine index of the iron status in the body, fact that encouraged us to asses the hepatosomatic index and the iron content in liver, during iron-deficiency anaemia in growing rats. In rats with iron-deficiency anaemia, iron deposits were deeply depleted, body weight and hepatic weight were lower, moreover the hepatic iron deposits were lower in anaemicrats. During the iron-deficiency, several regulatory factors of the hepcidin are impaired (the erythropoietic demand increase due to the decrease of the haematological parameters, there is a minor supply of oxygen to the tissues and the body stores are depleted, being the iron metabolism altered), facts that leads to a decrease of the above mentioned hormone, which will be translated in a minor interaction with the ferroportin1, avoiding its internalization and degradation, therefore increases the outflow of ferrous iron from the hepatocytes and consistently its storage diminishes in the above mentioned organ. On the other hand, the iron-deficiency impaired the body weight, fact that can be related with the lower levels of thyroid hormones found in this pathology. Moreover, since in iron deficiency situation the haemoglobin and red blood cells count diminish drastically, the supply of oxygen to the cells limits itself considerably, which affects in a negative way to the ATP synthesis andincrease of weight(AU)

Thyroid hormone mimetics: potential applications in atherosclerosis, obesity and type 2 diabetes.

Thyroid hormones influence heart rate, serum lipids, metabolic rate, body weight and multiple aspects of lipid, carbohydrate, protein and mineral metabolism. Although increased thyroid hormone levels can improve serum lipid profiles and reduce fat, these positive effects are counterbalanced by harmful effects on the heart, muscle and bone. Thus, attempts to use thyroid hormones for cholesterol-lowering and weight loss purposes have so far been limited. However, over the past decade, thyroid hormone analogues that are capable of uncoupling beneficial effects from deleterious effects have been developed. Such drugs could serve as powerful new tools to address two of the largest medical problems in developed countries--atherosclerosis and obesity.

Anti-thyroid drugs and thyroid hormone synthesis: effect of methimazole derivatives on peroxidase-catalyzed reactions.

Syntheses and characterization of the selenium analogue (MSeI) of anti-thyroid drug methimazole and a series of organoselenium compounds bearing N-methylimidazole pharmacophore are described. In contrast to the sulfur compound that exists predominantly in its thione form, the selenium analogue exists in a selenol form, which spontaneously oxidizes in air to produce the corresponding diselenide. The reduction of the diselenide by GSH or NaBH(4) affords the biologically active selenol, which effectively inhibits the lactoperoxidase (LPO) activity in vitro. The monoselenides having N-methylimidazole moiety are found to be much less active than the selenol, suggesting that the presence of a selenol moiety is important for the LPO inhibition. The kinetic and mechanistic studies reveal that MSeI inhibits the LPO activity by reducing the H(2)O(2), providing a novel method to reversibly inhibit the enzyme. Although MSeI strongly inhibits LPO, the enzyme's activity can be completely recovered by increasing the H(2)O(2) concentration. On the other hand, the inhibition by methimazole (MMI), the sulfur analogue, cannot be reversed by increasing the H(2)O(2) concentration, leading to a complete inactivation of the enzyme. The reversible inhibition of LPO by some of the selenium derivatives is correlated with their glutathione peroxidase (GPx) activity, and the high GPx activity of the selenium compounds as compared with their sulfur analogues suggests that the selenium derivatives may protect the thyroid gland from oxidative damage.

Thyroid hormone ligands and metabolic diseases.

Thyroid hormones regulate fundamental genes involved in the metabolism, development and homeostasis of vertebrates. The endogenous hormones, L-3, 5, 3'-triiodo-L-thyronine (T(3)) and L-3, 5, 3', 5'-tetraiodo-L-thyronine (T(4)), are of limited use in pharmacological intervention, mainly due to cardiovascular liabilities. There exist two subtypes of thyroid hormone receptors (TR), alpha and beta, unequally distributed in the body. As TRalpha is most abundant in the heart and most effects of thyroid hormones on the heart are mediated through TRalpha, a reasonable strategy is the development of TR agonists that either are tissue selective or that interact selectively with TRbeta. The prospects for the treatment of metabolic diseases with such ligands are considerable and this review describes the massive efforts of the academic and industrial communities during the last decade. It is, however, the author's view that the development of selective ligands only is in its infancy, an opinion highlighted by the limited chemical structural variation of TR ligands as well as the present lack of TR ligands for the treatment of metabolic diseases in clinical phases.

Selective thyromimetics: tissue-selective thyroid hormone analogs.

Thyroid hormone coordinates a diverse array of physiological events in development and homeostasis. Many of the actions of thyroid hormone are tissue-specific and are primarily mediated by a panel of thyroid hormone receptor isoforms that are expressed in different ratios in different tissues. Because these tissue-specific hormone signaling pathways are linked to a number of metabolic diseases, the development of synthetic thyroid hormone analogs that have tissue-selective hormone actions (i.e., selective thyromimetics) is highly desirable. There is a powerful collection of tools available today for this pursuit including efficient receptor binding and activation assays, receptor structures and a variety of thyroid hormone receptor knockout mice. The medicinal chemistry efforts in this area demonstrate that selective thyromimetics can be produced from a variety of approaches. These compounds are proving useful as probes to better define thyroid hormone actions and may one day find use in the clinic for the treatment of metabolic disorders.

Improved synthesis of the iodine-free thyromimetic GC-1.

Synthesis of the TRbeta-selective thyromimetic GC-1 has been improved using methoxymethyl (MOM) and triisopropylsilyl (TiPS) substituents as phenolic protecting groups. The new synthetic route is adaptable to analogue design.

Acute effects of thyroid hormone analogs on sodium currents in neonatal rat myocytes.

We previously reported that T3(3,3',5-triiodo-L-thyronine) acutely increases sodium currents (INa) in neonatal rat myocytes. Here we compare the effects of several thyroid hormone analogs, including T4(3,3',5,5'-tetraiodo-L-thyronine), rT3(3,3',5'-triiodo-L-thyronine), D-T3(3,3',5-triiodo-D-thyronine), 3,5-T2(3,5-diiodo-L-thyronine), DIT (3,5-diiodo-L-tyrosine), MIT (3-monoiodo-L-tyrosine), tetrac (3,3',5,5'-tetraiodo-thyroacetic acid), triac (3, 3',5-triiodo-thyroacetic acid), and tyrosine, on INa in cultured neonatal rat myocytes (n ranged from 9 to 28 for each comparison). T4, T3, 3,5-T2, and DIT (10 n m) all increased current density relative to control to a similar degree: to 1.22+/-0.2, 1.21+/-0.03, 1.16+/-0.02 and 1.16+/-0.03, respectively, P<0.05. In contrast, thyroid hormone analogs with an altered side group of the inner iodophenyl ring, including tetrac, triac, and D-T3, had no effect on INa nor did rT3, MIT or tyrosine. Pretreatment with rT3 inhibited the effects of T4, T3, 3,5-T2, and DIT. Conversely, the dose-dependent inhibitory effect of amiodarone, an iodinated benzofuran derivative that antagonizes thyroid hormone actions, on INa was blocked when myocytes were pretreated with T3(100 n m, n=3), suggesting an interaction of T3 with amiodarone. The enhancement of INa by T3 and 3, 5-T2 could not be blocked by propranolol, suggesting that the effects are not mediated through beta -adrenergic signaling pathways. In conclusion, the present results suggest that the acute effects of thyroid hormone and analogs on cardiac INa are mediated by a non-genomic thyroid hormone receptor with a unique structure-activity relationship.

An efficient substitution reaction for the preparation of thyroid hormone analogues.

The substitution of the sterically hindered carbon of the potent thyroid hormone agonist, GC-1, was effected by a reaction based on the solvolysis of the benzylic hydroxyl group. The reaction was found to proceed in high yield with a variety of nucleophiles including alcohols, thiols, allyl silanes and electron-rich aromatic compounds, providing a convenient route to the synthesis of new thyroid hormone analogues.

alpha-Methylated analogues of triiodothyroalkanoic acids: synthesis and biological activity.

Three novel thyroid hormone analogues: alpha-methyl-3,5,3'-triiodothyroacetic acid, alpha-methyl-3,5,3'-triiodothyropropionic acid, and alpha-methyl-3,5,3',5'-tetraiodothyropropionic acid were synthesized. The hepatic thyroid receptor affinity of these analogues was compared to that other available thyroid analogues. The ability of these compounds to increase the activity of two hepatic enzymes and to lower blood cholesterol was compared to that of L-triiodothyronine. alpha-Methyl-3,5,3'-triiodothyroacetic acid was shown to have less nuclear binding affinity, less enzyme inducing ability, but more blood cholesterol lowering ability than triiodothyroacetic acid. alpha-Methyl-3,5,3',5'-tetraiodothyropropionic acid showed less nuclear binding affinity and less enzyme-inducing activity than alpha-methyl-3,5,3'-triiodothyropropionic acid.

Production of a specific polyclonal antibody against the rat beta thyroid receptor, using synthetic peptide as antigen.

We have developed a polyclonal antibody to a synthetic peptide corresponding to the deduced amino acid residues 67-80 of the amino terminal sequence of the rat thyroid receptor beta cDNA. Immunopositive sera were identified by radioimmunoassay and purified by affinity chromatography. The antibody specifically immunoprecipitated the labelled thyroid receptor beta synthetized in vitro but not the rat thyroid receptor alpha. Furthermore, 38% of the L-T3 binding capacity of the rat liver nuclear receptor were immunoabsorbed by this antibody. By immunocytochemistry, this antibody stained specifically the nuclei of hepatocytes while no staining was observed in the rat testis. This study presents a specific polyclonal antibody against the thyroid receptor beta. This antibody will be of a great help in determining the role of the beta receptors in the mechanism of action of thyroid hormone.

Selective thyromimetics. Cardiac-sparing thyroid hormone analogues containing 3'-arylmethyl substituents.

Introduction of specific arylmethyl groups at the 3'-position of the thyroid hormone 3,3',5-triiodo-L-thyronine (T3), and its known hormonally active derivatives, gives liver-selective, cardiac-sparing thyromimetics, with potential utility as plasma cholesterol lowering agents. Selectivity-conferring 3'-substituents include substituted benzyl, e.g. p-hydroxybenzyl, and heterocyclic methyl, e.g. 2-oxo-1,2-dihydropyrid-5-ylmethyl and 6-oxo-1,6-dihydropyridazin-3-ylmethyl. Correlations between in vivo and in vitro receptor binding affinities show that liver/heart selectivity does not depend on receptor recognition but on penetration or access to receptors in vivo. QSAR studies of the binding data of a series of 20 3'-arylmethyl T3 analogues show that electronegative groups at the para position increase both receptor binding and selectivity in vivo. However, increasing 3'-arylmethyl hydrophobicity increases receptor binding but reduces selectivity. Substitution at ortho and meta positions reduces both binding and selectivity. Replacement of the 3,5-iodo groups by halogen or methyl maintains selectivity, with 3,5-dibromo analogues in particular having increased potency combined with oral bioavailability. Diphenyl thioether derivatives also have improved potency but are less orally active. At the 1-position, the D enantiomer retains selectivity, but removal of the alpha-amino group to give a propionic acid results in loss of selective thyromimetic activity.

Efectos de calcio y paratohormona en la sintesis de prostaciclina por tejido vascular

Se estudió la generación de prostaciclina por anillos de aorta de ratón en diferentes concentraciones de calcio. El calcio extracelular influyó en la síntesis de prostaciclina de un modo concentración dependiente, como reflejado por la liberación de 6-Keto-prostaglandina F1 alfa dentro del médio. Los niveles de calcio alrededor del rango fisiológico (1.12-1.25 mM de calcio mM de calcio iónico) estimularon marcadamente la producción de prostaciclina en relación a las soluciones libres de calcio. Por otro lado, la adición de paratohormona purificada no cambió la producción de 6-Ketoprostaglandina F1 alfa en ninguna de las concentraciones de calcio estudiadas. Estos datos sugieren que la hormona paratiroidea no tiene un efecto directo en la síntesis vascular de prostacilina, sin embargo puede influir en la generación de prostaciclina a través de cambios en los niveles extracelulares de calcio

3'-Acetyl-3,5-diiodo-L-thyronine: a novel highly active thyromimetic with low receptor affinity.

The 4'-phenolic hydroxyl group of thyroid hormones plays an important role in receptor binding, and it has been suggested that the interaction of this hydroxyl group with the receptor involves hydrogen bonding via donation of the acidic hydrogen in a trans disposition to the 3'-substituent of the hormones. In order to test this hypothesis we have synthesised, and measured the hepatic receptor affinity and thyromimetic activity of 3'-acetyl-3,5-diiodo-L-thyronine (3'-Ac-T2), a compound in which the formation of such a receptor-phenol hydrogen bond is precluded by the presence of a strong intramolecular hydrogen bond between the 3'-acetyl- and 4'-hydroxyl groups. In confirmation of the hypothesis, 3'-Ac-T2 has a low affinity (0.5% of that of 3,5,3'-triiodo-L-thyronine, T3) for the T3-receptor in isolated rat hepatic nuclei. By contrast the thyromimetic activity (assessed by its ability to induce rat hepatic glycerol-3-phosphate dehydrogenase and increase the qO2 of liver slices) was roughly equal to that of T3. This apparent discrepancy was resolved when it was found that the capacity of 3'-Ac-T2 to occupy hepatic receptors after in vivo administration, was about 100 times greater than predicted from its in vitro affinity. The reason for this difference between in vivo and in vitro nuclear binding is unknown at the present time.

Role of iodine in thyroid hormones: molecular conformation of a halogen-free hormone analogue.

The molecular conformation of the halogen-free thyroid hormone analogue, N-acetyl-4'-methoxy-3,5,3'-trimethyl-L-thyronine ethyl ester, has beeen determined by X-ray diffraction techniques. The observed molecular conformation is similar to that found for the natural hormone 3,5,3'-triiodo-L-thyronine (T3). In this structure, the 3'-methyl group is distal, the overall conformation is cisoid, and the diphenyl ether conformation is twist--skewed. These structural similarities with T3 show that the conformation features required by the active hormone can still be maintained with methyl substitution. The observation that the halogen-free analogues have relatively high activity but extremely low protein binding affinity implies that the role of iodine in hormone transport and biological activity can be deifferentiated. These data suggest that the iodines enhance hormone--protein binding by virtue of their electronic, as well as steric, properties.

Breast cancer. Relationship to thyroid supplements for hypothyroidism.

This study was undertaken to determine the relationship between thyroid supplements and breast cancer. The incidence of breast cancer among the patients who received thyroid supplements was 12.13%, while in the control group it was 6.2%. The incidence rate of breast cancer was 10%, 9.42%, and 19.48% among patients who received thyroid supplements for one to five, 5 to 15, and for more than 15 years, respectively. The incidence of breast cancer among nulliparous women who received thyroid supplements was 33%, while in the nulliparous women without thyroid supplements the incidence was only 9.25%. Even in a specific age group, the incidence rate of breast cancer was higher among patients receiving thyroid supplements, when compared to the control patients in the same age group.