Pharmacological effects of 3-iodothyronamine (T1AM) in mice include facilitation of memory acquisition and retention and reduction of pain threshold.

BACKGROUND AND PURPOSE: 3-Iodothyronamine (T1AM), an endogenous derivative of thyroid hormones, is regarded as a rapid modulator of behaviour and metabolism. To determine whether brain thyroid hormone levels contribute to these effects, we investigated the effect of central administration of T1AM on learning and pain threshold of mice either untreated or pretreated with clorgyline (2.5 mg·kg(-1) , i.p.), an inhibitor of amine oxidative metabolism. EXPERIMENTAL APPROACH: T1AM (0.13, 0.4, 1.32 and 4 µg·kg(-1) ) or vehicle was injected i.c.v. into male mice, and after 30 min their effects on memory acquisition capacity, pain threshold and curiosity were evaluated by the following tests: passive avoidance, licking latency on the hot plate and movements on the hole-board platform. Plasma glycaemia was measured using a glucorefractometer. Brain levels of triiodothyroxine (T3), thyroxine (T4) and T1AM were measured by HPLC coupled to tandem MS. ERK1/2 activation and c-fos expression in different brain regions were evaluated by Western blot analysis. RESULTS: T1AM improved learning capacity, decreased pain threshold to hot stimuli, enhanced curiosity and raised plasma glycaemia in a dose-dependent way, without modifying T3 and T4 brain concentrations. T1AM effects on learning and pain were abolished or significantly affected by clorgyline, suggesting a role for some metabolite(s), or that T1AM interacts at the rapid desensitizing target(s). T1AM activated ERK in different brain areas at lower doses than those effective on behaviour. CONCLUSIONS AND IMPLICATIONS: T1AM is a novel memory enhancer. This feature might have important implications for the treatment of endocrine and neurodegenerative-induced memory disorders.

Biosynthesis of 3-iodothyronamine (T1AM) is dependent on the sodium-iodide symporter and thyroperoxidase but does not involve extrathyroidal metabolism of T4.

3-Iodothyronamine (T(1)AM) is an endogenous thyroid hormone derivative with unknown biosynthetic origins. Structural similarities have led to the hypothesis that T(1)AM is an extrathyroidal metabolite of T(4). This study uses an isotope-labeled T(4) [heavy-T(4) (H-T(4))] that can be distinguished from endogenous T(4) by mass spectrometry, which allows metabolites to be identified based on the presence of this unique isotope signature. Endogenous T(1)AM levels depend upon thyroid status and decrease upon induction of hypothyroidism. However, in hypothyroid mice replaced with H-T(4), the isotope-labeled H-T(3) metabolite is detected, but no isotope-labeled T(1)AM is detected. These data suggest that T(1)AM is not an extrathyroidal metabolite of T(4), yet is produced by a process that requires the same biosynthetic factors necessary for T(4) synthesis.

3-Iodothyronamine: a modulator of the hypothalamus-pancreas-thyroid axes in mice.

BACKGROUND AND PURPOSE Preclinical pharmacology of 3-iodothyronamine (T1AM), an endogenous derivative of thyroid hormones, indicates that it is a rapid modulator of rodent metabolism and behaviour. Since T1AM undergoes rapid enzymatic degradation, particularly by MAO, we hypothesized that the effects of T1AM might be altered by inhibition of MAO. EXPERIMENTAL APPROACH We investigated the effects of injecting T1AM (i.c.v.) on (i) feeding behaviour, hyperglycaemia and plasma levels of thyroid hormones and (ii) T1AM systemic bioavailability, in overnight fasted mice, under control conditions and after pretreatment with the MAO inhibitor clorgyline. T1AM (1.3, 6.6, 13, 20 and 26 µg·kg(-1) ) or vehicle were injected i.c.v. in fasted male mice not pretreated or pretreated i.p. with clorgyline (2.5 mg·kg(-1) ). Glycaemia was measured by a glucorefractometer, plasma triiodothyronine (fT3) by a chemiluminescent immunometric assay, c-fos activation immunohistochemically and plasma T1AM by HPLC coupled to tandem-MS. KEY RESULTS T1AM, 1.3 µg·kg(-1) , produced a hypophagic effect (-24% vs. control) and reduced c-fos activation. This dose showed systemic bioavailability (0.12% of injected dose), raised plasma glucose levels and reduced peripheral insulin sensitivity (-33% vs. control) and plasma fT3 levels. These effects were not linearly related to the dose injected. Clorgyline pretreatment strongly increased the systemic bioavailability of T1AM and prevented the hyperglycaemia and reduction in fT3 induced by T1AM. CONCLUSIONS AND IMPLICATIONS T1AM induces central and peripheral effects including hyperglycaemia and a reduction in plasma fT3 levels in fasted mice. These effects critically depend on the concentration of T1AM or its metabolites in target organs.

Detection of 3-iodothyronamine in human patients: a preliminary study.

CONTEXT AND OBJECTIVE: The primary purpose of this study was to detect and quantify 3-iodothyronamine (T(1)AM), an endogenous biogenic amine related to thyroid hormone, in human blood. DESIGN: T(1)AM, total T(3), and total T(4) were assayed in serum by a novel HPLC tandem mass spectrometry assay, which has already been validated in animal investigations, and the results were related to standard clinical and laboratory variables. SETTING AND PATIENTS: The series included one healthy volunteer, 24 patients admitted to a cardiological ward, and 17 ambulatory patients suspected of thyroid disease, who underwent blood sampling at admission for routine diagnostic purposes. Seven patients were affected by type 2 diabetes, and six patients showed echocardiographic evidence of impaired left ventricular function. INTERVENTIONS: No intervention or any patient selection was performed. MAIN OUTCOME MEASURES: serum T(1)AM, total and free T(3) and T(4), routine chemistry, routine hematology, and echocardiographic parameters were measured. RESULTS: T(1)AM was detected in all samples, and its concentration averaged 0.219 ± 0.012 pmol/ml. The T(1)AM concentration was significantly correlated to total T(4) (r = 0.654, P < 0.001), total T(3) (r = 0.705, P < 0.001), glycated hemoglobin (r = 0.508, P = 0.013), brain natriuretic peptide (r = 0.543, P = 0.016), and γ-glutamyl transpeptidase (r = 0.675, P < 0.001). In diabetic vs. nondiabetic patients T(1)AM concentration was significantly increased (0.232 ± 0.014 vs. 0.203 ± 0.006 pmol/ml, P = 0.044), whereas no significant difference was observed in patients with cardiac dysfunction. CONCLUSIONS: T(1)AM is an endogenous messenger that can be assayed in human blood. Our results are consistent with the hypothesis that circulating T(1)AM is produced from thyroid hormones and encourage further investigations on the potential role of T(1)AM in insulin resistance and heart failure.

3-Iodothyronamine metabolism and functional effects in FRTL5 thyroid cells.

3-Iodothyronamine (T(1)AM), produced from thyroid hormones (TH) through decarboxylation and deiodination, is a potent agonist of trace amine-associated receptor 1 (TAAR1), a G protein-coupled receptor belonging to the family of TAARs. In vivo T(1)AM induces functional effects opposite to those produced on a longer time scale by TH and might represent a novel branch of TH signaling. In this study, we investigated the action of T(1)AM on thyroid and determined its uptake and catabolism using FRTL5 cells. The expression of TAAR1 was determined by PCR and western blot in FRTL5 cells, and cAMP, iodide uptake, and glucose uptake were measured after incubation with increasing concentrations of T(1)AM for different times. T(1)AM and its catabolites thyronamine (T(0)AM), 3-iodothyroacetic acid (TA(1)), and thyroacetic acid (TA(0)) were analyzed in FRTL5 cells by HPLC coupled to tandem mass spectrometry. The product of amplification of TAAR1 gene and TAAR1 protein was demonstrated in FRTL5 cells. No persistent and dose-dependent response to T(1)AM was observed after treatment with increasing doses of this substance for different times in terms of cAMP production and iodide uptake. A slight inhibition of glucose uptake was observed in the presence of 100 µM T(1)AM after 60 and 120 min (28 and 32% respectively), but the effect disappeared after 18 h. T(1)AM was taken up by FRTL5 cells and catabolized to T(0)AM, TA(1), and TA(0) confirming the presence of deiodinase and amine oxidase activity in thyroid. In conclusion, T(1)AM determined a slight inhibition of glucose uptake in FRTL5 cells, but it was taken up and catabolized by these cells.

Left-ventricular remodeling after myocardial infarction is associated with a cardiomyocyte-specific hypothyroid condition.

Similarities in cardiac gene expression in hypothyroidism and left ventricular (LV) pathological remodeling after myocardial infarction (MI) suggest a role for impaired cardiac thyroid hormone (TH) signaling in the development of heart failure. Increased ventricular activity of the TH-degrading enzyme type 3 deiodinase (D3) is recognized as a potential cause. In the present study, we investigated the cardiac expression and activity of D3 over an 8-wk period after MI in C57Bl/6J mice. Pathological remodeling of the noninfarcted part of the LV was evident from cardiomyocyte hypertrophy, interstitial fibrosis, and impairment of contractility. These changes were maximal and stable from the first week onward, as was the degree of LV dilation. A strong induction of D3 activity was found, which was similarly stable for the period examined. Plasma T(4) levels were transiently decreased at 1 wk after MI, but T(3) levels remained normal. The high D3 activity was associated with increased D3 mRNA expression at 1 but not at 4 and 8 wk after MI. Immunohistochemistry localized D3 protein to cardiomyocytes. In vivo measurement of TH-dependent transcription activity in cardiomyocytes using a luciferase reporter assay indicated a 48% decrease in post-MI mice relative to sham-operated animals, and this was associated with a 50% decrease in LV tissue T(3) concentration. In conclusion, pathological ventricular remodeling after MI in the mouse leads to high and stable induction of D3 activity in cardiomyocytes and a local hypothyroid condition.

Tissue distribution and cardiac metabolism of 3-iodothyronamine.

3-iodothyronamine (T1AM) is a novel relative of thyroid hormone, able to interact with specific G protein-coupled receptors, known as trace amine-associated receptors. Significant functional effects are produced by exogenous T1AM, including a negative inotropic and chronotropic effect in cardiac preparations. This work was aimed at estimating endogenous T1AM concentration in different tissues and determining its cardiac metabolism. A novel HPLC tandem mass spectrometry assay was developed, allowing detection of T1AM, thyronamine, 3-iodothyroacetic acid, and thyroacetic acid. T1AM was detected in rat serum, at the concentration of 0.3±0.03 pmol/ml, and in all tested organs (heart, liver, kidney, skeletal muscle, stomach, lung, and brain), at concentrations significantly higher than the serum concentration, ranging from 5.6±1.5 pmol/g in lung to 92.9±28.5 pmol/g in liver. T1AM was also identified for the first time in human blood. In H9c2 cardiomyocytes and isolated perfused rat hearts, significant Na+-dependent uptake of exogenous T1AM was observed, and at the steady state total cellular or tissue T1AM concentration exceeded extracellular concentration by more than 20-fold. In both preparations T1AM underwent oxidative deamination to 3-iodothyroacetic acid. T1AM deamination was inhibited by iproniazid but not pargyline or semicarbazide, suggesting the involvement of both monoamine oxidase and semicarbazide-sensitive amine oxidase. Thyronamine and thyroacetic acid were not detected in heart. Finally, evidence of T1AM production was observed in cardiomyocytes exposed to exogenous thyroid hormone, although the activity of this pathway was very low.