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

Abstract

BACKGROUND AND PURPOSEPreclinical 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 APPROACHWe 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 mg·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 mg·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 IMPLICATIONST1AM 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. AbbreviationsfT3,

In the brain of mice, 3-iodothyronamine (T1AM) is converted into 3-iodothyroacetic acid (TA1) and it is included within the signaling network connecting thyroid hormone metabolites with histamine

“…Clorgyline is an inhibitor of MAO activity and at the dose used in the present investigation it does not interfere with mouse behavior (Manni et al, 2012a(Manni et al, , 2012b(Manni et al, , 2013. T1AM pro-learning and hyperlagesic effects were not evident in the presence of clorgyline (Manni et al, 2013) and we now report that under these conditions, brain T1AM and TA1 levels did not increase, but rather decreased.…”

“…Many neurological effects of T1AM were prevented or reduced when animals were pre-treated with clorgyline, a monoamine oxidase (MAO) inhibitor (Manni et al, 2012a(Manni et al, , 2013. This observation accounts for several hypotheses, namely: i) increased sympathergic tone opposes T1AM signaling; ii) oxidative deamination of T1AM is required for its pharmacological effects; iii) increased T1AM levels induce desensitization and/or activation of different targets eliciting opposite responses.…”

3-iodothyronamine (T1AM), a novel antagonist of muscarinic receptors

“…Much is instead known on the pharmacological effects of T1AM. In this respect, we described that T1AM acutely modifies mice behavior and metabolism (Manni et al, 2012) (Manni et al, 2013) (Laurino et al, 2015) with a mechanism which remains to be defined but that depends, at least in part, on the activation of the histaminergic system and on T1AM biotransformation into TA1 (Manni et al, 2012) (Manni et al, 2013) (Laurino et al, 2015). In 2004, Scanlan et al described the hibernating effect of T1AM while recently James et al (2013) reported a pro-awaking effect of T1AM in rats.…”

Design, Synthesis, and Evaluation of Thyronamine Analogues as Novel Potent Mouse Trace Amine Associated Receptor 1 (mTAAR1) Agonists

“…23 Recent findings suggested that generation of TA 1 by deamination might contribute, at least in part, to the acute effects of T1AM in vivo and showed that oxidative deamination had a marked effect on T1AM pharmacokinetics. 20 Thus, to expand our SAR analysis on 4′-NH 2 -biaryl-methane thyronamine analogues, we synthesized the corresponding deamination product of compounds 1−3, namely 5, 7, and 9, as well as their 4′-NO 2 analogues, namely 6, 8, and 10 ( Figure 1).…”

“…Glycaemia was evaluated by a glucorefractometer 15 min after the ip injections, as described. 20 Data are expressed as mean ± SEM of independent experiments. Statistical analysis was performed by one-way ANOVA, followed by Student−Newman−Keuls multiple comparison post hoc test; the threshold of statistical significance was set at P < 0.05.…”