thyronines and Hypothermia

Thyronamines (TAMs) are a newly identified class of endogenous signaling compounds. Their structure is identical to that of thyroid hormone and deiodinated thyroid hormone derivatives, except that TAMs do not possess a carboxylate group. Despite some initial publications dating back to the 1950s, TAMs did not develop into an independent area of research until 2004, when they were rediscovered as potential ligands to a class of G protein-coupled receptors called trace-amine associated receptors. Since this discovery, two representatives of TAMs, namely 3-iodothyronamine (3-T(1)AM) and thyronamine (T(0)AM), have been detected in vivo. Intraperitoneal or central injection of 3-T(1)AM or T(0)AM into mice, rats, or Djungarian hamsters caused various prompt effects, such as metabolic depression, hypothermia, negative chronotropy, negative inotropy, hyperglycemia, reduction of the respiratory quotient, ketonuria, and reduction of fat mass. Although their physiological function remains elusive, 3-T(1)AM and T(0)AM have already revealed promising therapeutic potential because they represent the only endogenous compounds inducing hypothermia as a prophylactic or acute treatment of stroke and might thus be expected to cause fewer side effects than synthetic compounds. This review article summarizes the still somewhat scattered data on TAMs obtained both recently and more than 20 yr ago to yield a complete and updated picture of the current state of TAM research.

Topics: Adiposity; Animals; Cricetinae; Heart Rate; Humans; Hyperglycemia; Hypothermia; Ketosis; Male; Mice; Rats; Receptors, G-Protein-Coupled; Receptors, Thyroid Hormone; Signal Transduction; Stroke; Thyronines

Ectothermic animals rely on behavioral thermoregulation due to low capacity of heat production and storage. Previously, lizards were shown to achieve 'fever' during microbial infection by increasing their preferred body temperature (PBT) behaviorally, thereby attaining a relatively high survival rate. The purpose of this study was to investigate whether domesticated lizards pursued 'behavioral hypothermia' induced by a hypometabolic agent 3-iodothyronamine (T1AM). We found that treatment with 8.0 mg/kg T1AM caused a lizard species, the leopard gecko (Eublepharis macularius), to decrease its ventilation and oxygen consumption rates 0.64- and 0.76-fold, respectively, compared to those of the control (P<0.05). The lizards, habituated at an ambient temperature of 30 ± 0.5°C, also showed a significant decrease in the PBT range over a freely accessible thermal gradient between 5°C and 45°C. The upper limit of the PBT in the treated lizards lowered from 31.9°C to 30.6°C, and the lower limit from 29.5°C to 26.3°C (P<0.001). These findings demonstrate that the treated lizards pursued behavioral hypothermia in conjunction with hypoventilation and hypometabolism. Because prior studies reported a similar hypometabolic response in T1AM-injected laboratory mice, the domesticated lizards, as a part of the vertebrate phylogeny, may be a useful laboratory model for biological and pharmacological researches such as drug potency test.

Topics: Animals; Animals, Domestic; Behavior, Animal; Body Temperature Regulation; Energy Metabolism; Hypothermia; Lizards; Mice; Oxygen Consumption; Temperature; Thyronines

Mild hypothermia confers profound neuroprotection in ischemia. We recently discovered 2 natural derivatives of thyroxine, 3-iodothyronamine (T(1)AM) and thyronamine (T(0)AM), that when administered to rodents lower body temperature for several hours without induction of a compensatory homeostatic response. We tested whether T(1)AM- and T(0)AM-induced hypothermia protects against brain injury from experimental stroke.. We tested T(1)AM and T(0)AM 1 hour after and 2 days before stroke in a mouse model of focal ischemia. To determine whether T(1)AM and T(0)AM require hypothermia to protect against stroke injury, the induction of hypothermia was prevented.. T(1)AM and T(0)AM administration reduced body temperature from 37 degrees C to 31 degrees C. Mice given T(1)AM or T(0)AM after the ischemic period had significantly smaller infarcts compared with controls. Mice preconditioned with T(1)AM before ischemia displayed significantly smaller infarcts compared with controls. Pre- and postischemia treatments required the induction of hypothermia. T(1)AM and T(0)AM treatment in vitro failed to confer neuroprotection against ischemia.. T(1)AM and T(0)AM, are potent neuroprotectants in acute stroke and T(1)AM can be used as antecedent treatment to induce neuroprotection against subsequent ischemia. Hypothermia induced by T(1)AM and T(0)AM may underlie neuroprotection. T(1)AM and T(0)AM offer promise as treatments for brain injury.

Topics: Animals; Behavior, Animal; Body Temperature; Brain Ischemia; Cells, Cultured; Humans; Hypothermia; Ischemic Preconditioning; Male; Mice; Mice, Inbred C57BL; Molecular Structure; Neurons; Neuroprotective Agents; Stroke; Thyronines; Thyroxine

We have previously shown that several thyronamines, decarboxylated and deiodinated metabolites of the thyroid hormone, potently activate an orphan G protein-coupled receptor in vitro (TAAR1) and induced hypothermia in vivo on a rapid time scale [Scanlan, T. S.; Suchland, K. L.; Hart, M. E.; Chiellini, G.; Huang, Y.; Kruzich, P. J.; Frascarelli, S.; Crossley, D. A.; Bunzow, J. R.; Ronca-Testoni, S.; Lin, E. T.; Hatton, D.; Zucchi, R.; Grandy, D. K. 3-Iodothyronamine is an endogenous and rapid-acting derivative of thyroid hormone. Nat. Med. 2004, 10 (6), 638-642]. Herein, we report the synthesis of these thyronamines. Additionally, a large number of thyroamine derivatives were synthesized in an effort to understand the molecular basis of TAAR1 activation and hypothermia induction. Several derivatives were found to potently activate both rTAAR1 and mTAAR1 in vitro (compounds 77, 85, 91, and 92). When administered to mice at a 50 mg/kg dose, these derivatives all induced significant hypothermia within 60 min and exhibited a hypothermic induction profile analogous to 3-iodothyronamine (1, T(1)AM) except 91, which proved to be more efficacious. On the basis of this result, a dose-dependent profile for 91 was generated and an ED(50) of 30 mumol/kg was calculated. Compound 91 proved to be more potent than T(1)AM for TAAR1 activation and exhibits increased potency and efficacy for hypothermia induction. These data further strengthen the pharmacological correlation linking TAAR1 activation by thyronamines and hypothermia induction in mice.

Topics: Animals; Body Temperature; Cell Line; Cyclic AMP; Humans; Hypothermia; Mice; Mice, Inbred C57BL; Rats; Receptors, G-Protein-Coupled; Structure-Activity Relationship; Thyronines; Transfection

Thyroxine (T(4)) is the predominant form of thyroid hormone (TH). Hyperthyroidism, a condition associated with excess TH, is characterized by increases in metabolic rate, core body temperature and cardiac performance. In target tissues, T(4) is enzymatically deiodinated to 3,5,3'-triiodothyronine (T(3)), a high-affinity ligand for the nuclear TH receptors TR alpha and TR beta, whose activation controls normal vertebrate development and physiology. T(3)-modulated transcription of target genes via activation of TR alpha and TR beta is a slow process, the effects of which manifest over hours and days. Although rapidly occurring effects of TH have been documented, the molecules that mediate these non-genomic effects remain obscure. Here we report the discovery of 3-iodothyronamine (T(1)AM), a naturally occurring derivative of TH that in vitro is a potent agonist of the G protein-coupled trace amine receptor TAR1. Administering T(1)AM in vivo induces profound hypothermia and bradycardia within minutes. T(1)AM treatment also rapidly reduces cardiac output in an ex vivo working heart preparation. These results suggest the existence of a new signaling pathway, stimulation of which leads to rapid physiological and behavioral consequences that are opposite those associated with excess TH.

Topics: Animals; Body Temperature; Brain Chemistry; Cell Line; Dose-Response Relationship, Drug; Humans; Hypothermia; Ligands; Male; Mice; Mice, Inbred C57BL; Molecular Structure; Rats; Rats, Wistar; Receptors, G-Protein-Coupled; Receptors, Thyroid Hormone; Signal Transduction; Thyronines; Thyroxine; Time Factors