Novel Thyroxine Derivatives, Thyronamine and 3-iodothyronamine, Induce Transient Hypothermia and Marked Neuroprotection Against Stroke Injury

Abstract

Background and Purpose-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. Methods-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. Results-T 1 AM and T 0 AM administration reduced body temperature from 37°C to 31°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. Conclusions-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.

ApoB-100-containing Lipoproteins Are Major Carriers of 3-Iodothyronamine in Circulation

“…3 In addition, these T 1 AM doses do not induce hypothermia, hyperglycemia, or any of the other previously reported actions of T 1 AM. After 15 days of dosing, serum was collected and evaluated for VLDL, LDL, HDL, apoB (in the transgenic mice only), triglyceride, and total cholesterol content (supplemental Fig.…”

Pharmacologically induced hypothermia via TRPV1 channel agonism provides neuroprotection following ischemic stroke when initiated 90 min after reperfusion

“…While there have been prior studies evaluating drug-induced hypothermia through myriad mechanisms, they have typically been plagued with a number of adverse effects or limited effectiveness that have diminished the potential for translation to clinical application (3,11,23,31,52,53). Safer and more effective methods for producing TH are needed that are compatible with conscious subjects to make TH a viable treatment option for a broader patient population.…”

Genetic Deletion of Trace Amine 1 Receptors Reveals Their Role in Auto-Inhibiting the Actions of Ecstasy (MDMA)

“…The TAs, tyramine, tryptamine, and ␤-phenethylamine are implicated in psychiatric and neurological disorders associated with monoaminergic dysfunction (Branchek and Blackburn, 2003;Berry, 2004;Burchett and Hicks, 2006;Sotnikova et al, 2008), yet it remains unproven that they act via TA 1 Rs in vivo. Conversely, the thyroxine derivatives 3-iodothyronamine (T 1 AM) and o-phenyl-3-iodotyramine (o-PIT) behave as agonists at TA 1 Rs, and their hypothermic actions are blunted in TA 1 knock-out (TA 1 -KO) mice (Scanlan et al, 2004;Hart et al, 2006;Doyle et al, 2007) (M.J. Millan, unpublished observations).…”