Published Online
on August 9, 2007

A more recent version of this article appeared on September 1, 2007

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Submitted on December 21, 2006
Revised on March 1, 2007
Accepted on March 12, 2007

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

Kristian P. Doyle BSc; Katherine L. Suchland BS; Thomas M.P. Ciesielski BS; Nikola S. Lessov MD, PhD; David K. Grandy PhD; Thomas S. Scanlan PhD; and Mary P. Stenzel-Poore PhD^*

From the Departments of Molecular Microbiology and Immunology (K.P.D., T.M.P.C., N.S.L., M.P.S.-P.) and Physiology and Pharmacology (K.L.S., D.K.G., T.S.S.), Oregon Health & Science University, Portland, Ore.

^* To whom correspondence should be addressed. E-mail: poorem{at}ohsu.edu.

Background and Purpose—Mild hypothermia confers profound neuroprotection in ischemia. We recently discovered 2 natural derivatives of thyroxine, 3-iodothyronamine (T₁AM) and thyronamine (T₀AM), that when administered to rodents lower body temperature for several hours without induction of a compensatory homeostatic response. We tested whether T₁AM- and T₀AM-induced hypothermia protects against brain injury from experimental stroke.

Methods—We tested T₁AM and T₀AM 1 hour after and 2 days before stroke in a mouse model of focal ischemia. To determine whether T₁AM and T₀AM require hypothermia to protect against stroke injury, the induction of hypothermia was prevented.

Results—T₁AM and T₀AM administration reduced body temperature from 37°C to 31°C. Mice given T₁AM or T₀AM after the ischemic period had significantly smaller infarcts compared with controls. Mice preconditioned with T₁AM before ischemia displayed significantly smaller infarcts compared with controls. Pre- and postischemia treatments required the induction of hypothermia. T₁AM and T₀AM treatment in vitro failed to confer neuroprotection against ischemia.

Conclusions—T₁AM and T₀AM, are potent neuroprotectants in acute stroke and T₁AM can be used as antecedent treatment to induce neuroprotection against subsequent ischemia. Hypothermia induced by T₁AM and T₀AM may underlie neuroprotection. T₁AM and T₀AM offer promise as treatments for brain injury.

Key words: hypothermia • neuroprotection • stroke

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