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.