Novel thyroxine derivatives, thyronamine and 3-iodothyronamine, induce transient hypothermia and marked neuroprotection against stroke injury.
OBJECTIVE
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 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.


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.
Doyle
Kristian P
KP
Department of Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, OR 97239, USA.
Suchland
Katherine L
KL
Ciesielski
Thomas M P
TM
Lessov
Nikola S
NS
Grandy
David K
DK
Scanlan
Thomas S
TS
Stenzel-Poore
Mary P
MP
D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D001831:Body Temperature; D002545:Brain Ischemia / Q000473:pathology; D002478:Cells, Cultured; D006801:Humans; D007035:Hypothermia / Q000139:chemically induced*; D019194:Ischemic Preconditioning; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D018696:Neuroprotective Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D020521:Stroke / Q000473:pathology* / Q000517:prevention & control; D013970:Thyronines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D013974:Thyroxine / Q000031:analogs & derivatives*
C487948:3-iodothyronamine; D018696:Neuroprotective Agents; D013970:Thyronines; C004547:thyronamine; D013974:Thyroxine