Hypothermia‐Induced Ischemic Tolerance

Abstract

Delayed resistance to ischemic injury can be induced by a variety of conditioning stimuli. This phenomenon, known as delayed ischemic tolerance, is initiated over several hours or a day, and can persist for up to a week or more. The present paper describes recent experiments in which transient hypothermia was used as a conditioning stimulus to induce ischemic tolerance. A brief period of hypothermia administered 6 to 48 hours prior to focal ischemia reduces subsequent cerebral infarction. Hypothermia-induced ischemic tolerance is reversed by 7 days postconditioning, and is blocked by the protein synthesis inhibitor anisomycin. Electrophysiological studies utilizing in vitro brain slices demonstrate that hypoxic damage to synaptic responses is reduced in slices prepared from hypothermia-preconditioned animals. Taken together, these findings indicate that transient hypothermia induces tolerance in the brain parenchyma, and that increased expression of one or more gene products contributes to this phenomenon. Inasmuch as hypothermia is already an approved clinical procedure for intraischemic and postischemic therapy, it is possible that hypothermia could provide a clinically useful conditioning stimulus for limiting injury elicited by anticipated periods of ischemia.

Drug-Induced Hypothermia as Beneficial Treatment before and after Cerebral Ischemia

“…Nishio et al [4,27] demonstrated a significant reduction in infarct size by forced hypothermic preconditioning initiated 24 h before MCAO. Therefore, we also started induction of regulated hypothermic preconditioning at 26 h before MCAO and we obtained similar results.…”

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

“…Hypothermia-induced ischemic tolerance is initiated within 6 hours, peaks at approximately 1 or 2 days, and is reversed by 7 days after preconditioning stimulation. 13 It is likely that a hypothermic threshold must be reached for successful preconditioning to occur. Our findings support this possibility because T 0 AM failed to induce the same depth and duration of hypothermia as T 1 AM and failed to confer antecedent protection to ischemia.…”

“…26 In support of this postulate, hypothermia-induced preconditioning depends on de novo protein synthesis, and in SHSY5 cells, it requires modification of proteins by SUMOylation. 13,27 Transcription factors are the main targets of SUMO conjugation and SUMOylation of these proteins generally causes transcriptional suppression. Whether administration of T 1 AM and T 0 AM causes widespread SUMOylation of transcription factors is currently under investigation.…”

“…Previous studies have shown that brief exposure to hypothermia before ischemia induces tolerance to brain injury. [11][12][13] Such pretreatment offers hope to individuals in whom brain ischemia is anticipated such as those undergoing surgery (eg, coronary artery bypass grafting, arterectomy) and other "at-risk" populations.…”

Bilateral Common Carotid Artery Occlusion as an Adequate Preconditioning Stimulus to Induce Early Ischemic Tolerance to Focal Cerebral Ischemia

“…Particular attention requires maintenance of normothermic conditions of the mice throughout the complete period of anesthesia because hypothermia itself has a preconditioning effect and can therefore interfere with the BCCAO effect 16 . In awake and freely moving rodents, core temperatures are approximately between 0.5 and 1 degree Celsius higher than the corresponding brain temperatures 17 .…”