General versus Specific Actions of Mild-Moderate Hypothermia in Attenuating Cerebral Ischemic Damage

Abstract

Mild or moderate hypothermia is generally thought to block all changes in signaling events that are detrimental to ischemic brain, including ATP depletion, glutamate release, Ca 2 + mobilization, anoxic depolarization, free radical generation, inflammation, blood-brain barrier permeability, necrotic, and apoptotic pathways. However, the effects and mechanisms of hypothermia are, in fact, variable. We emphasize that, even in the laboratory, hypothermic protection is limited. In certain models of permanent focal ischemia, hypothermia may not protect at all. In cases where hypothermia reduces infarct, some studies have overemphasized its ability to maintain cerebral blood flow and ATP levels, and to prevent anoxic depolarization, glutamate release during ischemia. Instead, hypothermia may protect against ischemia by regulating cascades that occur after reperfusion, including blood-brain barrier permeability and the changes in gene and protein expressions associated with necrotic and apoptotic pathways. Hypothermia not only blocks multiple damaging cascades after stroke, but also selectively upregulates some protective genes. However, most of these mechanisms are addressed in models with intraischemic hypothermia; much less information is available in models with postischemic hypothermia. Moreover, although it has been confirmed that mild hypothermia is clinically feasible for acute focal stroke treatment, no definite beneficial effect has been reported yet. This lack of clinical protection may result from suboptimal criteria for patient entrance into clinical trials. To facilitate clinical translation, future efforts in the laboratory should focus more on the protective mechanisms of postischemic hypothermia, as well as on the effects of sex, age and rewarming during reperfusion on hypothermic protection.

Hypothermia blocks β-catenin degradation after focal ischemia in rats

“…As we recently reviewed [16], intra-ischemic hypothermia not only blocks excitatory neurotransmitter, glutamate release and inhibits intracellular Calcium increase during stroke, it also improves ATP recovery after reperfusion, inhibits free radical generation, inflammatory response and blood-brain barrier permeability. In addition, intra-ischemic hypothermia has multiple effects on necrotic and apoptotic pathways.…”

“…Mild (33-36°C) or moderate (28-32°C) hypothermia is one of the strongest neuroprotectants identified to date that protect against cerebral ischemia [1,3,14], but the exact mechanisms for its protective effects are not fully understood [15]. We have previously reported that intraischemic moderate hypothermia (30 °C) reduces infarct size in focal ischemia by regulating the Akt survival pathways [14].…”

Extracorporeal membrane oxygenation for cardiac arrest during moyamoya cerebral revascularization surgery: case report

“…24 The benefit of mild hypothermia for neuroprotection in vascular neurosurgical cases is controversial, despite encouraging animal data. 8,43 At our center we use mild hypothermia for all cerebral revascularization surgeries and, in addition to effective CPR, this may have contributed to reducing neurological damage during ECPR, especially since the patient was hypothermic (33°C) before he suffered a cardiac arrest. Hypothermia via an intravascular cooling system can be instituted as part of the ECMO setup as it has its own temperature control system.…”

Cerebral Ischemia and Post-Ischemic Treatment with Hypothermia

“…Thus, the benefit is only moderate even at substantially lower temperatures than are usually considered suitable for most therapeutic purposes. There is evidence, however, that hypothermia also expedites the recovery of ATP stores after a period of ischemia, as well as improving the return of energy metabolism to pre-ischemic levels (Erecinska et al, 2003;Zhao et al, 2007). The combination of reduced demand and improved recovery both during and after what is a state of failed energy supply is perhaps enough to explain the outstanding neuroprotection afforded by intraischemic hypothermia.…”