Therapeutic hypothermia for ischemic stroke; pathophysiology and future promise

Abstract

Therapeutic hypothermia, or cooling of the body or brain for the purposes of preserving organ viability, is one of the most robust neuroprotectants at both the preclinical and clinical levels. Although therapeutic hypothermia has been shown to improve outcome from related clinical conditions, the significance in ischemic stroke is still under investigation. Numerous pre-clinical studies of therapeutic hypothermia has suggested optimal cooling conditions, such as depth, duration, and temporal therapeutic window for effective neuroprotection. Several studies have also explored mechanisms underlying the mechanisms of neuroprotection by therapeutic hypothermia. As such, it appears that cooling affects multiple aspects of brain pathophysiology, and regulates almost every pathway involved in the evolution of ischemic stroke. This multifaceted mechanism is thought to contribute to its strong neuroprotective effect. In order to carry out this therapy in optimal clinical settings, methodological and pathophysiological understanding is crucial. However, more investigation is still needed to better understand the underlying mechanisms of this intervention, and to overcome clinical barriers which seem to preclude the routine use therapeutic hypothermia in stroke. This article is part of the Special Issue entitled 'Cerebral Ischemia'.

Keywords: Cerebral infarct; Cooling; Hypothermia; Infarction; Ischemia; Stroke.

Conflict of interest statement

Conflict of interest

There are no conflicts of interest to declare.

Published by Elsevier Ltd.

Figures

Fig 1.

Mechanisms affected by therapeutic hypothermia during the acute stage of ischemic stroke. Following ischemia, acute events such as loss of oxygen and glucose lead to energy loss (loss of ATP) and ion pump failure. The resulting loss of concentration gradients allows ions to flow down their concentration gradients, leading to cell swelling (cytotoxic edema) and the release of excitatory amino acids (EAAs). All of these events will induce acute cell death. Therapeutic hypothermia has been reported to affect almost every cellular event that leads to cell death.

Fig 2.

Mechanisms affected by therapeutic hypothermia on the sub-acute stage of ischemic stroke. Ischemia activates both intrinsic and extrinsic pathway which will lead cell apoptosis. Ischemia also triggers ROS production and inflammatory reaction. These promote endothelial cell damage and BBB disruption. Therapeutic hypothermia has been associated with suppression of both apoptotic and inflammatory pathways, while upregulating cell survival pathways. BCL-2: b-cell leukemia/lymphoma 2 protein; BAX: Bcl-2-associated X protein; PKC: phosphokinase C; ROS: reactive oxygen species; RNS: reactive nitrogen species; MMP: matrix metalloproteinase; BBB: Blood brain barrier.