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'.

Sexually dimorphic microglia and ischemic stroke

“…Pioneering studies from our laboratory have demonstrated that lowering of brain temperature by only a few degrees can ameliorate ischemic neuronal death . Therapeutic hypothermia has been widely regarded to be one of the most reliable neuroprotective therapies for several cerebral disorders and injuries, including stroke, traumatic brain and spinal cord injury, global ischemia after cardiac arrest, and hypoxic‐ischemic encephalopathy . The ischemic injury stimulates innate immune responses leading to activation of microglia and circulating leukocytes, and these immune cells can then release various molecules, including ROS, proteases, and pro‐inflammatory cytokines.…”

“…52 Therapeutic hypothermia has been widely regarded to be one of the most reliable neuroprotective therapies for several cerebral disorders and injuries, including stroke, traumatic brain and spinal cord injury, global ischemia after cardiac arrest, and hypoxic-ischemic encephalopathy. [53][54][55][56][57] The ischemic injury stimulates innate immune responses leading to activation of microglia and circulating leukocytes, and these immune cells can then release various molecules, including ROS, proteases, and pro-inflammatory cytokines. These molecules can activate more inflammatory cells, leading to a vicious cycle of death and inflammatory activation.…”

Targeted temperature management for ischemic stroke

“…Considering that neurovascular damage after an acute ischemic attack occurs over hours to days, the longer the duration of hypothermia is, the more significantly improved the outcomes can be. In support of this hypothesis, some experiments have already demonstrated better outcomes with longer duration of cooling [10]. Interestingly, van der Worp et al [30] concretely reported an inverse relationship between the duration of TH and infarct volume in a systemic review and meta-analysis of animal models.…”

“…The key cascades of this pathological process also commonly occur in various ischemic strokes. While the precise mechanism has not been fully understood, numerous hypotheses have suggested the neuroprotective effects of TH such as prevention of blood-brain barrier disruption; reduction of cerebral glucose metabolism and oxygen consumption; reduction of excitotoxic neurotransmitter accumulation, intracellular acidosis, intracellular calcium influx, and oxygen-free radical production; alteration of cold shock protein expression; reduction of brain edema; reduction of thrombosis risk; and reduction of the risk of epileptic activities [10]. In addition, TH can function as an antiedema therapy to prevent the increase in intracerebral pressure or impending cerebral herniation during an acute period of ischemic stroke [11].…”

“…1. Possible tissue damage mechanisms that therapeutic hypothermia (TH) can alleviate in ischemic stroke from acute stage to recovery phase [10]. (A) Acute events, such as loss of oxygen and glucose after stroke, can lead to energy loss (adenosine triphosphate [ATP] loss) and ion pump failure.…”