Hypothermia neuroprotection mechanisms

The neuroprotective properties of mild hypothermia have been demonstrated in numerous experimental animal models. Research in this area has been conducted for many years, yet the mechanisms of cerebral protection by mild hypothermia remain unclear and continue to be the subject of intense investigation. The neuroprotective effects of mild hypothermia have been attributed to alterations in metabolic rate (24), neurotransmitter release (25-27), activity of protein kinases (28), resynthesis of cellular repair proteins (29), cerebral blood flow (30), preservation of the blood-brain barrier (BBB) (31), attenuation of inflammatory processes (32,33), and decreases in free radical production (34). Although these may all be components of a complex cascade leading to neurologic injury, it has become increasingly clear that the primary mechanism of action of hypothermia may be different at various temperatures as well as under different ischemic and traumatic conditions. 

Elucidate the cellular and molecular mechanisms of hypothermic neuroprotection to optimize the use of mild hypothermia as a neuro-protective strategy. 

Although research in this area has been conducted for more than 40 yr, the mechanisms of cerebral protection by mild hypothermia remain unclear and are still a source of controversy. Proposed mechanisms of neuroprotection by mild hypothermia include suppression of neurotransmitter release (2,3), reduced free radical production (4), activity of protein kinases (5), resynthesis of cellular repair proteins (6),... 

The concept of neuroprotection relies on the fact that delayed neuronal injury occurs after ischemia, and each step along the ischemic cascade provides a target for therapeutic intervention. Thus, understanding the cellular and molecular mechanisms that underlie the development of neuronal and vascular injury is critical to optimize treatment. This chapter reviews experimental evidence from studies on focal cerebral ischemia and mild hypothermia, as well as the mechanisms involved in mild hypothermic neuroprotection. 

The main role of mild hypothermia against stroke may, perhaps, be to extend the therapeutic window of other treatment modalities. On the other hand, hypothermia is by far the most potent neuroprotectant available against experimental cerebral ischemia, and new technological advances are now facilitating its implementation in the clinical setting. Understanding the mechanisms by which mild hypothermia exerts its neuroprotective effects will allow us to optimize its use as a therapeutic strategy. 

A study by Georgiadis et al. (31) induced hypothermia (target temperature 33°C) in 14 patients with an acute anterior circulation infarction involving at least two thirds of the left MCA territory. Patients received norepinephrine via continuous intravenous infusion and were mechanically ventilated. Hypothermia was initiated 26 h after onset of symptoms as a means to control intracranial hypertension and not for neuroprotection. In that study, static cerebral autoregulation did not appear impaired in the unaffected hemisphere with the use of alpha-stat for pH maintenance. However, the main concern in patients with acute stroke is the perfusion of the affected hemisphere, specifically of the penumbra (18). 

Comprehensive and up-to-date, Hypothermia and Cerebral Ischemia Mechanisms and Clinical Applications summarizes for clinicians and basic scientists alike all that is known about the use of hypothermia as a neuroprotective strategy in the treatment of today s stroke and TBI patients. 

---