Protection in Animal Models of Brain and Spinal Cord Injury with Mild to Moderate Hypothermia

Abstract

For the past 20 years, various laboratories throughout the world have shown that mild to moderate levels of hypothermia lead to neuroprotection and improved functional outcome in various models of brain and spinal cord injury (SCI). Although the potential neuroprotective effects of profound hypothermia during and following central nervous system (CNS) injury have long been recognized, more recent studies have described clinically feasible strategies for protecting the brain and spinal cord using hypothermia following a variety of CNS insults. In some cases, only a one or two degree decrease in brain or core temperature can be effective in protecting the CNS from injury. Alternatively, raising brain temperature only a couple of degrees above normothermia levels worsens outcome in a variety of injury models. Based on these data, resurgence has occurred in the potential use of therapeutic hypothermia in experimental and clinical settings. The study of therapeutic hypothermia is now an international area of investigation with scientists and clinicians from every part of the world contributing to this important, promising therapeutic intervention. This paper reviews the experimental data obtained in animal models of brain and SCI demonstrating the benefits of mild to moderate hypothermia. These studies have provided critical data for the translation of this therapy to the clinical arena. The mechanisms underlying the beneficial effects of mild hypothermia are also summarized.

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“…Previous studies have assessed the cortical infarct volume and shown that it was significantly decreased by hypothermic treatment, while others have identified an improvement in recovery from spinal cord injury after intravascular cooling. (Cappuccino et al, 2010; Dietrich et al, 2009; Kawai et al, 2000; Levi et al, 2010). The neuroprotective mechanisms of hypothermia include suppression of excitotoxicity, free radical production, neuroinflammation, blood brain barrier (BBB) disruption and regulation of early gene expression.…”

“…Mild to moderate hypothermia is a promising neuroprotective intervention when induced during or after a central nervous system injury (Cappuccino et al, 2010; Dietrich et al, 2009; Kawai et al, 2000; Levi et al, 2010; Matsui et al, 2006). When localized and administered prior to trauma, these effects may be enhanced with little adverse effects on other biological phenomena or immune response (Purdy et al, 2013; Tzen et al, 2013).…”

“…Mild therapeutic hypothermia, defined as a temperature decrease of 4 to 6 °C below body temperature, has the potential to reduce or prevent oxidative stress (Balkany et al, 2005; Henry et al, 1984; Shintani et al, 2010). Prior literature, both from animal studies and clinical trials, has shown protective effects of therapeutic hypothermia on ischemic and traumatic injuries to neurons (Levi et al, 2010; Ohta et al, 2007; Shintani et al, 2010; Yanamoto et al, 1999; Yokobori et al, 2011) in cases of mild traumatic brain injury (mTBI), seizures (Atkins et al, 2010), ischemia and inflammatory response (Cappuccino et al, 2010; Kawai et al, 2000; Levi et al, 2010; Matsui et al, 2006) after cardiac arrest, and related to spinal cord injuries (Cappuccino et al, 2010; Dietrich et al, 2009). Unfortunately, systemic hypothermia has multiple side effects on functioning of organs and organ systems including impairment to immune response, higher infection, altered effects of other drugs and compromising vascular function.…”

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“…glutamate and dopamine), free radicals, lactic acid and pyruvate; increases in ischemic depolarization; blood-brain barrier breakdown; impaired enzymatic function, and reduced cytoskeletal stability [15]. These events may lead to cerebral edema, reduce cerebral perfusion pressure and secondarily lead to larger volumes of ischemic injury.…”

“…Some of the major mechanisms are described as follows: hypothermia reduces the cerebral infarct size, edema formation and damage to the blood-brain barrier [15,16]. Moreover, it diminishes activation of microglia, production of oxygen free radicals, and the release of excitotoxic neurotransmitters as well as lactate and pyruvate.…”