Neuroprotective Effect of Hypothermia on Neuronal Injury in Diffuse Traumatic Brain Injury Coupled With Hypoxia and Hypotension

Abstract

It is well established in mechanical head trauma that posttraumatic secondary insults, such as hypoxia and hypotension exacerbate neuronal injury and lead to worse outcome. In this study, the neuroprotective effect of hypothermia on the reduction of supraventricular subcortical neuronal damage was evaluated using an impact-acceleration model of diffuse traumatic brain injury coupled with both moderate and severe periods of hypoxia and hypotension. A total of 135 adult male Sprague-Dawley rats (340-375 g) were divided into three experimental studies: (I) physiological evaluation (n = 36); (II) quantitative analysis of the effect of trauma coupled with moderate and severe hypotension on neuronal damage assessed at 4 (n = 39) and 24 h (n = 24); and (III) the neuroprotective effect of hypothermia following moderate secondary insult (n = 36). Induction of hypothermia occurred at 15 min postinjury, to a level of 30 degrees C for 60 min. At the designated time points (4 and 24 h), the animals were sacrificed via standard transcardial perfusion techniques for histological processing. Quantitative assessment of neuronal damage using routine H&E staining at 4 hours showed neuronal damage which correlated with the severity of secondary insult. Animals exposed to trauma alone had a mean number of damaged neurons of 7.61 +/- 3.08/high powered field (hpf) compared with a mean of 1.21 +/- 0.30/hpf in the sham operated group (p = 0.015). Animals exposed to trauma with 10 min of hypoxia and hypotension (THH-10) showed a statistically significant number of damaged neurons compared to the sham-operated animals (7.50 +/- 2.15 damaged neurons/hpf, p = 0.013), whereas, neuronal damage in animals undergoing trauma with a 30-min secondary insult of hypoxia and hypotension (THH-30) was markedly increased (100 +/- 30.20/hpf, p = 0.002). Statistical analysis showed no significant difference in neuronal damage in animals subjected to secondary insult alone. At 24 h, the evolution of neuronal damage in the trauma alone group (5.08 +/- 1.63/hpf) was relatively static; however, there was a remarkable increase in the neuronal damage of the THH-10 group (29.88 50 +/- 8.20/hpf). However, hypothermia provided nearly complete protection against secondary insults, and neuronal damage was equal to that of the trauma alone group (p = 0.42). The results of this study confirm that hypothermia provides remarkable protection against the adverse effects of neuronal damage exacerbated by secondary injury. This study also presents a new model of secondary insult, which can be used experimentally to further define the mechanism of increased vulnerability of the injured brain.

Neurotoxic Zinc Translocation into Hippocampal Neurons is Inhibited by Hypothermia and is Aggravated by Hyperthermia after Traumatic Brain Injury in Rats

“…Posttraumatic hypothermia (301C) reduced acute sensorimotor, neurobehavioral and histopathologic sequelae of FPI (Bramlett et al, 1995;Dietrich et al, 1994;Lyeth et al, 1993) and chronic histopathologic sequelae (Bramlett et al, 1997). Hypothermia (301C) also provided protection against secondary posttraumatic injury associated with hypotension and hypoxia (Yamamoto et al, 1999). Posttraumatic hypothermia (301C) reduced and hyperthermia (391C) increased the inflammatory response to FPI in rats (Chatzipanteli et al, 2000).…”

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

“…Bramlett et al (1995) demonstrated that moderate hypothermia (308C) initiated 5 min after TBI improved hippocampal-dependent learning and memory using the Morris water maze. The beneficial effects of hypothermia on outcome after TBI have now been replicated in other models of brain injury (Dixon et al, 1998;Yamamoto et al, 1999;Matsushita et al, 2001). Additionally, studies have reported that traumatic axonal pathology, an important predictor of outcome in TBI patients, is also reduced with moderate post-injury hypothermia therapy (Koizumi and Povlishock, 1998;Buki et al, 1999).…”

The effect of hypothermia on the expression of TIMP-3 after traumatic brain injury in rats

“…It has been reported that therapeutic hypothermia targets various pathologic mechanisms, including temperature-dependent reductions in the cerebral metabolic rate of oxygen, decreases in free radical production (Hayashi et al, 1997), limitations of blood-brain barrier disruption Smith and Hall, 1996;Lotocki et al, 2006), and reductions in brain edema (Marion and White, 1996). Others have reported attenuation of ionic disruption (Yamamoto et al, 1999), decreased release of excitatory amino acids, increased expression of inflammatory response genes (Busto et al, 1989;, shunting of an increased fraction of glucose metabolism (Kaibara et al, 1999), and inhibition of excessive calcium neuronal entry and intracellular calcium overload . Although our findings suggest that hypothermic protection can downregulate TIMP-3 expression, more thorough investigations are needed of the mechanisms behind the regulation of TIMP-3 levels in the brain.…”

“…On the other hand, our early studies confirmed that mild to moderate hypothermia can significantly reduce mortality and improve behavioral outcomes in a rodent brain injury model . Furthermore, moderate hypothermia provided remarkable protection against secondary insults after impact acceleration in a model of diffuse TBI coupled with both moderate and severe periods of hypoxia and hypotension (Yamamoto et al, 1999).…”