Experimental and clinical findings demonstrate that traumatic brain injury (TBI) results in injury to both gray and white matter structures. The purpose of this study was to document patterns of oligodendrocyte vulnerability to TBI. Sprague Dawley rats underwent sham operated procedures or moderate fluid percussion brain injury. Animals were perfusion-fixed for quantitative immunohistochemical analysis at 3 (n=9) or 7 (n=9) days post-surgery. Within the ipsilateral external capsule and corpus callosum, numbers of APC-CC1 immunoreactive oligodendrocytes were significantly decreased at 3 or 7 days post-TBI compared to sham rats (p<0.03). At both posttraumatic survival periods, double-labeling studies indicated that oligodendrocytes showed increased Caspase 3 activation compared to sham. These data demonstrate regional patterns of oligodendrocyte vulnerability after TBI and that oligodendrocyte cell loss may be due to Caspase 3-mediated cell death mechanisms. Further studies are needed to test therapeutic interventions that prevent trauma-induced oligodendrocyte cell death, subsequent demyelination and circuit dysfunction.

Previous studies have demonstrated that moderate hypothermia reduces histopathological damage and improves behavioral outcome after experimental traumatic brain injury (TBI). Further investigations have clarified the mechanisms underlying the beneficial effects of hypothermia by showing that cooling reduces multiple cell injury cascades. The purpose of this study was to determine whether hypothermia could also enhance endogenous reparative processes following TBI such as neurogenesis and the replacement of lost neurons. Male Sprague-Dawley rats underwent moderate fluid-percussion brain injury and then were randomized into normothermia (37°C) or hypothermia (33°C) treatment. Animals received injections of 5-bromo-2′-deoxyuridine (BrdU) to detect mitotic cells after brain injury. After 3 or 7 days, animals were perfusion-fixed and processed for immunocytochemistry and confocal analysis. Sections were stained for markers selective for cell proliferation (BrdU), neuroblasts and immature neurons (doublecortin), and mature neurons (NeuN) and then analyzed using non-biased stereology to quantify neurogenesis in the dentate gyrus (DG). At 7 days after TBI, both normothermic and hypothermic TBI animals demonstrated a significant increase in the number of BrdU-immunoreactive cells in the DG as compared to sham-operated controls. At 7 days post-injury, hypothermia animals had a greater number of BrdU (ipsilateral cortex) and doublecortin (ipsilateral and contralateral cortex) immunoreactive cells in the DG as compared to normothermia animals. Because adult neurogenesis following injury may be associated with enhanced functional recovery, these data demonstrate that therapeutic hypothermia sustains the increase in neurogenesis induced by TBI and this may one of the mechanisms by which hypothermia promotes reparative strategies in the injured nervous system.

The purpose of this study was to document patterns of oligodendrocyte vulnerability to TBI and determine whether posttraumatic hypothermia prevents oligodendrocyte cell loss. Sprague Dawley rats underwent moderate fluid percussion brain injury. Thirty minutes after TBI, brain temperature was reduced to 33°C for 4 hrs or maintained at normothermic levels (37°C). Animals were perfusion-fixed for quantitative immunohistochemical analysis at 3 (n=9) or 7 (n=9) days post-TBI. Within the cerebral cortex, external capsule and corpus callosum, numbers of APC-CC1 immunoreactive oligodendrocytes at 3 and 7 days following TBI were significantly decreased compared to sham operated rats (p<0.02). Double-labeling studies showed that vulnerable oligodendrocytes expressed increased Caspase 3 activation compared to sham. Posttraumatic hypothermia significantly reduced the number of CC1 positive oligodendrocytes lost after normothermia TBI in white matter tracts (p<0.01). This model of TBI leads to quantifiable regional patterns of oligodendrocyte vulnerability. Posttraumatic hypothermia protects oligodendrocytes by interfering with Caspase 3-mediated cell death mechanisms. Therapeutic hypothermia may improve functional outcome by attenuating trauma-induced oligodendrocyte cell death, subsequent demyelination and circuit dysfunction.

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