Brain edema formation associated with trauma-induced intracerebral hemorrhage (ICH) is a clinical complication with high mortality. Studies have shown that heme oxygenase-1 (HO-1) plays an important role in ICH-induced brain edema. In order to understand the role of HO-1 in the protective effect of selective brain cooling (SBC), we investigated the time course of HO-1 changes following penetrating ballistic-like brain injury (PBBI) in rats. Samples were collected from injured and control animals at 6, 24, 48, and 72 h, and 7 days post-injury to evaluate HO-1 expression, heme concentration, brain water content, and immunohistochemistry (IHC). Following a 10% frontal PBBI, HO-1 mRNA and protein was increased at all time points studied, reaching maximum expression levels at 24-48 h post-injury. An increase in the heme concentration and the development of brain edema coincided with the upregulation of HO-1 mRNA and protein during the 7-day post-injury period. SBC significantly decreased PBBI-induced heme concentration, attenuated HO-1 upregulation, and concomitantly reduced brain water content. These results suggest that the neuroprotective effects of SBC may be partially mediated by reducing the heme accumulation, which reduced injury-mediated upregulation of HO-1, and in turn ameliorated edema formation. Collectively, these results suggest a potential value of HO-1 as a diagnostic and/or therapeutic biomarker in hemorrhagic brain injury.

Closed-head concussive injury is one of the most common causes of traumatic brain injury (TBI). While single concussions result in short-term neurologic dysfunction, multiple concussions can result in cumulative damage and increased risk for neurodegenerative disease. Despite the prevalence of concussion, knowledge about what occurs in the brain following this injury is limited, in part due to the limited number of appropriate animal research models. To study clinically relevant concussion we recently developed a simple, non-invasive rodent model of closed-head projectile concussive impact (PCI) TBI. For this purpose, anesthetized rats were placed on a platform positioned above a torque-sealed microcentrifuge tube packed with fixed amounts of dry ice. Upon heating, rapid sublimation of the dry ice produced a build-up of compressed CO2 that triggered an eruptive force causing the cap to launch as an intact projectile, resulting in a targeted PCI head injury. A stainless steel helmet was implemented to protect the head from bruising, yet allowing the brain to sustain a mild PCI event. Depending on the injury location and the application of the helmet, PCI-induced injuries ranged from severe (i.e., head injury with subdural hematomas, intracranial hemorrhage, and brain tissue damage), to mild (no head injury, intracranial hemorrhage, or gross morphological pathology). Although no gross pathology was evident in mild PCI-induced injury, the following protein changes and behavioral abnormalities were detected between 1 and 24 h after PCI injury: (1) upregulation of glial fibrillary acidic protein (GFAP) in hippocampal regions; (2) upregulation of ubiquitin carboxyl-terminal hydrolase L1 (UCHL-1) in cortical tissue; and (3) significant sensorimotor abnormalities. Overall, these results indicated that this PCI model was capable of replicating salient pathologies of a clinical concussion, and could generate reproducible and quantifiable outcome measures.