Experimental Traumatic Brain Injury and Cell Death - in vivo and in vitro aspects

Sammanfattning: Traumatic and ischemic brain damage are major causes of disability and death. While much effort has been spent on developing pharmacological treatments for these conditions, no neuroprotective drugs are in clinical use. Neuronal death following trauma and ischemia occurs in selected cell populations of the brain at various time points after the injury, and causes cognitive and behavioral dysfunction. The injury mechanisms are similar in both types of injury. Brain trauma causes ischemia, and mitochondrial dysfunction is an important initiator of both types of cell death. In the first part of the study, a clinically relevant model of traumatic brain injury (TBI) in the rat was used to evaluate the rotating pole test as a test of neuromotor function, as well as the neuroprotective effect of administration of a low dose of prostacyclin following TBI. The rotating pole test was useful to assess outcome and functional improvement following injury, and administration of prostacyclin led to a significantly reduced cortical lesion volume, presumably through an improved microcirculation. Here we show that a low dose of prostacyclin without side effects such as systemic hypotension reduces cell death following experimental TBI. In the second part of the study, the role of mitochondria in cell death following acute brain injury was studied. A flow cytometric method for the analysis of minute samples of isolated brain mitochondria was developed, and applied to compare mitochondria from hippocampal subregions. Cell vulnerability correlated with an increased mitochondrial production of reactive oxygen species and increased sensitivity to calcium-induced mitochondrial permeability transition (mPT). In the final study, we used a functional genomics approach to identify potentially neuroprotective genes that were upregulated following ischemic preconditioning. Increased expression of the mitochondrial protein UCP-2 correlated with cell survival, and overexpression of UCP-2 was neuroprotective both in vivo and in vitro. The results suggest that under basal conditions, UCP-2 may signal through cellular redox systems to upregulate neuroprotective genes. Following injury, UCP-2 inhibits mPT, activation of caspases and cell death. Mitochondrial involvement in ischemic and traumatic brain injury is supported by the strong neuroprotective effect of inhibitors of mPT (e.g. cyclosporin A). The uncoupling proteins have attracted much interest as potential targets for the treatment of obesity, which have led to devlopment of pharmacological inducers of these proteins. The results of this study suggest that such compounds may also be used to induce neuroprotection.