Delayed Cell Death after Traumatic Brain Injury Role of Reactive Oxygen Species

Clausen, F. 2004. Delayed Cell Death after Traumatic Brain Injury. Role of Reactive Oxygen Species. Acta Universitatis Upsaliensis. Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine 1359. 75 pp. Uppsala ISBN 91-554-5990-0 Traumatic brain injury (TBI) is a leading cause of death and disability. TBI survivors often suffer from severe disturbances of cognition, memory and emotions. Improving the treatment is of great importance, but as of yet no specifi c neuroprotective treatment has been found. After TBI there are changes in ion homeostasis and protein regulation, causing generation of reactive oxygen species (ROS). Overproduction of ROS can lead to damage in cell membranes, proteins and DNA and secondary cell death. In the present thesis experimental TBI in rats were used to study the effects of the ROS scavengers -phenyl-N-tert-butyl-nitrone (PBN) and 2-sulfophenyl-N-tertbutyl-nitrone (S-PBN) on morphology, function, intracellular signalling and apoptosis. Posttreatment with PBN and S-PBN resulted in attenuation of tissue loss after TBI and S-PBN improved cognitive function evaluated in the Morris water maze (MWM). Pretreatment with PBN protected hippocampal morphology, which correlated to better MWM-performance after TBI. To detect ROS-generation in vivo, a method using 4-hydroxybenzoic acid (4-HBA) microdialysis in the injured cortex was refi ned. 4-HBA reacts with ROS to form 3,4-DHBA, which can be quantifi ed using HPLC, revealing that ROS-formation was increased for 90 minutes after TBI. It was possible to attenuate the formation signifi cantly with PBN and S-PBN treatment. The activation of extracellular signal-regulated kinase (ERK) is generally considered benefi cial for cell survival. However, persistent ERK activation was found in the injured cortex after TBI, coinciding with apoptosis-like cell death 24 h after injury. Pretreatment with the MEK-inhibitor U0126 or S-PBN signifi cantly decreased ERK activation and reduced apoptosis-like cell death. Posttreatment with U0126 or S-PBN showed robust protection of cortical tissue. To conclude: ROS-mediated mechanisms play an important role in secondary cell death following TBI. The observed effects of ROS in intracellular signalling may be important for defi ning new targets for neuroprotective intervention.