Traumatic brain injury (TBI) is a major cause of mortality and disability. As common sequelae in survivors of TBI are disabling functional, emotional and cognitive disturbances, improved treatment of TBI patients is urgently needed. At present, no neuroprotective pharmacological treatment exists. The formation of oxygen-centered free radicals, reactive oxygen species (ROS), is considered an important event in the pathophysiology of TBI. In the present thesis, the fluid percussion (FPI) and controlled cortical contusion injury models of TBI in rats were used. Two nitrone radical scavengers, α-Phenyl-N-tert -butyl nitrone (PBN) and the sulfonated analogue of PBN, 2-sulfophenyl-N-tert-butyl nitrone (S-PBN), were used as tools to study the role of ROS in TBI. Pre-treatment with PBN (30 mg/kg) improved morphological and cognitive outcome after severe controlled cortical contusion injury. Treatment with equimolar doses of PBN and S-PBN administered 30 min after FPI followed by a 24 h intravenous infusion improved morphological outcome. Only S-PBN improved cognitive outcome as assessed in the Morris Water Maze. Surprisingly, pre-treatment with PBN increased the number of apoptotic neurons at 24 hours after injury despite a reduced lesion volume. FPI resulted in an early increase in glucose uptake and a reduction in regional cerebral blood flow (rCBF) assessed by fluoro-2-deoxyglucose (FDG) and hexamethylpropylene amine oxime (HMPAO) autoradiography. At 12 h, a marked reduction in glucose uptake and rCBF ensued. These TBI-induced changes were attenuated by PBN and S-PBN pre-treatment. A method for ROS detection using 4-hydroxybenzoate in conjunction with microdialysis was evaluated. The results showed a marked increase in ROS formation as assessed by an increase in the single adduct 3,4-DHBA, lasting 90 min after injury. In a separate study, PBN and S-PBN equally reduced 3,4-DHBA formation despite no detectable brain concentrations of S-PBN at 30 or 60 min post-injury. In conclusion, ROS play an important role in the injury process after TBI. We report a method for ROS detection with potential clinical utility. Nitrones increased ROS elimination and improved functional and morphological outcome. Nitrone treatment may have a clinical potential as a neuroprotective concept in TBI.

It is a major clinical problem that survival rates after out-of-hospital cardiac arrest have not markedly improved during the last decades, despite extensive research and the introduction of new interventions. However, recent studies have demonstrated promising treatments such as targeted temperature management (TTM) and methylene blue (MB). In our first study, we investigated the effect of MB administered during experi-mental cardiopulmonary resuscitation (CPR) in the setting of postponed hypother-mia in piglets. We set out to study if MB could compensate for a delay to establish targeted TTM. The study demonstrated that MB more than compensated for 30 min delay in induction of TTM. The effect of MB added to that of TTM. The second study examined the effects of TTM and S-PBN on the endothelin system and nitric oxide synthases (NOS) after prolonged CA in a porcine CPR mod-el. The study was designed to understand the cardioprotective mechanism of S-PBN and TTM by their influence on the endothelin system and NOS regulation. We veri-fied for the first time, that these two cardioprotective postresuscitative interventions activate endothelin-1 and its receptors concomitantly with eNOS and nNOS in the myocardium. We concluded that nitric oxide and endothelin pathways are implicated in the postresuscitative cardioprotective effects of TTM. The third study compared survival and hemodynamic effects of low-dose amio-darone and vasopressin to vasopressin in a porcine hypovolemic CA model. The study was designed to evaluate whether resuscitation with amiodarone and vasopressin compared to vasopressin alone would have an impact on resuscitation success, survival, and hemodynamic parameters after hemorrhagic CA. We found that combined resuscitation with amiodarone and vasopressin after hemorrhagic circulatory arrest resulted in greater 3-hour survival, better preserved hemodynamic parameters and smaller myocardial injury compared to resuscitation with vasopressin only. In our fourth study we planned to compare hemodynamic parameters between the treatment group (milrinone, esmolol and vasopressin; MEV) and control group (vasopressin only) during resuscitation from prolonged cardiac arrest in piglets. The study was designed to demonstrate if MEV treatment improved hemodynamics or cardiac damage compared to controls. We demonstrated that MEV treatment reduced cardiac injury compared with vasopressin alone.