SUMMARY 1. Post-traumatic inflammation may play a significant role in the development of delayed secondary brain damage following traumatic brain injury. 2. During post-traumatic inflammation, metabolic products of arachidonic acid, known as prostanoids (prostaglandins and thromboxanes) are released and aggravate the injury process. Prostanoid synthesis is regulated by the enzyme cyclo-oxygenase (COX), which is present in at least two isoforms, COX-1 (the constitutive form) and COX-2 (the inducible form). 3. In the present study, we examine the temporal and spatial profiles of COX-2 expression and the effects of the COX-2 inhibitor nimesulide on motor and cognitive outcome following diffuse traumatic brain injury in rats. 4. Adult male Sprague-Dawley rats were injured using the 2 m impact acceleration model of diffuse traumatic brain injury. At preselected time points after injury, animals were killed and the expression of COX-2 was measured in the cortex and hippocampus by western blotting techniques. 5. Increased expression of COX-2 was found in the cortex at 3 days and in the hippocampus as early as 3 h postinjury and this persisted for at least 12 days. 6. Administration of nimesulide (6 mg/kg, i.p.) at 30 min after injury and daily over a 10 day post-traumatic neurological assessment period resulted in a significant improvement com- pared with vehicle (2% dimethylsulphoxide diluted in isotonic saline)-treated controls in cognitive deficits, as assessed by the Barnes circular maze. There was also a significant improvement in motor dysfunction as assessed by the rotarod test on days 1 and 2 post-trauma compared with vehicle-treated controls. 7. These results implicate the involvement of COX-2 in cognitive and motor dysfunction following diffuse traumatic brain injury. Key words: diffuse axonal injury, neurological outcome, neurotrauma, nimesulide. INTRODUCTION It is now known that much of the brain damage produced by head impact is not the result of the initial trauma but, rather, develops over a period of hours to days after the primary event. Indeed, it is the complex secondary mechanisms initiated at the time of trauma that play an important role in the delayed progression of the brain damage. The identification of these secondary factors involved in the injury process is important because it may lead to new therapeutic strategies that improve functional outcome. 1 One of the secondary processes that may play a role in delayed neuronal death is post-traumatic inflammation, in which prostanoids, metabolic products of arachidonic acid, are among the pivotal regulators. 2 Prostanoid synthesis is regulated by cyclo-oxygenase (COX; or prostaglandin H synthase) that is present in at least two isoforms, COX-1, the constitutive form and COX-2, the inducible form. 3 Cyclo-oxygenase-2 regulates the key metabolic step in the biosyn- thesis of prostanoids, which are believed to play an important role in the control of cerebral circulation and neuronal signalling. 4 Moreover, because increased prostaglandin (PG) synthesis has been demonstrated in the brain following traumatic brain injury, 5 PG have been implicated in the pathogenesis of the physiological and mor- phological sequelae of traumatic brain injury (TBI). Consistent with this, it has recently been shown that an inhibition of prostanoid syn- thesis protects against neuronal damage following ischaemic brain injury. 6 Increased COX-2 activity and enhanced release of prostanoids have been shown to be associated with the generation of highly reactive oxygen species (ROS). 4 Reactive oxygen species have potent deleterious effects on lipids, proteins and DNA and have been implicated in the development and progression of apoptotic cell death in the central nervous system. 7 Expression of COX-2 has also been shown to be an important determinant of cytotoxicity connected with inflammation. 3 Finally, induction of COX-2 has been demon- strated following experimental ischaemia, 8 after kainate treatment 9 and following lateral cortical impact injury. 10 However, no studies have examined the role of COX-2 in models of traumatic brain injury that have diffuse axonal injury as a major component. Accordingly, the aim of the present study was to examine the temporal and spatial Annual Scientific Meeting of ASCEPT 2000: Pharmacological Interventions for Neurological Injury Symposium ACTIVATION OF CYCLO-OXYGENASE-2 CONTRIBUTES TO MOTOR AND COGNITIVE DYSFUNCTION FOLLOWING DIFFUSE TRAUMATIC BRAIN INJURY IN RATS I Cernak, C O’Connor and R Vink Department of Physiology and Pharmacology, James Cook University, Townsville, Queensland, Australia Correspondence: Dr Ibolja Cernak, Georgetown University Medical Center, Department of Neuroscience, Research Bld Room EP04, 3970 Reservoir Road NW, Washington, DC 20001, USA. Email: ifc@georgetown.edu Presented at the 34th Annual Scientific Meeting of the Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists, Newcastle, 3–6 December 2000. Received 18 December 2000; revision 18 May 2001; accepted 24 May 2001. Clinical and Experimental Pharmacology and Physiology (2001) 28, 922–925