Brain Research, 463 (1988) 63-68 63 Elsevier BRE 14001 Effects of BW755C, a mixed cyclo-oxygenase-lipoxygenase inhibitor, following traumatic spinal cord injury in rats Alan I. Faden 1'2, Matthias Lemke 2 and Paul Demediuk 1'2 1Department of Neurology, University of California, San Francisco, CA (U.S.A.) and 2Center for Neural Injury (127), San Francisco Veterans Administration Medical Center, San Francisco, CA (U.S.A.) (Accepted 11 May 1988) Key words: Spinal cord injury; Trauma; Eicosanoid; Lipoxygenase; Cyclo-oxygenase; Cation BW755C is an inhibitor of both cyclo-oxygenase and lipoxygenase, which has been found to have protective effects after myocardial ischemia in dogs. Impact injury to the spinal cord is associated with tissue ischemia as well as with the accumulation of eicosanoids. In the present studies we evaluated the effects of BW755C after traumatic spinal cord injury in rats. Drug treatment reduced thrombox- ane B2 levels and improved neurological recovery as compared to treatment with equal-volume physiological saline. The findings sug- gest that this drug or related compounds may be useful for the treatment of clinical spinal cord injury. INTRODUCTION Traumatic spinal cord injury causes biochemical changes in the tissue that are thought to contribute to delayed or secondary damage s . Among the proposed injury factors are products of membrane lipid metab- olism, particularly arachidonic acid and certain of its metabolites (eicosanoids) 7"9. The latter are derived predominantly through two enzymatic pathways: (1) cyclo-oxygenase, which yields prostaglandins and thromboxanes; and (2) lipoxygenase, which produc- es leukotrienes, lipoxins and hydroxy/hydroperoxy derivatives 24,27. A number of studies have shown that eicosanoids increase in spinal cord tissue following traumatic in- jury. Hsu et al. reported elevations in thromboxane B 2 levels following impact trauma in rabbits and cats 15. Demediuk et al. found increases in prostaglan- din E 2, prostaglandin F2,, and thromboxane B 2 fol- lowing impact injury in dogs and compression injury in cats 6'7. Anderson et al. also showed that peptidyl- leukotrienes as well as thromboxane B 2 increased af- ter compression trauma in cats ~. More recently, we have found that thromboxane B 2, but not peptidyl leukotrienes, were elevated following impact trauma to the thoracic spinal cord of rats 5. The increase in thromboxane B 2 was present as early as 5 min after trauma, with maximal levels at 1 h but with eleva- tions persisting up to 7 days after injury. Moreover, thromboxane levels were closely correlated with the severity of trauma. Eicosanoids may exacerbate injury after trauma in a number of ways. Thromboxane A 2, as well as leu- kotrienes C4, D~ and E~, are potent vasoconstric- tors22"25'26~ which may contribute to secondary tissue ischemia following trauma. These compounds also promote platelet aggregation (thromboxane A2), in- crease vascular permeability (LTB 4, LTC4, LTD4) and may serve as potent chemoattractive agents (LTB4)21,27.28. Taken together, these compounds can therefore lead to post-traumatic hypoperfusion, platelet aggregation, leukocyte infiltration and ede- ma formation. Two studies have examined the effects of cyclo-ox- ygenase inhibition in spinal cord injury. Hallenbeck et al. found that the cyclo-oxygenase inhibitor in- Correspondence: A.I. Faden, Center for Neural Injury (127), San Francisco Veterans Administration Medical Center, 4150 Clement Street, San Francisco, CA 94121, U.S.A. 0006-8993/88/$03.50 © 1988 Elsevier Science Publishers B.V. (Biomedical Division)