366 The Unique Histopathological Responses of the Injured Spinal Cord Implications for Neuroprotective Therapy LLOYD GUTH, a,b,c ZIYIN ZHANG, a AND OSWALD STEWARD a,d a Department of Neuroscience, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA b Department of Biology, College of William and Mary, Williamsburg, Virginia 23187, USA ABSTRACT: Tissue destruction at the primary site of a spinal cord injury leads to persistent necrosis that progressively enlarges the lesion. Steroids attenuate this necrotizing process and promote tissue repair even though such anti-in- flammatory drugs interfere with wound healing in non-CNS organs. To ad- dress this paradox, the spinal cord of rats and mice was crushed extradurally and the effects of the following anti-inflammatory agents studied by light mi- croscopical image analysis: allopurinol, aminoguanidine, indomethacin, a bac- terial lipopolysaccharide, naproxen, and pregnenolone. The contribution of Wallerian degeneration to progressive necrosis was studied in a mutant mouse strain (Wld S ) that is characterized by delayed Wallerian degeneration. In rats, the anti-inflammatory agents selectively attenuated progressive ne- crosis and encouraged wound healing. In mice, considerable tissue repair oc- curred without pharmacological intervention; this wound-healing process was delayed in the mutant Wld S strain. Since spinal cord injury results in concom- itant tissue necrosis and wound healing, a goal of neuroprotective therapy is to regulate the dynamic balance between these destructive and reparative processes. RELATION OF INFLAMMATORY PROCESSES TO THE HISTOPATHOLOGY OF SPINAL CORD INJURY Overview of the Inflammatory Response Anti-inflammatory agents are among the most useful neuroprotective agents for treating spinal cord trauma. It is puzzling why this should be so, since steroidal and non-steroidal anti-inflammatory agents generally inhibit tissue repair. In order to ex- plain the paradoxical neuroprotective effects of anti-inflammatory agents, we begin with a review of the mechanisms by which inflammation leads to tissue repair. c Corresponding author: Dr. Lloyd Guth, 111 Gullane, Williamsburg, VA 23188-7438. Phone, 757/258-3705. e-mail, lloydguth@erols.com d Present address: Department of Anatomy and Neurobiology, College of Medicine, University of California at Irvine, Irvine, CA 92697-4292, USA.