Research Report Geranylgeranylacetone limits secondary injury, neuronal death, and progressive necrosis and cavitation after spinal cord injury Minoru Fujiki * , Yoshie Furukawa, Hidenori Kobayashi, Tatsuya Abe, Keisuke Ishii, Susumu Uchida, Tohru Kamida Department of Neurosurgery, School of Medicine, Oita University, 1-1 Idaigaoka, Hasama-machi, Oita 879-5593, Japan Accepted 17 June 2005 Available online 27 July 2005 Abstract This study evaluates the neuroprotective effects of geranylgeranylacetone (GGA), which is known as an antiulcer agent and more recently as a heat-shock and other neuroprotective protein inducer, on secondary degeneration after spinal cord injury in rats. Crush injuries were produced at the T8 level using an extradural approach. Optimal administration conditions of GGA were established in an initial experiment by evaluating the appearance of lesions 24 h after injury in sections stained with H – E. Then, in a second experiment, animals treated with the optimal condition (600 mg/kg, 24 h before injury and thereafter every 24 h) were allowed to survive for 6 and 24 h and 1, 3, and 8 weeks after injury, and spinal cords were prepared for histological evaluation by staining for H – E for general histopathology and by silver staining for axons. There was a significant reduction (46%) in lesion volume 24 h after injury in animals treated with optimal administration conditions. The increase in tumor necrosis factor-a (TNF-a) and the accumulation of neutrophils in the damaged segment of the spinal cord 4 h after injury were significantly inhibited in animals that received GGA. Lesion size and cavitation area remained smaller in treated animals throughout the post-injury survival interval. These results suggest that GGA administration significantly reduces the secondary degeneration that would otherwise occur. The mechanism by which GGA exerts its beneficial effect is unknown but may involve reduction of TNF-a activation at the injured cord and/or inhibition of inflammation. D 2005 Elsevier B.V. All rights reserved. Theme: Development and regeneration Topic: Neuronal death Keywords: Geranylgeranylacetone; Spinal cord injury; Neuronal death; Neuroprotection; Necrosis; Cavitation 1. Introduction Spinal cord injury leads to a progressive series of degenerative processes that contribute to progressive necrosis and cavitation at the injury site. The destruction of the neural parenchyma and associated glial scar formation create an environment that inhibits neuronal regeneration from intact spinal cord. Presumably, the poor prognosis that follows spinal cord injury is due, in part, to the predomi- nance of these secondary degenerative processes. The mechanisms that are responsible for progressive necrosis and cavitation are not well understood. One hypothesis is that the bloodborne cells that infiltrate the injury site release trophic as well as toxic cytokines (e.g., Giulian and Robertson, 1990) [11]. These molecules could then both induce further reactive changes in cells and also contribute to progressive necrosis. As more and more neurons degenerate, there is greater and greater activation of tissue phagocytes with a corresponding increased release of trophic and toxic cytokines. In this way, it is thought that cellular degeneration propagates through the tissue environment in a fulminating cascade. At the same time, other studies have implicated excitotoxic cell death as an important mechanism in secondary degeneration 0006-8993/$ - see front matter D 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.brainres.2005.06.055 * Corresponding author. Fax: +81 97 586 5869. E-mail address: fujiki@med.oita-u.ac.jp (M. Fujiki). Brain Research 1053 (2005) 175 – 184 www.elsevier.com/locate/brainres