MECHANISM OF BRAIN PROTECTION BY NITROXIDE RADICALS IN EXPERIMENTAL-MODEL OF CLOSED-HEAD INJURY

Reactive oxygen-derived species wen previously implicated in mediation of post-traumatic brain damage: however, the efficacy of traditional antioxidants in preventing/reversing the damage is sometimes limited. The present work focused on the mechanisms underlying the neuroprotect ive activity of cell permeable, nontoxic, antioxidants, namely stable nitroxide radicals in an experimental model of rat closed-head injury. Brain damage was induced by the weight-drop method and the clinical s tatus was evaluated according to a neurological severity score at 1 h and 24 h, where the difference between these scores reflects the exten t of recovery. The metal chelator deferoxamine as well as three nitrox ide derivatives, differing in hydrophilicity and charge, and one hydro xylamine (a reduced nitroxide) facilitated the clinical recovery and d ecreased the brain edema. The nitroxides. but neither the hydroxylamin e nor deferoxamine, protected the integrity of the blood-brain barrier . Superoxide dismutase also improved the clinical recovery but did not affect brain edema or the blood-brain barrier. The results suggest th at by switching back and forth between themselves, the nitroxide and h ydroxylamine act catalytically as self-replenishing antioxidants, and protect brain tissue by terminating radical-chain reactions, oxidizing deleterious metal ions, and by removal of intracellular superoxide. ( C) 1998 Elsevier Science Inc.