Nitroxide stable radicals are unreactive toward most diamagnetic molecules, but readily undergo one-electron redox reactions with paramagnetic species such as free radicals and transition metals, thus serving as cell permeable antioxidants. The involvement of reactive oxygen species in the pathophysiology of neurotrauma has been well established. The neuroprotective properties of three nitroxides: 2,2,6,6-tetramethylpiperidine-1-N-oxyl (TPO), the hydrophilic analog: TPL, and its reduced form: TPH, were tested in a rat model of closed head injury (CHI). CHI was induced in ether anesthetized rats by a weight drop device and recovery was followed for up to 24 h. The "clinical status' was evaluated according to a "Neurological Severity Score' (NSS), at 1 h and 24 h, the difference between these scores, delta NSS, reflecting the extent of recovery. Edema was assessed by measurement of water content at 24 h. The integrity of the blood-brain barrier (BBB) was investigated using Evans Blue extravasation. TPL, TPH and TPO facilitated clinical recovery, the latter causing a more pronounced effect (delta NSS = 7.63 +/- 0.26 in treated rats vs 4.94 +/- 0.48 in control rats, P < 0.001). TPL was found to significantly reduce edema formation (80.13% +/- 0.26 vs 83.65% +/- 0.49, P < 0.001) and to ameliorate BBB disruption (P < 0.001). The therapeutic window of TPL was found to be in the range of 4 h after CHI. The mechanisms underlying the nitroxide neuroprotective activity presumably involve: (a) reoxidation of reduced transition metal ions; (b) a selective radical-radical reaction; and (c) catalytic removal of intracellular and extracellular .O2-. The results indicate that nitroxides could be used in neuroprotective treatment of CHI.