CEREBROPROTECTIVE EFFECT OF STABLE NITROXIDE RADICALS IN CLOSED-HEAD INJURY IN THE RAT

Nitroxide stable radicals are unreactive toward most diamagnetic molec ules, but readily undergo one-electron redox reactions with paramagnet ic species such as free radicals and transition metals, thus serving a s cell permeable antioxidants. The involvement of reactive oxygen spec ies in the pathophysiology of neurotrauma has been well established, T he neuroprotective properties of three nitroxides: 2,2,6,6-tetramethyl piperidine-1-N-oxyl (TPO), the hydrophilic analog: TPL, and its reduce d form: TPH, were tested in a rat model of closed head injury (CHI). C HI was induced in ether anesthetized rats by a weight drop device and recovery was followed for up to 24 h. The 'clinical status' was evalua ted according to a 'Neurological Severity Score' (NSS), at 1 h and 24 h, the difference between these scores, Delta NSS, reflecting the exte nt 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 = 7.6 3 +/- 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 neuroprotect ive activity presumably involve: (a) reoxidation of reduced transition metal ions; (b) a selective radical-radical reaction; and (c) catalyt ic removal of intracellular and extracellular O-.(2)-. The results ind icate that nitroxides could be used in neuroprotective treatment of CH I.