Peroxynitrite scavengers for the acute treatment of traumatic brain injury

Recent evidence has suggested that the superoxide and nitric oxide-derived reactive oxygen species peroxynitrite (ONOO^-) may play a significant role in the acute pathophysiology of brain injury. One pharmacological mechanism by which ONOO^--mediated damage might be interrupted is by the administration of scavenging compounds such as the thiol-containing compound penicillamine. In the present study, we examined the ability of either penicillamine (Pen) or the more brain penetrable penicillamine methyl ester (PenME) (0.01, 0.1, 1.0 or 10.0 mg/kg i.v. 5 min post-injury) to improve the early (1 hr) neurological recovery (grip score) of male CF-1 mice after a severe (900 g-cm; 50 g x 18 cm) injury. Pen produced a dose-related improvement in grip score. At 1.0 mg/kg, a +112% improvement was observed compared to vehicle-treated mice, and at 10.0 mg/kg, the increase was +168% (both, p < 0.05). PenME more potently improved the 1-hr grip score, but the magnitude of the optimal effect (+96% at 0.1 mg/kg; p < 0.02) was no greater than that observed with Pen, which largely remains in the cerebral microvasculature. These results are consistent with a role of ONOO^- in acute head injury, but suggest that microvascular scavenging may be of primary therapeutic importance during the early post-traumatic period.