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 × 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.