Neuroprotective and Nootropic Actions of a Novel Cyclized Dipeptide after Controlled Cortical Impact Injury in Mice

Abstract

1-ARA-35b (35b) is a cyclized dipeptide that shows considerable neuroprotective activity in vitro and improves neurologic recovery after fluid percussion–induced traumatic brain injury in rats. The authors evaluated the effects of treatment with 35b in mice subjected to controlled cortical impact brain injury. Animals treated with intravenous 35b after traumatic injury showed significantly enhanced recovery of beam walking and place learning functions compared with vehicle-treated controls, in addition to reduced lesion volumes. Beneficial effects were dose related and showed an inverted U-shaped dose–response curve between 0.1 and 10 mg/kg. Protective actions were found when the drug was administered initially at 30 minutes or 1, 4, or 8 hours, but not at 24 hours, after trauma. In separate experiments, rats treated with 35b on days 7 through 10 after injury showed remarkably improved place learning in comparison with injured controls. These studies confirm and extend the neuroprotective effects of this diketopiperazine in traumatic brain injury. In addition, they show that 35b has a relatively wide therapeutic window and improves cognitive function after both acute and chronic injury.