PET study of the neuroprotective effect of TRA-418, an antiplatelet agent, in a monkey model of stroke.

Abstract

The aim of this study was to evaluate the neuroprotective effect of TRA-418, an antiplatelet agent, using PET in a monkey model of stroke. TRA-418 is a nonprostanoid compound with dual action: antagonistic effects on thromboxane A(2) receptors and agonistic effects on prostaglandin I(2) receptors. Via a transorbital approach, cynomolgus monkeys underwent a 3-h occlusion of the right middle cerebral artery (MCA), followed by reperfusion and observation for 4 d. Starting 2 h after the MCA occlusion, TRA-418 was administered at low and high doses (6 animals at each dose). Six control animals received a bolus and infusion of drug vehicle after MCA occlusion. Steady-state (15)O continuous inhalation was used for assessment of local cerebral blood flow, cerebral metabolic rate of oxygen, and oxygen extraction fraction using high-resolution PET. Five consecutive PET scans (before occlusion; 2 h after occlusion; and 2 h, 24 h, and 4 d after reperfusion) were obtained for each monkey. The extent of the cerebral damage due to ischemia was measured histologically at 4 d after reperfusion. Histologic observation 4 d after MCA occlusion showed that cerebral damage was less (P = 0.05) in animals treated with high-dose TRA-418 than in control animals. Although not affecting cerebral blood flow during the experiments, treatment with TRA-418 significantly (P < 0.05) suppressed reduction of the cerebral metabolic rate of oxygen after reperfusion. Our observations suggest that TRA-418 has neuroprotective action, as displayed in a primate model of stroke using PET monitoring.