Prevention of delayed neuronal death in gerbil hippocampus by a novel vinca alkaloid derivative (vinconate).

We investigated the effect of vinconate, a novel vinca alkaloid derivative, on delayed neuronal death using Mongolian gerbils. The animals were allowed to survive for 7 d after 3 or 5 min of forebrain ischemia induced by bilateral occlusion of the common carotid arteries. Morphological changes and calcium (45Ca) accumulation were evaluated in the CA1 sector of the hippocampus after ischemia. Vinconate (50, 100, and 300 mg/kg) showed protective effects against neuronal death in a dose-dependent manner when administered intraperitoneally (ip) 10 min before 5 min of ischemia. However, the administration of vinconate (100 and 300 mg/kg, ip) immediately after 5 min of ischemia showed no therapeutic effect, whereas a marked therapeutic effect of vinconate (50 and 100 mg/kg, ip) was observed when administered immediately after 3 min of ischemia. An anesthetic dose of pentobarbital (40 mg/kg, ip) also produced significant protection against neuronal death. Furthermore, a 45Ca autoradiographic study indicated that a marked calcium accumulation was found in the Ca1 sector at 7 d after 5 min of ischemia, which was consistent with the extent of histological neuronal damage. When vinconate (100 and 300 mg/kg, ip) was administered 10 min before 5 min of ischemia, the abnormal calcium accumulation was not detected in the CA1 sector. These data indicate that suppression of abnormal neuronal activity may be owing to the antagonistic action of vinconate on calcium accumulation.