PROTECTIVE EFFECTS OF VANOXEAMINE (GBR-12909) AGAINST ISCHEMIA-INDUCED HYPERACTIVITY AND NEURODEGENERATION IN THE GERBIL MODEL OF CEREBRAL-ISCHEMIA

In Mongolian gerbils, bilateral carotid occlusion (BCO) followed by re perfusion causes uniform destruction of the CA1 pyramidal neurons in t he hippocampus, and this damage correlates with an increase in locomot or activity. Various drugs, such as NMDA antagonists,calcium channel b lockers, and free radical scavengers, have provided neuroprotection ag ainst ischaemia-induced damage. More recently, the neuroprotective eff ects of dopamine have been investigated. A large release of dopamine h as been shown to occur at the onset of ischaemia, and dopamine levels return to basal values following reperfusion. In the present study, we investigated the effects of vanoxeamine (GBR 12909) (5 or 10 mg/kg IF , administered 1 h prior to occlusion) on behavioural and histological changes following global ischaemia in the Mongolian gerbil. Ischaemia was induced by bilateral carotid occlusion for 5 min. Both doses of G BR 12909 significantly potientiated the hyperactivity of the BCO anima ls measured in the home cage during the first 24 h following surgery a nd in the locomotor activity arena after 24 h and 48 h. Significant ne uroprotection of cells in the CA1 region of the hippocampus was observ ed in drug-treated animals 96 h postsurgery. The neuroprotective effec t of GBR 12909 may be ascribed to sensitisation of the dopamine D-2 au toreceptor, consequently reducing the release of dopamine that occurs following ischaemia. Alternatively, GBR 12909 may have a direct intera ction with the Na+ ion channel-glutamate complex, resulting in reduced release of glutamate and thereby reducing NMDA receptor activation an d neuronal damage. (C) 1997 Elsevier Science Inc.