Protective effects of vanoxeamine (GBR 12909) against ischaemia-induced hyperactivity and neurodegeneration in the gerbil model of cerebral ischaemia.
In Mongolian gerbils, bilateral carotid occlusion (BCO) followed by reperfusion causes uniform destruction of the CA1 pyramidal neurons in the hippocampus, and this damage correlates with an increase in locomotor activity. Various drugs, such as NMDA antagonists, calcium channel blockers, and free radical scavengers, have provided neuroprotection against ischaemia-induced damage. More recently, the neuroprotective effects of dopamine have been investigated. A large release of dopamine has 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 i.p., 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 GBR 12909 significantly potientiated the hyperactivity of the BCO animals measured in the home cage during the first 24 h following surgery and in the locomotor activity arena after 24 h and 48 h. Significant neuroprotection of cells in the CA1 region of the bippocampus was observed in drug-treated animals 96 h postsurgery. The neuroprotective effect of GBR 12909 may be ascribed to sensitisation of the dopamine D, autoreceptor, consequently reducing the release of dopamine that occurs following ischaemia. Alternatively, GBR 12909 may have a direct interaction with the Na+ ion channel-glutamate complex, resulting in reduced release of glutamate and thereby reducing NMDA receptor activation and neuronal damage.
Maginn
M
M
Department of Pharmacology, University College Galway, Ireland.
Kelly
J P
JP
Leonard
B E
BE
D000818:Animals; D002545:Brain Ischemia / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D016923:Cell Death / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D005849:Gerbillinae; D006624:Hippocampus / Q000187:drug effects* / Q000473:pathology; D008297:Male; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*
D018765:Dopamine Uptake Inhibitors; D018696:Neuroprotective Agents; D010879:Piperazines; C043425:vanoxerine; D004298:Dopamine