NEUROPROTECTIVE PROPERTIES OF LIFARIZINE COMPARED WITH THOSE OF OTHERAGENTS IN A MOUSE MODEL OF FOCAL CEREBRAL-ISCHEMIA

1 Changes in the peripheral type benzodiazepine binding site density f ollowing middle cerebral artery occlusion in the mouse, have been used as a marker of neuronal damage. These sites can be identified using t he selective ligand [H-3]-PK 11195 located on non neuronal cells, macr ophages and astroglia, within the CNS. Glial cell proliferation and ma crophage invasion is an unvoidable sequelae to cerebral ischaemic inju ry, secondary to neuronal loss. Following occlusion of the left middle cerebral artery (left MCA) a reproducible lesion was found in the par ietal cortex within 7 days which gave rise to a significant increase i n [H-3]-PK 11195 binding. 2 Treatment of animals with the sodium chann el blocker, lifarizine, significantly reduced the ischaemia-induced in crease in [H-3]-PK 11195 binding when given either 30 min pre-ischaemi a and three times daily for 7 days at 0.5 mg kg(-1), i.p. (P < 0.01) o r delayed until 15 min post-ischaemia and three times daily for 7 days at 0.5 mg kg(-1), i.p. (P < 0.001). Lifarizine was an effective neuro protective agent in this model of focal ischaemia in the mouse. 3 Lifa rizine also showed a dose-related protection against the ischaemia-ind uced increase in [H-3]-PK 11195 binding with significant protection at doses of 0.1 mg kg(-1), i.p. (P < 0.05), 0.25 mg kg(-1), i.p, (P < 0. 01) or 0.5 mg kg(-1), i.p. (P < 0.01) 15 min post-ischaemia and b.i.d. for 7 days. No significant change is seen in the K-d for [H-3]-PK 111 95. The first dose could be delayed for up to 4 h after cerebral arter y cauterization and protection was maintained. 4 Phenytoin (28 mg kg(- 1), i.v. 15 min and 24 h post-ischaemia) was also neuroprotective in t his model (P < 0.01). This agent is thought to interact with voltage-d ependent sodium channels to effect its anticonvulsant actions and this mechanism may also underlie its neuroprotective actions in focal cere bral ischaemia. 5 Agents with other mechanisms of action were also sho wn to have significant neuroprotection in this model. The non-competit ive NMDA antagonist, MK 801, showed significant neuroprotection in the model when given at 0.5 mg kg(-1), i.p. 30 min pre-ischaemia with t.i .d. dosing for 7 days (P < 0.001). The dihydropyridine calcium antagon ist, nimodipine was not protective when given using the same dosing pr otocol as MK 801, 0.5 mg kg(-1) 30 min pre-occlusion and three times d aily for 7 days but showed significant protection when given at 0.05 m g kg(-1) 15 min post-ischaemia and three times daily for 7 days. The l ipid peroxidation inhibitor, tirilazad (single dose 1 mg kg(-1) i.v.) showed significant neuroprotection when given 5 min post-ischaemia but not when the first dose was delayed for 4 h.