4 Features of DND were distributed evenly throughout the CA1 subfield in both hemispheres in all groups of gerbils. Nicardipine, lidoflazine and flunarizine, but not nimodipine, were protective. This protection extended linearly throughout the hippocampus without altering the pattern of neuronal damage. 5 Compared to saline-treated (78.3 + 2.9% DND) and nimodipine-treated (76.5 + 3.4% DND) gerbils, the overall protection afforded by nicardipine (41.8 + 3.8% DND) was statistically significant. The effects of lidoflazine (53.6 + 7.1%) and flunarizine (55.8 ± 3.9% DND) were of borderline significance. 6 Abnormal neurones appeared in normal and sham-operated brains to the extent of 4.5 + 1.0% and 4.6 + 0.4%, respectively. Such changes can be attributed to fixation artefacts. 7 The results demonstrate that overall protection is conferred on ischaemic hippocampal CA1 neurones by nicardipine and to a lesser extent by flunarizine and lidoflazine, but not by nimodipine.

Unilateral ligation of the right common carotid artery in the anaesthetized gerbil for 3 h caused a 62.7% decrease in ipsilateral dopamine in the corpus striatum from 1.40 (± 0.13, n = 27) μg g−1 in the non‐ischaemic hemisphere to 0.47 (± 0.07, n = 27) μg g−1 in the ischaemic hemisphere (all results are expressed as mean ± s.e.mean). In sham‐operated animals there were no differences in the dopamine levels (1.31 ± 0.14 μg g−1, n = 11, left; 1.27 ± 0.13 μg g−1, n = 11 in the right hemisphere). Animals with intact communicating arteries in the circulus arteriosus were excluded. Lifarizine (RS‐87476; 250, 500, but not 50, μg kg−1, i.p.) protected against this dopamine depletion showing only a 9.2% decrease at 250 μg kg−1, i.p. (P < 0.01) and no decrease at 500 μg kg−1, i.p. (P < 0.01). Nicardipine (250 μg kg−1, p.o.) was effective when administered chronically once daily for 10 days (26.6% decrease, P < 0.05) but not when administered acutely at 50 μg kg−1, i.p.

5 Agents with other mechanisms of action were also shown to have significant neuroprotection in this model. The non-competitive NMDA antagonist, MK 801, showed significant neuroprotection in the model when given at 0.5 mg kg-', i.p. 30 min pre-ischaemia with t.i.d. dosing for 7 days (P< 0.001). The dihydropyridine calcium antagonist, nimodipine was not protective when given using the same dosing protocol as MK 801, 0.5 mg kg-' 30 min pre-occlusion and three times daily for 7 days but showed significant protection when given at 0.05 mg kg-' 15 min post-ischaemia and three times daily for 7 days. The lipid peroxidation inhibitor, tirilazad (single dose 1 mg kg-', i.v.) showed significant neuroprotection when given 5 min post-ischaemia but not when the first dose was delayed for 4 h.

The objective of this study was to evaluate the broad neurocytoprotective potential of the novel sodium‐calcium ion channel modulator, lifarizine (RS‐87476), in two rodent 72 h survival models of forebrain ischaemia. Under fluothane anaesthesia, rats were subjected to 10 min four vessel occlusion and gerbils to either (i) 5 or (ii) 10 min bilateral carotid artery occlusion. Rats were dosed parenterally solely post‐ischaemia (reperfusion) in a series of five studies covering a range of intra‐arterial/intraperitoneal (i.a./i.p.) combination doses from 2/10, 5/20, 20/100, 50/200 and 100/500 μ kg−1, where the initial loading dose was injected i.a. at 5 min. An i.p. dose was given at 15 min and repeated twice daily. In a sixth study, treatment at 50/200 μg kg−1 was deferred for 1 h. Gerbils were treated (i) 15 min pre‐ischaemia with either (a) 250, (b) 500 μg kg−1 i.p., or (c) 5 mg kg−1 by gavage (p.o.) for 3 days then at 1 h pre‐ischaemia. Animals treated as (ii) received 500 μg kg i.p. 15 min pre‐ischaemia. The above doses were repeated twice daily for 3 days post‐ischaemia for the respective groups. In rats, the protective effect of lifarizine was regionally and cumulatively assessed in six brain regions (anterior and posterior neocortex, hippocampal CA1 subfield, thalamus, striatum, cerebellar Purkinje cells‐brain stem) at each dose level. Cumulative (total) mean ± s.e.mean neurohistopathological scores (0–4) of 1.16±0.09 (n = 5), 1.02±0.10 (n = 5), 0.93±0.06 (n = 6), 0.79±0.09 (n = 9) and 0.45±0.16 (n = 7), respectively, were obtained for the above treatment groups compared to the control (2.01 ±0.17, n =16) group (P< 0.0035). The score for the 1 h deferred treatment group was also significant at 0.77 ±0.10, n = 5 (P< 0.0035). The normal group without ischaemia showed a score of 0.52 ±0.09 (n = 6). In gerbils, (i) percentage delayed neuronal death (DND) of hippocampal pyramidal cells in the CA1 subfield was prevented at 250 (a) and 500 μg kg−1 i.p. (b) (27.2±14.6, n = 6 and 26.9±10.4%, n =10 respectively, P<0.02) compared to controls (78.3 ±8.5%, n = 12) and by 5 mg kg−1 p.o. (c) (2.9±0.8%, n =11, P< 0.002). Mean ± s.e.mean total brain scores (0–4) for each of 4 different features denoting cerebral ‘oedema’ were lower for normal brains (1.60 ±0.34, n = 6) and reduced in animals dosed at 250 (a) (3.00±0.79, n = 6) and 500 μg kg−1 i.p. (b) (3.75±0.36, n =10) compared to controls (6.58±1.00, n =12) (P< 0.02‐0.03). There was a linear relationship (r = 0.97) between the ‘oedema’ scores and percentage CA1 DND. Percentage CA1 DND in response to 10 min ischaemia (ii) was reduced (53.0±21.0%, n = 6, P<0.05) compared to controls (100.0±0.0%, n = 1). The significant neuroprotection shown by lifarizine in rodents substantiates findings in other species. These observations, together with its effect on ion channels and efficacy at extremely low doses offers novelty and suggests a broad spectrum of activity in ischaemia.

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