REDUCTION BY LIFARIZINE OF THE NEURONAL DAMAGE-INDUCED BY CEREBRAL-ISCHEMIA IN RODENTS

1 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. 2 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. 3 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 mu g 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 mu g kg(-1) was deferred for 1 h. 4 Gerbils were treated (i) 15 min pre-ischaemia with either (a) 250, (b) 500 mu g 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 mu g kg(-1) i.p. 15 min pre-ischaemia. The above doses were repeated twice daily for 3 days post-ischaemia for the respective groups. 5 In rats, the protective effect of lifarizine was regionally and cumulatively assessed in six brain regions (anterior and posterior neocortex, hippocampal CAI 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). 6 In gerbils, (i) percentage delayed neuronal death (DND) of hippocampal pyramidal cells in the CA(1) subfield was prevented at 250 (a) and 500 mu g 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 pg 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 CA(1) DND. Percentage CA(1) 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 = 7). 7 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.