Reduction by lifarizine of the neuronal damage induced by cerebral ischaemia 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 micrograms 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 micrograms kg-1 was deferred for 1 h. 4. Gerbils were treated (i) 15 min pre-ischaemia with either (a) 250, (b) 500 micrograms 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 micrograms 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 CA1 subfield, thalamus, striatum, cerebellar Purkinje cells-brain stem) at each dose level. Cumulative (total) means +/-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 CA1subfield was prevented at 250 (a) and 500 microg kg-' 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 =l1, 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 microg 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=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.
Alps
B J
BJ
Department of Pharmacology, Syntex Research Centre, Heriot Watt University Research Park, Riccarton, Edinburgh.
Calder
C
C
Wilson
A D
AD
McBean
D E
DE
Armstrong
J M
JM
D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000473:pathology; D001929:Brain Edema / Q000188:drug therapy; D002339:Carotid Arteries / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D004569:Electroencephalography; D005849:Gerbillinae; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D007274:Injections, Intraperitoneal; D002546:Ischemic Attack, Transient / Q000150:complications* / Q000188:drug therapy; D008297:Male; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000473:pathology; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley
D007093:Imidazoles; D018696:Neuroprotective Agents; D010879:Piperazines; C067927:lifarizine