Comparative protective effects of nicardipine, flunarizine, lidoflazine and nimodipine against ischaemic injury in the hippocampus of the Mongolian gerbil

Abstract

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.

The effect of lifarizine (RS‐87476), a novel sodium and calcium channel modulator, on ischaemic dopamine depletion in the corpus striatum of the gerbil

“…Nicardipine showed weak protection following chronic dosing but not following single doses. In this respect, flunarizine and nicardipine but not nimodipine have been shown to be effective in preventing delayed neuronal cell death in the CAl region of the hippocampus following 5 min bilateral occulsion of the common carotid arteries in the gerbil (Alps et al, 1988), and the weak protective effects of nicardipine against dopamine depletion following chronic dosing support these earlier findings. Nicardipine has previously been shown to be effective in models of cerebral ischaemia and to have a high brain uptake (Grotta et al, 1987;1988;Hadani et al, 1988).…”

“…Different types of calcium-antagonists have shown different abilities to protect against the deleterious effects of cerebral ischaemia in animal models and in man (Siesjo, 1981;1988;Spedding & Middlemiss, 1985;Alps & Hass, 1987;Alps et al, 1988;Spedding et al, 1989) but selective L-type calcium channel antagonists may be insufficient. We have therefore developed lifarizine (RS-87476) a sodium and calcium channel modulator, which has only weak calcium-antagonistic and vasodilator effects, as a polyvalent modulator of ion channels, which is effective in a range of animal models of ischaemic stroke.…”

Functional, Behavioral, and Histological Changes Induced by Transient Global Cerebral Ischemia in Rats: Effects of Cinnarizine and Flunarizine

“…Calcium antagonists have been used with some success in myocardial ischemia and their potential benefits in experimental cerebral ischemia are now under intensive investigation (Van Reempts et al , 1983Alps et al , 1988;Deshpande and Wie loch, 1986). The effect of transient global cerebral ischemia induced by four-vessel occlusion upon the neuronal integrity of the striatum, neocortex, and hippocampus of the rat have been amply reported (Pulsinelli et al , 1982), but few authors have stud ied the effects of calcium antagonists in this model.…”

Reduction by lifarizine of the neuronal damage induced by cerebral ischaemia in rodents

“…A detailed description of the methodology used to induce forebrain ischaemia in gerbils has been presented previously (Alps et al, 1988). Briefly, animals of either sex, weighing 50-80 g, were anaesthetized with fluothane in a 30% oxygen: 70% nitrous oxide gas mixture and subjected either to (i) 5 min, or (ii) 10 min, bilateral carotid artery occlusion with a 72 h postischaemia survival period.…”

“…Rodent models of transient cerebral ischaemia such as four vessel occlusion (4VO) in the rat (Pulsinelli & Brierley, 1979;Alps & Hass, 1987) and bilateral carotid artery occlusion in the gerbil (Kirino, 1982) develop a reproducible and quantifiable morphological lesion in some brain areas (Alps et al, 1988;Ginsberg & Busto, 1989). It is evident that the damage in selectively vulnerable regions worsens with time, indicating that the cascade of biochemical events initiated by ischaemia progresses even after tissue reperfusion (Pulsinelli et al, 1982;Siesjo & Wieloch, 1985).…”