NEUROPROTECTIVE EFFICACY OF LIFARIZINE (RS-87476) IN A SIMPLIFIED RATSURVIVAL MODEL OF 2 VESSEL OCCLUSION

1 A new, modified rat two vessel occlusion model (with hypotension) wa s established and the neuroprotective efficacy of the novel agent lifa rizine (RS-87476) was examined. 2 The two vessel occlusion model used in the study was a modification of the model described in the literatu re, whereby we have obviated the need to use a muscle relaxant and int ubate the trachea to provide ventilatory support by providing a tight fitting face mask attached to the ventilator. Furthermore, the need to combine exsanguination and additional pharmacological means of induci ng the mandatory hypotension (50 mmHg), required to decrease brain blo od perfusion pressure, has been removed by simply manipulating the con centration of the already present halothane anaesthetic. 3 The appropr iate level of hypotension having been reached, microvascular clips wer e applied to bilaterally occlude the common carotid arteries for 12 mi n. This resulted in a loss of the cortical EEG activity. Local cerebra l blood flow was measured 6 min into the occlusion period, using the f ully quantitative [C-14]-iodoantipyrine autoradiographic technique, in a separate group of rats (n=5). This illustrated the lack of any bloo d flow, in the areas under study, during the period when there was an isoelectric cortical EEG pattern. 4 The high grade global ischaemic le sion which occurred gave quantifiable neuronal damage in several vulne rable regions of the brain, namely, the hippocampal CA(1) sub-field, c ortex, thalamus, striatum, and cerebellar brain stem (Purkinje cells). 5 Following the global ischaemic insult the rats were allowed to reco ver for 72 h before assessment of the damage, during which time one gr oup of rats (n = 11) received 100 mu g kg(-1) lifarizine i.a. 5 min po stocclusion, 500 mu g kg(-1) lifarizine i.p. 15 min post-occlusion, an d 500 mu g kg(-1) lifarizine i.p. twice daily for 72 h. A second group of rats (n = 12) was treated with appropriate volumes of vehicle (0.4 ml kg(-1) i.a. and 2 ml kg(-1) i.p.) at identical time points. 6 Hist opathological damage was assessed, from cresyl violet and haematoxylin e/eosin stained sections, using a scoring system of 0-6 (no damage - c omplete neuronal death). The dosing regimen of lifarizine gave reduced damage in the hippocampal CA(1) sub-field (4.1+/-0.3 to 2.8+/-0.6) an d striatum (1.7+/-0.3 to 1.2+/-0.3) and significant neuroprotection in the anterior cortex (2.0+/-0.2 to 1.2+/-0.2; P<0.05), thalamus (1.5+/ -0.2 to 0.8+/-0.2; P<0.01), posterior cortex (1.5+/-0.2 to 1.0+/-0.2; P<0.05) and cerebellar brain stem (0.9+/-0.2 to 0.4+/-0.1; P<0.01). Th e overall mean brain score was significantly reduced (from 1.5+/-0.1 t o 0.9+/-0.2). 7 These data show that the newly modified 2 vessel occlu sion model produced a quantifiable level of ischaemic damage and that the novel agent lifarizine is neuroprotective in the model.