Neuroprotective properties of lifarizine compared with those of other agents in a mouse model of focal cerebral ischaemia

Brown, C. M.; Calder, C.; Linton, C.; Small, Catherine B.; Kenny, Barry; Spedding, Michael; Patmore, Leslie

doi:10.1111/j.1476-5381.1995.tb16633.x

Cited by 21 publications

(8 citation statements)

References 55 publications

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“…Although Mex is already used in the clinic (Johansson et al, 1984), a short therapeutic window, as observed in the second series of animals, may limit its application in the treatment of stroke. Our results are consistent with the limited therapeutic windows of other voltagedependent Na ϩ channel blockers, such as BW619C89, tetrodotoxin, and lifarizine, and perhaps suggest that combining Mex with other neuroprotective agents may be necessary for establishing an extended therapeutic window (Granam et al, 1994;Xie et al, 1994;Brown et al, 1995;Chen et al, 1995;Pringle et al, 1997). It is also possible that the therapeutic window for Mex may be better than observed here, since we gave it as only one acute dose to counteract a severe permanent MCA occlusion.…”

Section: Discussionsupporting

confidence: 85%

Mexiletine and magnesium independently, but not combined, protect against permanent focal cerebral ischemia in Wistar rats

et al. 1999

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The neuroprotective effect of mexiletine (Mex), a potent Na(+) channel blocker which decreases neuronal energy demands and prevents energy depletion during ischemia, was evaluated in Wistar rats subjected to permanent middle cerebral artery (MCA) occlusion. Postmortem infarct volumes were determined by quantitative image analysis of triphenyltetrazolium (TTC)-stained brain sections. Pretreatment with Mex resulted in a significant infarct volume reduction when administered intraperitoneally, either at the dosage of 50 or 60 mg/kg, 1 hr before MCA occlusion (P < 0.05). Delayed treatment with Mex (50 mg/kg) also had neuroprotective effects when given at 0.5 hr (< 0.05), but not 2-4 hr, after MCA occlusion. Intraarterial administration of MgSO(4) (90 mg/kg), in combination with Mex at 60 mg/kg, showed no additive neuroprotective effect, although each agent independently reduced the MCA occlusion-induced infarction volume (P < 0.05). Our results indicate that a single, acute administration of Mex is neuroprotective against permanent focal cerebral ischemia, but perhaps chronic administration is needed to establish a more effective therapeutic window beyond 0.5 hr. Moreover, the present in vivo data do not favor a combined use of Mg(2+) with Mex for limiting ischemic injury in the brain, since these agents caused cardiopulmonary suppression, which may have led to the loss of the neuroprotective effect of each agent independently.

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Section: Discussionsupporting

confidence: 85%

Mexiletine and magnesium independently, but not combined, protect against permanent focal cerebral ischemia in Wistar rats

et al. 1999

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“…The neuroprotective profile of the diphenylpiperazine derivative, lifarizine (RS-87476; 1-[(2-(4-methylphenyl)-5-methyl)-1H-imidazol-4-yl-methyl]-4-diphenylmethyl-piperazine) has been shown to be neuroprotective in both global and focal models of cerebral ischaemia: the rat 4VO model (Alps et al, 1990); gerbil unilateral carotid artery occlusion (Brown et al, 1993); rat rose Bengal photochemical lesion (McBean et al, 1995b); and mouse middle cerebral artery occlusion (Brown et al, 1994). This neuroprotective efficacy led to the compound being tested in the cat permanent middle cerebral artery occlusion model by magnetic resonance imaging as well as histopathological techniques (Kucharczyk et al, 1991).…”

Section: Neuropathological Scorementioning

confidence: 99%

Neuroprotective efficacy of lifarizine (RS‐87476) in a simplified rat survival model of 2 vessel occlusion

McBean

Winters

Wilson

et al. 1995

British J Pharmacology

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1 A new, modified rat two vessel occlusion model (with hypotension) was established and the neuroprotective efficacy of the novel agent lifarizine (RS-87476) was examined. 2 The two vessel occlusion model used in the study was a modification of the model described in the literature, whereby we have obviated the need to use a muscle relaxant and intubate 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 inducing the mandatory hypotension (50 mmHg), required to decrease brain blood perfusion pressure, has been removed by simply manipulating the concentration of the already present halothane anaesthetic. 3 The appropriate level of hypotension having been reached, microvascular clips were applied to bilaterally occlude the common carotid arteries for 12 min. This resulted in a loss of the cortical EEG activity. Local cerebral blood flow was measured 6 min into the occlusion period, using the fully quantitative ["4C]-iodoantipyrine autoradiographic technique, in a separate group of rats (n = 5). This illustrated the lack of any blood flow, in the areas under study, during the period when there was an isoelectric cortical EEG pattern. 4 The high grade global ischaemic lesion which occurred gave quantifiable neuronal damage in several vulnerable regions of the brain, namely, the hippocampal CA, sub-field, cortex, thalamus, striatum, and cerebellar brain stem (Purkinje cells). 5 Following the global ischaemic insult the rats were allowed to recover for 72 h before assessment of the damage, during which time one group of rats (n = 11) received 100 jig kg-1 lifarizine i.a. 5 min postocclusion, 500 jig kg-' lifarizine i.p. 15 min post-occlusion, and 500 jug kg-' 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-' i.a. and 2 ml kg-' i.p.) at identical time points. 6 Histopathological damage was assessed, from cresyl violet and haematoxyline/eosin stained sections, using a scoring system of 0-6 (no damage -complete neuronal death). The dosing regimen of lifarizine gave reduced damage in the hippocampal CA, sub-field (4.1 0.3 to 2.8 + 0.6) and 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). The overall mean brain score was significantly reduced (from 1.5+0.1 to 0.9+0.2). 7 These data show that the newly modified 2 vessel occlusion model produced a quantifiable level of ischaemic damage and that the novel agent lifarizine is neuroprotective in the model.

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“…Treatment with MCAO is employed to make an animal model of transient focal cerebral ischemia (Brown et al, 1995;Sydserff et al, 2002). In the present study, a short (2 h) MCAO produced small to mid-sized infarcted regions with increasing post-operative days in the caudate putamen and cerebral cortex, when compared with the usual MCAO method (4 h) (Mishima et al, 2003) (Fig.…”

Section: Discussionmentioning

confidence: 59%

Cyclosporin A Aggravates Electroshock-Induced Convulsions in Mice with a Transient Middle Cerebral Artery Occlusion

et al. 2005

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1. To test whether an ischemic insult increases the susceptibility to cyclosporine A (CsA)-induced neurotoxicity, we examined the effect of CsA on the minimal electroshock-induced convulsions in mice treated with a transient middle cerebral artery occlusion (MCAO) for a short period (2 h). 2. This MCAO produced small to mid-sized infarcted regions in the cerebral hemisphere with increasing post-operative days. In MCAO mice, CsA (30 mg/kg, i.p.) elevated the incidence of minimal electroshock-induced convulsions to 90-100% over that in sham mice (20-30%) at 1-7 days but not 14 days post-surgery. 3. In light of these findings, the possibility that CsA increases the risk of convulsions in patients with cerebral infarction and/or at an early stage following focal cerebral ischemia would have to be considered.

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Neuroprotective properties of lifarizine compared with those of other agents in a mouse model of focal cerebral ischaemia

Cited by 21 publications

References 55 publications

Mexiletine and magnesium independently, but not combined, protect against permanent focal cerebral ischemia in Wistar rats

Mexiletine and magnesium independently, but not combined, protect against permanent focal cerebral ischemia in Wistar rats

Neuroprotective efficacy of lifarizine (RS‐87476) in a simplified rat survival model of 2 vessel occlusion

Cyclosporin A Aggravates Electroshock-Induced Convulsions in Mice with a Transient Middle Cerebral Artery Occlusion

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