Activators and Inactivators of Calcium Channels: Effects in the Central Nervous System

Spedding, Michael; Kilpatrick, Andrew T.; Alps, B. J.

doi:10.1111/j.1472-8206.1989.tb00472.x

Cited by 22 publications

(23 citation statements)

References 155 publications

(145 reference statements)

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“…Sodium and calcium overload is a critical factor in the initiation of the pathological conditions leading to cell death following cerebral ischaemia (Siesjo, 1981;Hass, 1983;Simon et al, 1984;Gelmers, 1985;Spedding et al, 1989;Pulsinelli, 1992). Lifarizine, through its block of neuronal sodium and calcium channels, has the potential to suppress ischaemiainduced recurrent depolarization, limit the cellular accumulation of Na+ and Ca2+ and therefore reduce neurological damage following cerebral ischaemia.…”

Section: Drugs and Chemicalsmentioning

confidence: 99%

“…However, extensive attempts to limit cellular calcium entry following cerebral ischaemia with L-type calcium antagonists have, at best, proved inconclusive (Hossman, 1988;Spedding et al, 1989). In this paper, we have assessed the potential neuroprotective properties of sodium channel blockers in the mouse middle cerebral artery-occlusion Bridsh Joumal of Phamacology (1995) 115, 1425 1432 model and compared them with agents which act by alternative mechanisms, including the NMDA antagonist, MK 801, the Ltype calcium channel blocker, nimodipine and the lipid peroxidase inhibitor, tirilazad.…”

Section: Introductionmentioning

confidence: 99%

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

Brown

Calder

Linton

et al. 1995

British J Pharmacology

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5 Agents with other mechanisms of action were also shown to have significant neuroprotection in this model. The non-competitive NMDA antagonist, MK 801, showed significant neuroprotection in the model when given at 0.5 mg kg-', i.p. 30 min pre-ischaemia with t.i.d. dosing for 7 days (P< 0.001). The dihydropyridine calcium antagonist, nimodipine was not protective when given using the same dosing protocol as MK 801, 0.5 mg kg-' 30 min pre-occlusion and three times daily for 7 days but showed significant protection when given at 0.05 mg kg-' 15 min post-ischaemia and three times daily for 7 days. The lipid peroxidation inhibitor, tirilazad (single dose 1 mg kg-', i.v.) showed significant neuroprotection when given 5 min post-ischaemia but not when the first dose was delayed for 4 h.

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Section: Drugs and Chemicalsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Brown

Calder

Linton

et al. 1995

British J Pharmacology

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“…6 Newer excitatory amino acid antagonists are being evaluated but may have unacceptable toxicity (e.g., psychosis and cardiac arrhythmias), and it remains to be seen whether the benefit in animals can be translated into benefit in elderly stroke patients. 7 Using the second approach, hemodilution is ineffective in the generality of ischemic stroke patients. 8 Antithrombotic therapy (with heparin, warfarin, or aspirin) has not been properly tested in large randomized clinical trials.…”

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confidence: 99%

Thrombolysis in acute ischemic stroke: does it work?

Wardlaw

Warlow

1992

Stroke

164

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Background: This article is presented to provoke further discussion regarding the use of thrombolj drugs to treat acute ischemic stroke.Summary of Review: Overview analysis of the six randomized trials of thrombolysis in acute ischer stroke available in the world literature shows a 20% increase in the odds of death and a 30% reduction the odds of death or deterioration (both with wide confidence intervals, neither result significant) af thrombolytic treatment for acute ischemic stroke. Exclusion of the two trials conducted without I benefit of computed tomographic scanning shows a 37% reduction in the odds of death (95% confidence interval, 74% reduction to 40% excess) and a significant reduction of 56% in the odds of death or deterioration after thrombolytic treatment (95% confidence interval, 20-76% reduction; 2p=0.007). Analysis of all published studies (randomized and nonrandomized) shows that there does not appear to be an excess risk of hemorrhagic transformation of the cerebral infarct or of severe edema formation.Conclusions: We believe the present evidence is sufficiently encouraging to warrant proper testing of thrombolysis in sufficiently large and well-designed randomized clinical trials to influence clinical practice. (Stroke 1992;23:1826-1839 KEY WORDS • cerebral ischemia • clinical trials • thrombolytic therapy

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“…The CA, neurones have L-type Ca2" channels which show increased binding by [3H]-PN200-1 1O in ischaemia (Magnoni et al, 1988) and are especially vulnerable to ischaemic damage in animal models (Kirino, 1982;Suzuki et al, 1983a,b;Alps et al, 1988;Spedding et al, 1989), and in man (Zola-Morgan et al, 1986), where damage of these cells may be excessively stimulated during the ischaemic reperfusion period via the Schaeffer collaterals which release excitatory amino acids (Suzuki et al, 1983a,b claimed to slow the transition of the Ca2" channel from the active to the closed state (see Sanguinetti et al, 1986;Kass, 1987). Since it is possible that such agents may have a role to play in the pathogenesis of cerebral ischaemia (Patmore et al, 1989), it is important to consider that, in addition to its blockade of L-type Ca2" channels, the marked inhibition of Ca2" channel activators by lifarizine (Fraser & Spedding, 1991) may constitute an added neuroprotective mechanism.…”

Section: Discussionmentioning

confidence: 99%

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

Alps

Calder

Wilson

et al. 1995

British J Pharmacology

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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. 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. 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 μ 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 μg kg−1 was deferred for 1 h. Gerbils were treated (i) 15 min pre‐ischaemia with either (a) 250, (b) 500 μg 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 μg kg i.p. 15 min pre‐ischaemia. The above doses were repeated twice daily for 3 days post‐ischaemia for the respective groups. 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) 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). In gerbils, (i) percentage delayed neuronal death (DND) of hippocampal pyramidal cells in the CA1 subfield was prevented at 250 (a) and 500 μg 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 μg 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 = 1). 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.

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Activators and Inactivators of Calcium Channels: Effects in the Central Nervous System

Cited by 22 publications

References 155 publications

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

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

Thrombolysis in acute ischemic stroke: does it work?

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

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