Comparative study of voltage-sensitive sodium channel blockers in focal ischaemia and electric convulsions in rodents

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Abstract

This study evaluates the neuroprotective properties of some voltage-sensitive sodium channel blockers in a model of focal ischaemia. After curative treatment (0.5 and 24.5 h after insult), well known voltage-sensitive sodium channel blockers, phenytoin (2 × 100 mg/kg i.p.), carbamazepine (2 × 50 mg/kg i.p.), lamotrigine (2 × 50 mg/kg i.p.) and RP 66055 (2 × 8 mg/kg i.p.) were found to protect rats against brain damage induced by occlusion of the middle cerebral artery, by 40%, 24%, 28% and 44% respectively. These compounds were also active in protecting both mice and rats against tonic convulsions induced by electroshock, Intraperitoneal ED50 values in mice and rats respectively were of 5.2 and 12.5 mg/kg for phenytoin, 8.4 and 3.6 mg/kg for carbamazepine, 4.4 and 3.1 mg/kg for lamotrigine, 3.9 and 0.22 mg/kg for RP 66055. In contrast, lifarizine was totally devoid of activity in these three tests. This study extends an accumulation of data in the literature pointing to a therapeutic potential for voltage-dependent sodium channel blockers which penetrate the blood brain barrier. Such compounds as phenytoin, carbamazepine, lamotrigine or RP 66055 may act at sodium channels to prevent depolarization, inhibit release of neurotransmitters such as glutamate and thus protects the cortex against cellular damage induced by focal ischaemia by both pre- and post-synaptic inhibition of abnormal neurotransmission.

References (37)

  • R. Bullock

    Introducing NMDA antagonists into clinical practice: why head injury trials

    Br. J. Clin. Pharmacol.

    (1992)
  • D.W. Choi

    Cerebral hypoxia: some new approaches and unanswered questions

    J. Neurosci.

    (1990)
  • D.W. Choi

    Excitotoxicity

  • G.L. Jones et al.

    Hydantoins

  • J. Kucharczyk et al.

    Ischemic brain damage: reduction by sodium-channel modulator RS-87476

    Radiology

    (1991)
  • M.J. Leach et al.

    Pharmacological studies on lamotrigine, a novel potential antiepileptic drug. II. Neurochemical studies on the mechanism of action

    Epilepsia

    (1986)
  • M.J. Leach et al.

    Biochemical and behavioural aspects of lamotrigine

    Epilepsia

    (1991)
  • P.D. Leeson et al.

    Drugs interacting with the glycine binding site

  • Cited by (0)

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