Comparison of anticonvulsive and acute neuroprotective activity of three 2,3-benzodiazepine compounds, GYKI 52466, GYKI 53405, and GYKI 53655

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Abstract

GYKI 52466 [1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine], a non-competitive AMPA [α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate] and kainate receptor antagonist and its two analogues, GYKI 53405 [1-(4-aminophenyl)-3-acetyl-4-methyl-3,4-dihydro-7,8-methylenedioxy-5H-2,3-benzodiazepine] and GYKI 53655 [1-(4-aminophenyl)-3-methylcarbamyl-4-methyl-3,4-dihydro-7,8-methylenedioxy-5H-2,3-benzodiazepine] were investigated in two seizure models and in MgCl2 induced global cerebral ischaemia, as an acute neuroprotective model. The ED50 values of GYKI 52466 for suppression of the tonic and clonic phases of sound-induced seizures were 3.6 and 4.3 mg/kg, respectively. The corresponding data for GYKI 53405 were 1.1 and 3.1 mg/kg, while ED50 values of GYKI 53655 were 1.3 and 2.0 mg/kg, respectively. The inhibition of seizure evoked by maximal electroshock was also found to be remarkable: the ED50 values of GYKI 52466 and its two analogues were 6.9, 2.6, and 2.2 mg/kg, respectively. All compounds prolonged the survival times in MgCl2 induced global cerebral ischaemia test in a dose-dependent fashion, with PD50 (dose of 50% prolongation) values of 24.1, 8.3, and 8.2 mg/kg intraperitoneal, respectively. In audiogenic seizure model the duration of anticonvulsant action of 10 mg/kg GYKI 52466 and 5 mg/kg GYKI 53405, GYKI 53655 were examined, too. The effect of GYKI 52466 decreased to 50% after 2 h, while the analogues showed more than 80% seizure suppression 3 h after treatment. After 6 h the effect of GYKI 53655 decreased to zero, while the effect of GYKI 52466, remained on the 50% level.

Introduction

In the last 20 years numerous in vitro 4, 13, 18 and in vivo 11, 16 experimental evidences suggest that overexcitation of excitatory amino acid receptors would be an important factor in neuronal degeneration associated with acute brain insults, such as cerebral ischaemia and/or hypoxia, hypoglycaemia, cerebral trauma, and epileptic seizure. The 2,3-benzodiazepine 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine (GYKI 52466) and its two 3-N-substituted 3,4-reduced analogues, 1-(4-aminophenyl)-3-acetyl-4-methyl-3,4-dihydro-7,8-methylenedioxy-5H-2,3-benzodiazepine (GYKI 53405) and [1-(4-aminophenyl)-3-methylcarbamyl-4-methyl-3,4-dihydro-7,8-methylenedioxy-5H-2,3-benzodiazepine (GYKI 53655) have been reported to prevent the excitotoxic action of high extracellular glutamate levels due to their potent non-competitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor antagonist effect 10, 11, 14. Neuroprotective action of GYKI 52466 was investigated in experimental models of global [3] and focal [19] cerebral ischaemia in rat, global cerebral ischaemia in gerbil 16, 12, and in mice (Gigler et al., in preparation). In these reports it has been demonstrated, that GYKI 52466 possess neuroprotective effect both in vitro and in vivo. Several studies were also published about the anticonvulsant activity of GYKI 52466 in relation to its non-competitive AMPA receptor binding properties. The compound was widely investigated in experimental seizure models, where it provided effective protection against convulsions evoked by chemical agents such as AMPA [5] or kainate 11, 24, electroshock 11, 17, 22, 24 and audiogenic stimulation 5, 8. However, at present, no data are available for the two analogues GYKI 53405 and GYKI 53655 in the audiogenic seizure (AS) test and in global cerebral ischaemia model in mice. Therefore, in this study we compared the anticonvulsant efficacy of the three GYKI compounds against maximal electroshock (MES) and audiogenic stimulus induced convulsions and demonstrated the neuroprotective activity of the compounds in MgCl2 induced global cerebral ischaemia. In addition we determined the time course of anticonvulsant activity for GYKI compounds in the AS model.

Section snippets

Animals

In MgCl2 induced global cerebral ischaemia and MES experiments male NMRI mice (Crl: NMRI BR-outbread) weighing 20–25 g were used. The animals were supplied by LAB-TECH Kft. (Isaszeg, Hungary) and kept in polycarbonate cages (Macrolon, Lignifer, Hungary) in a thermostatically controlled room at 23 ± 2°C at relative humidity of 60 ± 10%. The room was artificially illuminated from 0600–1800 h. The mice were given commercial pellet rat-mouse feed and sterile filtered tap water, ad libitum. In the

Anticonvulsant activity

All GYKI compounds blocked the sound-induced clonic and tonic convulsions in a dose-dependent manner. Tonic fit and death were completely prevented by GYKI 53405 and GYKI 53655 at doses over 2.5 and 5.0 mg/kg, respectively, while the corresponding value for GYKI 52466 was 10.0 mg/kg. The ED50 values for the inhibition of clonic and tonic extensor convulsions are summarised in Table 1. Similarly to earlier reports 11, 22 the compounds protected mice against tonic extensor seizures in the MES

Discussion

In the present study the efficacies of three 2,3-benzodiazepine compounds, GYKI 52466, GYKI 53405, and GYKI 53655 were investigated in two seizure and one acute neuroprotective models. Numerous investigations were published about the anticonvulsive property of GYKI 52466 5, 8, 9, 22, 24, but only few papers focused on the two analogues 11, 13, 21, 22. According to our studies, all GYKI compounds investigated were effective against the audiogenic stimulation, although the two analogues displayed

Acknowledgements

The authors gratefully acknowledge Boda Lászlóné and József Baranyai for their expert technical assistance.

References (24)

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