Comparison of anticonvulsive and acute neuroprotective activity of three 2,3-benzodiazepine compounds, GYKI 52466, GYKI 53405, and GYKI 53655
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)
- et al.
Activity of 2,3-benzodiazepines at native rat and recombinant human glutamate receptors in vitroStereospecificity and selectivity profiles
Neuropharmacology
(1996) - et al.
Pretreatment but not posttreatment with GYKI-52466 reduces functional deficits and neuronal damage after global ischaemia in rats
J. Neurosci.
(1996) - et al.
Investigations of non-NMDA receptor-induced toxicity in serum-free antioxidant-rich primary cultures of murine cerebellar granule cells
Neurochem. Int.
(1998) - et al.
The anticonvulsant effect of the non-NMDA antagonists, NBQX and GYKI 52466, in mice
Epilepsy Res.
(1991) The Ca2+ channel and 5-HT2 receptor antagonist (s)-emopamil in cerebral ischaemia
TIPS
(1989)- et al.
Anticonvulsant actions of DS 103–282
Neuropharmacology
(1984) - et al.
GYKI 52466 and related 2,3-benzodiazepines as anticonvulsant agents in DBA/2 mice
Eur. J. Pharmacol.
(1995) - et al.
Effect of a glutamate receptor antagonist (GYKI 52466) on 4-aminopyridine-induced seizure activity developed in rat cortical slices
Brain Res. Bull.
(1999) - et al.
GYKI 52466, a 2,3-benzodiazepine, is a highly selective, non-competitive antagonist of AMPA/kainate receptor responses
Neuron
(1993) - et al.
The neuroprotective and hypothermic effect of GYKI-52466, a non-competitive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-antagonist on histological and behavioural variables in the gerbil global ischaemia model
Brain Res. Bull.
(1999)
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