Gamma-aminobutyric acid and mefloquine-induced seizures in mice

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Abstract

The role of GABAergic mechanism in the convulsant effect of mefloquine was investigated in mice. Mefloquine dose dependently induced tonic seizures in mice. Aminooxyacetic acid, diaminobutyric acid and muscimol significantly protected mice against mefloquine-induced seizures by significantly delaying the onset and decreasing the incidence of the seizures. Bicuculline and picrotoxin significantly enhanced the seizure producing effect of mefloquine and also significantly antagonised the protective effect of muscimol against the seizures. Phenobarbitone and diazepam effectively protected mice against mefloquine-induced seizures. Phenytoin did not alter mefloquine-induced seizures. These data indicate that GABA mechanisms might be involved in seizures produced by mefloquine in mice.

Introduction

Prophylactic antimalarial drugs have been reported, at standard dosages, to produce convulsions in healthy subjects and more frequently in subjects with a history of epilepsy (Zaccara et al., 1990). Mefloquine, a 4-aminoquinoline methanol, is used for prophylaxis of chloroquine-resistant Plasmodium falciparum malaria (Rang et al., 1999a, Rosenthal and Goldsmith, 2001). However, severe neurological and psychiatric adverse effects including acute psychosis, affective disorders, acute confusional states and seizures have been reported (Piening and Young, 1996, Laffitte, 1997, Heeringa et al., 1998, Rang et al., 1999a, Rosenthal and Goldsmith, 2001). The mechanism of mefloquine-elicited convulsions has not been reported in literature. Quinine, an antimalarial agent, which is chemically related to mefloquine has been shown to cause seizures by impairing gamma aminobutyric acid (GABA) neurotransmission (Amabeoku and Chikuni, 1992, Rosenthal and Goldsmith, 2001). GABA is a major inhibitory neurotransmitter and through its receptors, GABAA receptors, is widely implicated in epilepsy (Olsen, 1981, Homeida and Cooke, 1982, De Deyn et al., 1990, Gale, 1992). This study was, therefore, designed to investigate the role of GABA mechanism in mefloquine-induced seizures by studying the effects of aminooxyacetic acid hemihydrochloride (AOAA), dl-2,4-diamino-n-butyric acid hydrochloride (DABA), muscimol, bicuculline, picrotoxin, diazepam and phenobarbitone on the seizures in mice. The role of phenytoin, a standard anticonvulsant agent, known to exert its anticonvulsant effect by blocking sodium ion entry into brain cells (Porter and Meldrum, 2001), in mefloquine seizures was also investigated in mice.

Section snippets

Animals

Male albino mice bought from the University of Cape Town, South Africa, and weighing 20–30 g were used throughout the study. The animals were housed in groups of eight per cage and maintained on tap water and food ad libitum. A daily 12-h light–dark cycle was maintained. Eight mice per dose of drug or control vehicle were used in the study and each animal was used for one experiment only.

Drugs

Mefloquine hydrochloride (Roche), aminooxyacetic acid hemihydrochloride (AOAA, Sigma Chemical Co.), dl

Convulsant effect of mefloquine

Mefloquine (100–137.5 mg/kg, i.p.) elicited tonic seizures in a dose-dependent manner. The onset and incidence of the seizures shortened and increased respectively with increase in the dose of mefloquine (Table 1). The control vehicles did not alter the gross behaviour of animals, such as rearing, sniffing, grooming, exploration patterns and so on, or the convulsant effect of mefloquine. Mefloquine seizures were characterised by wild running in all directions in the cage by the animals,

The effects of muscimol and bicuculline on mefloquine-induced seizures

The role of GABA, a major inhibitory neurotransmitter, and its receptors, GABAA receptors, in epilepsy has been widely reported (Leidenheimer et al., 1991, Gale, 1992, Rang et al., 1999b). Blockade and stimulation of GABAA receptors in the brain have been shown to elicit and attenuate seizures respectively (Gale, 1992). The results of this study show that mefloquine in a dose-related manner induced tonic seizures in mice. Muscimol (1 mg/kg, i.p.) was shown to effectively protect mice against

Conclusions

The present study shows that AOAA, DABA, muscimol, diazepam and phenobarbitone, which enhance GABA neurotransmission, attenuated mefloquine seizures while those such as bicuculline and picrotoxin, which block GABA neurotransmission enhanced the seizures. Conversely, phenytoin, known to exert its antiepileptic effect by blocking sodium ion entry into the brain cells, did not alter mefloquine-induced seizures. These findings, therefore, suggest that GABA mechanism may be involved in mefloquine

Acknowledgements

We wish to thank Roche Products (Pty) Ltd., South Africa, for their generous gift of mefloquine hydrochloride. We also thank Mr. B. Minnis for his technical assistance and for the welfare of the animals.

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