The anticonvulsant effects of the enantiomers of losigamone

Abstract

1 Losigamone is a novel anticonvulsant undergoing phase III clinical trials in patients with partial and secondary generalized seizures. This study investigated the eects of the S(+)-and R(7)-enantiomers of losigamone on endogenous amino acid release from BALB/c mouse cortical slices, spontaneous depolarizations in the cortical wedge preparation of the DBA/2 mouse and audiogenic seizures in DBA/2 mice. 2 S(+)-losigamone (100 and 200 mM) signi®cantly reduced both potassium-and veratridine-elicited release of glutamate and aspartate from cortical slices. R(7)-losigamone had no eect on release at concentrations up to 400 mM. 3 Cortical wedges exhibit spontaneous depolarizations when perfused with magnesium-free arti®cial cerebrospinal¯uid. S(+)-losigamone signi®cantly reduced these depolarizations at 50 ± 200 mM whilst R(7)-losigamone had a signi®cant eect at 200 ± 800 mM. 4 DBA/2 mice are susceptible to audiogenic seizures and S(+)-losigamone dose-dependently (5, 10 and 20 mg kg 71 , i.p.) signi®cantly inhibited clonic/tonic convulsions with 91% of the mice protected at 20 mg kg 71 . There was no protection at 20 mg kg 71 with R(7)-losigamone. 5 These results, from both in vitro and in vivo experiments, con®rm that the pharmacological activity pro®les of the two losigamone enantiomers are not identical and suggest further that excitatory amino acid-mediated processes are involved in the mode of action of S(+)-losigamone whereas R(7)-losigamone does not possess such properties. For the treatment of neurological conditions involving exaggerated excitatory amino acid function the use of S(+)-losigamone might therefore be more eective clinically than losigamone or its R(7)-enantiomer.

Effects of Bilobalide on Cerebral Amino Acid Neurotransmission

“…Amino acid release from mouse cortical slices Male or female BALC/c mice were killed by cervical dislocation and coronal cortical slices (400 mm) were prepared as previously described [12]. Slices were placed on a gauze disc and transferred to a heated (378C) tissue bath and perfused with gassed (95 % oxygen/5 % carbon dioxide) aCSF (1 ml/minute) and the slices were left for 60 minutes to equilibrate.…”

Treatment of epilepsy existing therapies and future developments

“…Losigamone (5-(2-chlorophenylhydroxymethyl)-4-methoxy-2(5H)-furanone; Figure 15) is a tetronic acid derivative in clinical trials as an AED (458). The drug is being developed as a racemate (459), though its enantiomers have somewhat different properties (56,460). Although the mechanism of action is unclear, losigamone probably acts via the NMDA system; it also affects the GABA A receptor-linked chloride channel.…”

“…This is partly due to what is referred to as "sudden unexpected death in epilepsy" (SUDEP; [45][46][47][48][49][50][51]. Furthermore, patients are subject to considerable risk of physical injury during seizures (52)(53)(54)(55)(56)(57)(58)(59)(60)(61).…”

An overview on antiepileptic drugs

“…Initially it was thought that the anticonvulsant effect of losigamone may be due to NMDA (N-methyl-Daspartic acid) antagonism and inhibition of excitatory amino acid release (95). In vitro and in vivo experiments carried out on genetically epilepsy prone DBA/2 mice by Jones and Davies suggested that the clinically effective anticonvulsant activity of LSG is attributed to its S (+)-enantiomer rather than R (−)-enantiomer or its racemic mixture (96). Present data suggests that the drug decreases neuronal excitability via a decrease in the persistent Na + current in rat hippocampal neurons (97).…”