Comparison of the preclinical anticonvulsant profiles of tiagabine, lamotrigine, gabapentin and vigabatrin

Abstract 

Tiagabine is a novel antiepileptic drug which has clinical efficacy against complex refractory and myoclonic seizures. The anticonvulsant mechanism of action of tiagabine results from its blockade of neuronal and glial GABA-uptake, thereby increasing GABA levels in the synaptic cleft. Here we present a comparison of the preclinical anticonvulsant profile of tiagabine with that of lamotrigine, gabapentin and vigabatrin in the following tests (all antiepileptic drugs were administered i.p.): seizures induced by pentylentetrazol (PTZ), 6,7-dimethoxy-4-ethyl-b-carboline-3-carboxylate (DMCM) and maximal electroshock (MES); sound induced seizures in DBA/2 mice and finally acute amygdala kindled seizures. Tiagabine was the most potent drug in antagonizing tonic convulsions induced by PTZ, DMCM and sound induced seizures in DBA/2 mice with ED₅₀ values of 2, 2 and 1 μmol/kg, respectively, followed by lamotrigine with ED₅₀ values of 9, 43 and 6 μmol/kg, respectively. Gabapentin and vigabatrin had ED₅₀ values in the same tests of 185, 452, 66 μmol/kg and 2322, >7740, 3883 μmol/kg, respectively. Tiagabine was the only drug capable of blocking PTZ-induced clonic convulsions (ED₅₀=5 μmol/kg), an effect seen at low but not high doses of tiagabine. Lamotrigine was the only drug which antagonized tonic convulsions in the MES test (ED₅₀=36 μmol/kg). Therapeutic index (TI) of antiepileptic drugs in NMRI-and DBA/2-mice ranked with decreasing TI lamotrigine>gabapentin>vigabatrin>tiagabine. All drugs reduced the generalized seizures in amygdala kindled rats, but tiagabine and gabapentin furthermore attenuated afterdischarge duration of amygdala kindled seizures. However, an ED₅₀ value against amygdala kindled focal seizures was only obtained for tiagabine (36 μmol/kg). The data here presented show that tiagabine, lamotrigine, gabapentin and vigabatrin posses different preclinical anticonvulsant profiles which is of relevance to the clinical anticonvulsant profiles of the drugs.

Keywords:  Tiagabine, Lamotrigine, Gabapentin, Vigabatrin, Preclinical anticonvulsant profiles