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 mumol/kg, respectively, followed by
lamotrigine with ED50 values of 9, 43 and 6 mumol/kg, respectively.
Gabapentin and
vigabatrin had ED50 values in the same tests of 185, 452, 66 mumol/kg and 2322, > 7740, 3883 mumol/kg, respectively.
Tiagabine was the only
drug capable of blocking PTZ-induced clonic convulsions (ED50 = 5 mumol/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 mumol/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 mumol/kg). The data here presented show that
tiagabine,
lamotrigine,
gabapentin and
vigabatrin possess different preclinical
anticonvulsant profiles which is of relevance to the clinical
anticonvulsant profiles of the drugs.