Presently, most strategies for development of antiepileptic drugs (AED
s) center around seizure models that are known to respond to presently
marketed AEDs. These strategies do not take into account that epileps
y can be a progressive disease. Moreover, region-specific aspects of e
pileptogenesis are rarely considered when new AEDs are developed. Seiz
ures in the temporal lobe are often difficult to treat. Animal studies
on various seizure models in the hippocampus and the entorhinal corte
x (EC) suggest that these structures do not a priori produce seizures
that are difficult to treat. However, seizure-like events in the EC te
nd to progress to a state of status epilepticus-like activity that can
not be suppressed by presently marketed AEDs. Loss of gamma-aminobutyr
ic acid (GABA)ergic neurotransmission and increased excitatory synapti
c coupling seem to cooperate for induction of this state. Epilepsy ind
uced alterations in the interaction between the EC and the hippocampus
may lead to alterations that facilitate precipitation of seizures. Be
cause of the recurrent interaction between the hippocampus and the EC,
these seizures may reach an intensity that is no longer controllable
by presently available AEDs. Ontogenetic alterations of the circuitry
between the EC and the hippocampus, seizure-induced stabilization of s
ynaptic connections overexpressed during ontogenesis, seizure-induced
lesions and subsequent rearrangements of internal cell properties, and
synaptic arrangements and kindling-like alterations of nerve cell and
glial behavior may all be involved in the generation of a neuronal ag
gregate whose balance between inhibitory and excitatory processes beco
mes readily disturbed. Strategies for the development of AEDs treating
such seizures should suppress hyperactivity and prevent progression o
f epileptogenesis. AEDs directed against seizures may be effective if
they can be given in sufficient concentrations to suppress very intens
e local seizures.