Models in Research of Pharmacoresistant Epilepsy: Present and Future in Development of Antiepileptic Drugs
R. Kovacs and U. Heinemann
Affiliation: Institute for Neurophysiology, Charite-Universitatsmedizin Berlin, 13347, Germany.
Keywords: Blood-brain barrier, brain slices, electrical kindling, kainate, multidrug transporter, neuroinflammation, pharmacoresistance,
pilocarpine, slice cultures, temporal lobe epilepsy.
Currently available antiepileptic drugs (AEDs) were developed to suppress seizure activity but less for prevention
of epileptogenesis or for treatment of epileptogenic encephalopathies. Despite considerable efforts towards pharmacological
control of seizures, about 30 % of epileptic patients do not achieve complete seizure control, and these numbers
are even higher in patients suffering from partial seizures - a common form of epilepsy in adults. The mechanisms behind
drug-resistance are far from being understood. Likely several unrelated mechanisms might lead in concert to reduced efficacy
of the AEDs. Consequently, there is a need for predictive biomarkers of susceptibility to pharmacoresistant seizures
and for new therapies interfering with epileptogenesis and preventing development of drug-resistance instead of merely
suppressing seizures. This also necessitates the design of novel in vitro and in vivo epilepsy models that would better
mimic the progressive nature of epilepsy and resemble the state of a chronic epileptic tissue. In this review we discuss current
theories of drug-resistance and give a short summary of the epilepsy models that are frequently used for testing
AEDs. We will also highlight caveats of the different models and consider novel approaches to overcome these difficulties.
Finally we give a short outlook on unconventional therapies interfering with epileptogenesis as well as with drug delivery
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