Molecular and cellular mechanisms of pharmacoresistance in epilepsy

Abstract

Epilepsy is a common and devastating neurological disorder. In many patients with epilepsy, seizures are well-controlled with currently available anti-epileptic drugs (AEDs), but a substantial (approximately 30%) proportion of patients continue to have seizures despite carefully optimized drug treatment. Two concepts have been put forward to explain the development of pharmacoresistance. The transporter hypothesis contends that the expression or function of multidrug transporters in the brain is augmented, leading to impaired access of AEDs to CNS targets. The target hypothesis holds that epilepsy-related changes in the properties of the drug targets themselves may result in reduced drug sensitivity. Recent studies have started to dissect the molecular underpinnings of both transporter- and target-mediated mechanisms of pharmacoresistance in human and experimental epilepsy. An emerging understanding of these underlying molecular and cellular mechanisms is likely to provide important impetus for the development of new pharmacological treatment strategies.

Cross-species pharmacological characterization of the allylglycine seizure model in mice and larval zebrafish

“…1 Topiramate showed partial protection in the zebrafish AG model but not in mice. 2 Gabapentin showed activity in mice but not in the zebrafish PTZ test. 3 Levetiracetam decreased the number of SWDs induced by PTZ.…”

“…Diverse potential mechanistic causes have been proposed [1][2][3][4], and new experimental approaches have been established in order to discover therapies providing better efficacy [5,6]. Nevertheless, a clear medical need remains in order to achieve complete seizure control in a substantial population of patients with treatmentresistant epilepsy [7].…”

Lentiviral RNAi-induced downregulation of adenosine kinase in human mesenchymal stem cell grafts: A novel perspective for seizure control

“…Epilepsy affects about 1% of the population; currently available antiepileptic drugs (AEDs) fail to prevent seizures in about 35 percent of patients with partial epilepsy and new treatment strategies are urgently needed (Dichter, 2007;Kwan and Brodie, 2006;Loscher and Schmidt, 2004;Remy and Beck, 2006). In addition, pronounced side effects may compromise the most favorable use of AEDs (Sabers and Gram, 2000).…”

Electroresponsive Nanoparticles Improve Antiseizure Effect of Phenytoin in Generalized Tonic-Clonic Seizures

“…Despite advances in pharmacotherapy for epilepsy, > 30 % of patients still have incompletely controlled seizures [36]. One of the main reasons is that the expression or function of multidrug transporters in the brain is augmented in epilepsy, leading to impaired access to the targets of CNS for AEDs [37,38]. The relatively narrow therapeutic window of AEDs results in intolerable side effects when one tries to increase dosages.…”