Choosing the Correct Antiepileptic Drugs: From Animal Studies to the Clinic

Abstract

Epilepsy is a chronic condition caused by an imbalance of normal excitatory and inhibitory forces in the brain. Antiepileptic drug therapy has been directed primarily toward reducing excitability through blockage of voltage-gated Na + or Ca 2+ channels, or increasing inhibition through enhancement of γ-aminobutyric acid currents. Prior to clinical studies, putative antiepileptic drugs are screened in animals, usually rodents. Maximal electrical shock, pentylenetetrazol, and kindling are typically used as non-mechanistic screens for antiseizure properties and the rotorod test for assessing acute toxicity. While antiseizure drug screening has been successful in bringing drugs to the market and improving our understanding of the pathophysiology of seizures, it should be emphasized that the vast majority of drug screening occurs in mature male rodents and involves models of seizures, not epilepsy. Effective drugs in acute seizures may not be effective in chronic models of epilepsy. Seizure type, clinical and electroencephalographic phenotype, syndrome, and etiology are often quite different in children with epilepsy than adults. Despite these age-related unique features, drugs used in children are generally the same as used in adults. As awareness of the unique features of seizures during development increases, it is anticipated that more drug screening in the immature animal will occur.

Validation of the Zebrafish Pentylenetetrazol Seizure Model: Locomotor versus Electrographic Responses to Antiepileptic Drugs

“…DZP, ETS, VPA and TGB counteracted PTZ-evoked electrographic seizures in both rodents [4], [16]–[18] and zebrafish (our data), while CBZ, LTG, PHT, and TPR were inactive in both species [4,15,16,18,19, and our data]. DZP, ETS, and VPA also inhibited convulsions in the locomotor tracking assay, while TGB showed no activity.…”

Anticonvulsant profile of 2-ethylthio-7-methyl-4-(4-methylphenyl)pyrazolo[1,5-a][1,3,5]triazine

“…This presumption was confirmed in the in vitro test with tritiated flunitrazepam ( 3 H-FNZ). Interactions at voltage dependent sodium channels are frequently observed with drugs that are effective in the MES model (Holmes and Zhao, 2008). Such is the case with anticonvulsants like lamotrigine and zonizamide (Vohora et al, 2010), which, in addition, possess MAO-B inhibitory properties.…”

Antidepressant-like profile and MAO-A inhibitory activity of 4-propyl-2H-benzo[h]-chromen-2-one

“…Indeed, sodium channel antagonists, including carbamazepine and phenytoin, protect against tonic clonic seizures induced by electroshock (Holmes and Zhao 2008) and antagonists of t-type calcium channels, including ethosuximide and valproate, protect against seizures induced by PTZ (Kupferberg and Schmutz 1997). Furthermore, GABA-A receptor agonists such as barbiturates and benzodiazepines give positive results in the electroshock, pentylenetetrazole, light-dark box and pentobarbitone sleeping time tests (Lapa et al 2002).…”