Long-term vigabatrin treatment modifies pentylenetetrazole-induced seizures in mice: focused on GABA brain concentration

• DOI: 10.1007/s43440-019-00037-6
• Publication Date: 2020-03-03T16:47:20Z
• Authors: Mariusz J. Świąder; Katarzyna Świąder; Izabela Zakrocka; Maciej Krzyżanowski; Andrzej Wróbel; Jarogniew J. Łusz...; Stanisław J. Czuc...
• Keywords: Time Factors; Dose-Response Relationship, Drug; Valproic Acid; Brain; Clonazepam; Vigabatrin; 3. Good health; Disease Models, Animal; Mice; 03 medical and health sciences; 0302 clinical medicine; Seizures; 4-Aminobutyrate Transaminase; Animals; Ethosuximide; Pentylenetetrazole; Anticonvulsants; Drug Therapy, Combination; gamma-Aminobutyric Acid

Abstract Background The goal of our study was to examine the long-term effect of vigabatrin (VGB), a γ-aminobutyric acid aminotransferase (GABA-AT) inhibitor on clonazepam (CLO), ethosuximide (ETX) and valproate (VPA) anticonvulsive activity against pentylenetetrazole (PTZ)-induced seizures in mice.

Methods VGB was administered for 3 and 7 days. Convulsions were evoked by PTZ at its CD97 (99 mg/kg). The influence of CLO, ETX and VPA alone or in combination with VGB on motor performance and long-term memory was analyzed. γ-aminobutyric acid (GABA) concentration in mice brain and plasma as well as glutamate decarboxylase (GAD) activity was measured.

Results After 3 days of treatment, VGB in doses up to 500 mg/kg increased PTZ-induced seizure threshold, whereas after 7 days VGB (at the dose of 125 mg/kg) inhibited clonic seizures in experimental mice. 7 days of VGB administration did not change the protective effect of CLO, ETX and VPA against PTZ-induced seizures. 7 days of VGB treatment at a subthreshold dose of 75 mg/kg decreased TD50 of ETX and CLO in the chimney test, but did not affect TD50 value for VPA. 7 days of VGB administration in combination with AEDs did not affect long-term memory in mice. VGB after 3 days or 7 days of administration increased brain GABA concentration. GAD activity was decreased after 3 and 7 days of VGB administration.

Conclusions The presented results confirm anticonvulsive activity of VGB through GABA metabolism alteration and suggest care when combining VGB with ETX or CLO in the therapy.