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

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.

• Authors: Mariusz J Świąder, Katarzyna Świąder, Izabela Zakrocka, Maciej Krzyżanowski, Andrzej Wróbel, Jarogniew J Łuszczki, Stanisław J Czuczwar
• Journal: Pharmacological reports : PR (Pharmacol Rep) Vol. 72 Issue 2 Pg. 322-330 (Apr 2020) ISSN: 2299-5684 [Electronic] Switzerland
• PMID: 32048251 (Publication Type: Journal Article)

Chemical References

• Anticonvulsants
• gamma-Aminobutyric Acid
• Clonazepam
• Ethosuximide
• Valproic Acid
• 4-Aminobutyrate Transaminase
• Vigabatrin
• Pentylenetetrazole

Topics

• 4-Aminobutyrate Transaminase (antagonists & inhibitors)
• Animals
• Anticonvulsants (pharmacology)
• Brain (drug effects, metabolism)
• Clonazepam (pharmacology)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Drug Therapy, Combination
• Ethosuximide (pharmacology)
• Mice
• Pentylenetetrazole (pharmacology)
• Seizures (drug therapy, metabolism)
• Time Factors
• Valproic Acid (pharmacology)
• Vigabatrin (administration & dosage, pharmacology)
• gamma-Aminobutyric Acid (metabolism)