Tiagabine

Tiagabine (NO050328; NO328; TGB) is an orally active, highly selective, and reversible GAT-1 inhibitor and anticonvulsant that crosses the blood-brain barrier. By blocking the reuptake of GABA in neurons and glial cells, tiagabine increases extracellular GABA levels to enhance inhibitory signal transduction, thereby exerting multiple activities such as anticonvulsant, neuroprotective, and antioxidant effects. Tiagabine exhibits linear pharmacokinetic properties. Although it is metabolized by CYP3A and has a high protein binding rate, it carries a low risk of cognitive impairment. Tiagabine is widely used in research on related diseases including epilepsy (including refractory partial seizures), alcohol withdrawal symptoms, and Huntington's disease^{[1][2][3][4][5][6]}. In Vitro:Tiagabine (0.1-5 μM; 4 days) protects Tet-off PC12 cells expressing mutant huntingtin against toxicity, with significant effects detected at concentrations of 0.5, 2, and 5 μM after 4 days of treatment^[1].
Tiagabine potently and selectively inhibits GABA uptake in glial, neuronal, and synaptosomal preparations, with IC₅₀ values of 0.18 μmol/L, 0.45 μmol/L, and 0.07 μmol/L, respectively^[3].
Tiagabine (2-100 μM; 5-15 min) induces long-lasting, repetitive slow depolarizations in cortical wedges from 20-30 day-old DBA/2 mice, with consistent amplitude and frequency across tested concentrations of 2, 5, 50, and 100 μM following 15-min perfusion, and following shorter 5-10 min perfusions of 50 μM^[4].
Tiagabine (50 μM; 15 min)-induced depolarizations in cortical wedges from 20-30 day-old DBA/2 mice are Ca²⁺-dependent, mediated via GABA_A receptors, require voltage-dependent sodium channel activity, are unaffected by NMDA receptor blockade, are partially inhibited by AMPA receptor blockade, are abolished by Dextromethorphan, and are potentiated by potassium channel blockade^[4].
Tiagabine (50 μM; 15 min) induces depolarizations in cortical wedges from 50 day-old DBAr2 mice and BALB/c mice, similar to responses in 20-30 day-old DBAr2 mice^[4]. In Vivo:Tiagabine (2-5 mg/kg; i.p., daily administration, lifelong treatment) extends the survival of male N171-82Q transgenic Huntington's disease mice (up to 33.4 days at the 5 mg/kg dose), improves their motor function, and alleviates brain atrophy and neurodegeneration^[1].
Tiagabine (5 mg/kg; i.p.; daily; lifelong administration) extends the survival of male and female R6/2 transgenic Huntington's disease mice (17.8 days of extension at the dose of 5 mg/kg), improves their motor function, and alleviates brain atrophy^[1].
Tiagabine (0.4 mg/kg; i.p.; single administration; 30 min prior to seizure testing) exerts a protective effect against audiogenic tonic seizures in male DBA/2 mice, with an ED₅₀ of 0.4 mg/kg^[2].
Tiagabine (1.2-1.3 mg/kg; i.p.; single administration; 30 min prior to seizure tests) exerts a protective effect against PTZ-induced tonic convulsions in male NMRI mice, with an ED₅₀ of 1.2 mg/kg, while providing approximately 50% partial protection against clonic convulsions^[2].
Tiagabine (15-30 mg/kg; p.o.; twice daily; for consecutive 21 days) induces tolerance to cognitive effects in mice, but does not induce tolerance to its anticonvulsant effects in DMCM-induced epileptic mice^[3].
Tiagabine (9 mg/kg; subcutaneous injection; once daily for 8 consecutive days; single injection 30 min prior to locomotor activity test) initially reduces short-term spontaneous ethanol intake in ad libitum-fed C57BL/6 mice, but tolerance develops rapidly, resulting in ethanol intake exceeding pre-treatment levels on days 7-8^[5].