Effect of 1-methyl-1,2,3,4-tetrahydroisoquinoline on the protective action of various antiepileptic drugs in the maximal electroshock-induced seizure model: a type II isobolographic analysis

• Published in: Journal of Neural Transmission 2013-12, Vol.120 (12), p.1651-1663
• Main Authors: Andres-Mach, Marta, Zadrożniak, Anna, Haratym-Maj, Agnieszka, Florek-Luszczki, Magdalena, Raszewski, Grzegorz, Antkiewicz-Michaluk, Lucyna, Luszczki, Jarogniew J.
• Format: Article
• Language: English
• Subjects: Animals; Anticonvulsants - therapeutic use; Antiepileptic agents; Brain - metabolism; Disease Models, Animal; Dopamine Antagonists - therapeutic use; Dose-Response Relationship, Drug; Drug Therapy, Combination; Electroshock - adverse effects; Male; Medicine; Medicine & Public Health; Mice; Muscle Strength - drug effects; Muscle, Skeletal - drug effects; Muscle, Skeletal - pathology; Muscle, Skeletal - physiopathology; Neurology; Neurology and Preclinical Neurological Studies - Original; Neurology and Preclinical Neurological Studies - Original Article; Neurosciences; Psychiatry; Psychomotor Performance - drug effects; Seizures - drug therapy; Seizures - etiology; Seizures - pathology; Tetrahydroisoquinolines - therapeutic use
• ISSN: 0300-9564; 1435-1463
• DOI: 10.1007/s00702-013-1047-4

The aim of this study was to characterize the interaction between 1-methyl-1,2,3,4-tetrahydroisoquinoline (1-MeTHIQ—an endogenous parkinsonism-preventing substance) and various antiepileptic drugs [AEDs: clonazepam (CZP), ethosuximide (ETS), gabapentin (GBP), levetiracetam (LEV), tiagabine (TGB) and vigabatrin (VGB)] in the mouse maximal electroshock (MES)-induced seizure model. Results indicate that 1-MeTHIQ in combination with CZP (at the fixed ratios of 50:1 and 25:1), ETS (1:10) and GBP (1:1, 1:2, 1:5 and 1:10) exerted supra-additive (synergistic) interactions in the mouse MES model. In contrast, 1-MeTHIQ in combination with CZP (200:1 and 100:1), ETS (1:1, 1:2 and 1:5), LEV and VGB (1:1, 1:2, 1:5 and 1:10), and TGB (200:1, 100:1, 50:1 and 25:1) produced additive interaction in the mouse MES model. Total brain AED concentrations were unaffected by 1-MeTHIQ, and inversely, CZP, ETS and GBP had no impact on total brain concentrations of 1-MeTHIQ, indicating pharmacodynamic nature of synergistic interactions between 1-MeTHIQ and the tested AEDs in the mouse MES model. In conclusion, the supra-additive interactions of 1-MeTHIQ with CZP (at the fixed ratios of 50:1 and 25:1), ETS (1:10) and GBP (1:1, 1:2, 1:5 and 1:10) in the mouse MES model appear to be particularly favorable combinations from a clinical viewpoint. The additive combinations of 1-MeTHIQ with CZP (100:1, 50:1), ETS (1:1, 1:2 and 1:5), LEV and VGB (1:1, 1:2, 1:5, and 1:10), and TGB (200:1, 100:1, 50:1 and 25:1) seem to be neutral and worthy of consideration in further clinical practice.