1-Methyl-1,2,3,4-tetrahydroisoquinoline enhances the anticonvulsant action of carbamazepine and valproate in the mouse maximal electroshock seizure model.
1-Methyl-1,2,3,4-tetrahydroisoquinoline (1-MeTHIQ - an endogenous parkinsonism-preventing substance) administered intraperitoneally at a dose of 20 mg/kg considerably elevated the threshold for electroconvulsions in mice from 6.4 to 8.4 mA (P < 0.05). In contrast, the agent administered at 5 and 10 mg/kg had no significant impact on the electroconvulsive threshold in mice. Moreover, 1-MeTHIQ (at a subthreshold dose of 10 mg/kg) potentiated the anticonvulsant action of valproate (VPA) against maximal electroshock (MES)-induced seizures in mice, reducing its median effective dose (ED50) from 232 to 170 mg/kg (P < 0.001). Similarly, 1-MeTHIQ (at 10 mg/kg) enhanced the antielectroshock activity of carbamazepine (CBZ) in mice, decreasing its ED50 from 10.8 to 7.8 mg/kg (P < 0.05). In contrast, 1-MeTHIQ (at 10 mg/kg) did not affect the anticonvulsant action of phenytoin and phenobarbital against MES-induced seizures in mice. The evaluation of acute neurotoxic effects of the studied antiepileptic drugs (AEDs) in combination with 1-MeTHIQ, as regards motor coordination impairment in the chimney test, revealed no significant changes in median toxic doses (TD50) of conventional AEDs after systemic administration of 1-MeTHIQ (up to 10 mg/kg). Pharmacokinetic characterization of interactions between 1-MeTHIQ (10 mg/kg) and VPA (170 mg/kg) or CBZ (7.8 mg/kg) revealed no significant changes in total brain concentrations of CBZ and VPA, indicating that the observed enhancement of antiseizure effects of CBZ and VPA by 1-MeTHIQ was pharmacodynamic in nature. Based on our preclinical study, it may be concluded that 1-MeTHIQ exerts the anticonvulsant effects increasing the threshold for electroconvulsions and potentiating the antiseizure action of CBZ and VPA against maximal electroshock. The antiseizure properties of 1-MeTHIQ (an endogenous parkinsonism-preventing substance) and its exact physiological role in the brain need extensive examination in further neuropharmacological studies.
Luszczki
Jarogniew J
JJ
Department of Pathophysiology, Medical University of Lublin, Jaczewskiego 8, 20-090 Lublin, Poland. jluszczki@yahoo.com
Antkiewicz-Michaluk
Lucyna
L
Czuczwar
Stanislaw J
SJ
D000818:Animals; D000927:Anticonvulsants / Q000493:pharmacokinetics / Q000494:pharmacology*; D002220:Carbamazepine / Q000493:pharmacokinetics / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000493:pharmacokinetics / Q000494:pharmacology*; D004409:Dyskinesia, Drug-Induced / Q000517:prevention & control / Q000523:psychology; D004597:Electroshock; D008297:Male; D051379:Mice; D020258:Neurotoxicity Syndromes / Q000523:psychology; D010672:Phenytoin / Q000493:pharmacokinetics / Q000494:pharmacology; D044005:Tetrahydroisoquinolines / Q000493:pharmacokinetics / Q000494:pharmacology*; D014635:Valproic Acid / Q000493:pharmacokinetics / Q000494:pharmacology*
D000927:Anticonvulsants; D018492:Dopamine Antagonists; D044005:Tetrahydroisoquinolines; D002220:Carbamazepine; C050386:1-methyl-1,2,3,4-tetrahydroisoquinoline; D014635:Valproic Acid; D010672:Phenytoin