Enhanced glutamatergic transmission reduces the anticonvulsant potential of lamotrigine but not of felbamate against tonic-clonic seizures.
The efficacy of lamotrigine and felbamate against maximal electroshock (MES)-induced seizures was assessed under conditions mimicking the pharmacoresistance associated with an increased excitatory neurotransmission. N-methyl-D-aspartate (NMDA), but not kainate applied at subconvulsive dose, reduced the activity of lamotrigine against MES-induced seizures increasing its ED50 value from 4.3 (3.2-5.6) to 6.1 (5.2-7.2) mg/kg (p < 0.001). This effect was reversed by co-application of an NMDAreceptor antagonist D-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid (CGP 40116) at 0.1 mg/kg [4.5 (3.7-5.6) vs. 6.1 (5.2-7.2) mg/kg; p < 0.001]. The anticonvulsive action of felbamate was altered by neither NMDAnor kainate. In conclusion, the data presented here indicate that felbamate, but not lamotrigine, effectively prevents generalized tonic-clonic seizures, also when NMDA-mediated neurotransmission is enhanced. The impaired antiepileptic potential of lamotrigine might be restored in such scenario by the co-administration of a very low dose of NMDA receptor antagonist.
Tomczyk
Tomasz
T
Department of Pharmacology and Clinical Pharmacology, Skubiszewski Medical University of Lublin, Jaczewskiego 8, PL 20-090 Lublin, Poland.
Haberek
Grzegorz
G
Zuchora
Beata
B
Jarosławska-Zych
Agata
A
Kowalczyk
Mieczysław S
MS
Wielosz
Marian
M
Urbańska
Ewa M
EM
D015763:2-Amino-5-phosphonovalerate / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004597:Electroshock / Q000379:methods; D000078328:Felbamate; D018698:Glutamic Acid / Q000502:physiology*; D007274:Injections, Intraperitoneal; D007608:Kainic Acid / Q000008:administration & dosage / Q000494:pharmacology; D000077213:Lamotrigine; D008297:Male; D051379:Mice; D016202:N-Methylaspartate / Q000008:administration & dosage / Q000494:pharmacology; D048448:Phenylcarbamates / Q000008:administration & dosage / Q000494:pharmacology*; D011409:Propylene Glycols / Q000008:administration & dosage / Q000494:pharmacology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D012640:Seizures / Q000503:physiopathology / Q000517:prevention & control*; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology; D014227:Triazines / Q000008:administration & dosage / Q000494:pharmacology*
D000927:Anticonvulsants; D048448:Phenylcarbamates; D011409:Propylene Glycols; D016194:Receptors, N-Methyl-D-Aspartate; D014227:Triazines; C064539:2-amino-4-methyl-5-phosphono-3-pentenoic acid; D018698:Glutamic Acid; D016202:N-Methylaspartate; D015763:2-Amino-5-phosphonovalerate; D007608:Kainic Acid; D000077213:Lamotrigine; D000078328:Felbamate