Lamotrigine does not protect from 3-mercaptopropionic acid induce- seizures

GIRARDI E, HÖCHT C, LAZAROWSKI A, OPEZZO J, TAIRA C,.

Huerta Grande, Córdoba

Congreso; Primera Reunión Conjunta de Neurociencia (IRCN). Sociedad Argentina de Investigación en Neurociencia (SAN) y Taller Argentino de Neurociencia; 2009

SAN

In previous works we have observed that repetitive administration of the convulsant drug 3-mercaptopropionic acid (MP) enhances brain MDR-1 gene expression and develops refractory phenotype to phenytoin and phenobarbital treatment. In the present work we examine the effect of lamotrigine (LTG) in this experimental model of epilepsy. Lamotrigine is a broad spectrum antiepileptic drug in partial and generalized syndromes. Methods: Wistar rats were divided in 4 groups. Groups A received a single dose i.p. of MP (40-45mg/kg) daily injected during 10days. During the same period, group B, was daily treated with LTG (20mg/kg), 30 minutes previous to MP administration, group C received nimodipine (2mg/kg) 1 hour previous to  MP and as control (groupD) rats were injected with saline solution (V). Hippocampal and plasma pharmacokinetics of LTG were evaluated in the different groups after single iv administration of 10 mg/kg by using central microdialysis and traditional blood sampling. Results: Pharmacodynamics studies showed that LTG and Nimo did not protect from MP induces seizures. In coincidence with pharmacodynamic assays, no differences were found in LTG hippocampal and plasma levels comparing all groups. In rats pretreated with V, hippocampal LTG levels were in MP rats (maximal concentration (Cmax):1.36±0.42 µg/ml) compared to C animals (Cmax: 1.80±0.19 µg/ml µg/ml). NIMO pretreatment did not modify central kinetics of LTG in C and MP animals (C rats: Cmax: 1.68±0.50 µg/ml; MP rats: Cmax: 1.58±0.41 µg/ml).    Our results indicate that LTG does not protect from MP seizures. Hippocampal LTG levels were similar in MP rats than in controls and in the presence of the Pgp inhibitor NIMO, suggesting that LTG is not a good substrate of P-gp. Therefore, LTG is not an adecuate antiepileptic drug to prevent daily seizures or after repetititive MP administration.