Ahmad, Shagufta; (1996) Investigation of the in vivo pharmacological properties of lamotrigine (lamictal™) in epileptic and non-epileptic rats. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

There is compelling evidence to suggest that epileptic seizures may be associated with neurochemical imbalances, leading to long-term neuronal excitability and the generation of epileptiform activity. Consequently, agents capable of stabilising hyperexcitable neuronal membranes may be effective for the management of epilepsy. Lamotrigine (Lamictal™; LTG) is a novel anticonvulsant, considered to act as a use- and voltage-dependent inhibitor of type Ila Na+ channels, thereby stabilising excitable neuronal membranes, and reducing pathologically-altered neurotransmission. In view of these findings, intracerebral microdialysis has been used to show LTG to specifically and significantly inhibit the Na+-dependent (veratridine-evoked), rather than basal- or Ca2+-dependent (elevated K+-evoked), efflux of amino acids, predominantly glutamate, from the ventral hippocampus of non-epileptic rats, both acutely and chronically (up to 21 days), at therapeutically relevant doses. However, unlike LTG, the well-established Na+ channel modulators phenytoin and carbamazepine. agents with which LTG has been likened and shown to resemble in experimental seizure models, failed to significantly alter veratridine-evoked glutamate efflux, exhibiting a somewhat different neurochemical profile to that of LTG. Additionally, a number of clinical studies have shown LTG to be effective at ameliorating non-convulsive absence and partial seizures, proving to be of particular benefit in combination with sodium valproate - possibly due to manipulation of opposite sides of the neurochemical balance, with sodium valproate enhancing GABAergic inhibition and LTG inhibiting excitation. Sub-chronic (5 days) LTG- administration failed to suppress electroencephalographic spike-and-wave discharges from the ventrolateral thalamus of Genetic Absence Epilepsy Rats from Strasbourg (an experimental correlate of the human condition). In contrast, sodium valproate potently attenuated spike-and-wave discharges, but neither an additional beneficial effect nor complementary neurochemical effects, were observed in combination with LTG.

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