Role of Lacosamide in Preventing Pentylenetetrazole Kindling-Induced Alterations in the Expression of the Gamma-2 Subunit of the GABAA Receptor in Rats

Author(s): Zsolt Gáll*, Krisztina Kelemen, István Mihály, Pál Salamon, Ildikó Miklóssy, Brigitta Zsigmond, Melinda Kolcsár

Journal Name: Current Molecular Pharmacology

Volume 13 , Issue 3 , 2020

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Abstract:

Background: Epilepsy remains challenging to treat still no etiologic treatment has been identified, however, some antiepileptic drugs (AEDs) are able to modify the pathogenesis of the disease. Lacosamide (LCM) has been shown to possess complex anticonvulsant and neuroprotective actions, being an enhancer of the slow inactivation of voltage-gated sodium channels, and it has the potential to prevent epileptogenesis. Recent evidence has shown that LCM indirectly improves the function of GABAA receptors. Receptors at most GABAergic synapses involve the gamma-2 subunit, which contributes to both phasic and tonic inhibition, and its presence assures benzodiazepine sensitivity. Moreover, mutant gamma-2 subunits were associated with generalized epilepsy syndromes. In animal models, the expression of the gamma-2 subunit of the gamma-aminobutyric acid A receptor (GABAAg2) was shown to be increased in pentylenetetrazole (PTZ)-induced chemical kindling in Wistar rats.

Objective: This study hypothesized that LCM might affect the kindling process by influencing the expression of GABAA receptors in the hippocampus.

Methods: The gene and protein expression levels of the GABAAg2 were studied using RT-qPCR and immunofluorescent staining.

Results: It was found that LCM treatment (10 mg/kg i.p. daily for 57 days) reduced the maximal intensity of the PTZ-induced seizures but did not prevent kindling. On the other hand, LCM treatment reverted the increase of mRNA expression of GABAAg2 in the hippocampus and prevented the decrease of GABAAg2 protein in the hippocampal CA1 region.

Conclusion: LCM could exhibit modulatory effects on the GABAergic system of the hippocampus that may be independent of the anticonvulsant action.

Keywords: Lacosamide, anticonvulsant, PTZ kindling model, epilepsy, GABAA receptor, gamma 2 subunit.

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Article Details

VOLUME: 13
ISSUE: 3
Year: 2020
Published on: 09 July, 2020
Page: [251 - 260]
Pages: 10
DOI: 10.2174/1874467213666200102095023
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