Generic placeholder image

Current Molecular Pharmacology


ISSN (Print): 1874-4672
ISSN (Online): 1874-4702

Research Article

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 and Melinda Kolcsár

Volume 13, Issue 3, 2020

Page: [251 - 260] Pages: 10

DOI: 10.2174/1874467213666200102095023

Price: $65


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.

Graphical Abstract
Löscher, W.; Schmidt, D. Modern antiepileptic drug development has failed to deliver: ways out of the current dilemma. Epilepsia, 2011, 52(4), 657-678.
[] [PMID: 21426333]
Goldberg, E.M.; Coulter, D.A. Mechanisms of epileptogenesis: a convergence on neural circuit dysfunction. Nat. Rev. Neurosci., 2013, 14(5), 337-349.
[] [PMID: 23595016]
Pitkänen, A. Therapeutic approaches to epileptogenesis--hope on the horizon. Epilepsia, 2010, 51(Suppl. 3), 2-17.
[] [PMID: 20618393]
Löscher, W. Strategies for antiepileptogenesis: Antiepileptic drugs versus novel approaches evaluated in post-status epilepticus models of temporal lobe epilepsy. Antiepileptic Drugs versus Novel Approaches Evaluated in Post-Status Epilepticus Models of Temporal Lobe Epilepsy, 2012, 51
[] [PMID: 22787664]
Rogawski, M.A.; Tofighy, A.; White, H.S.; Matagne, A.; Wolff, C. Current understanding of the mechanism of action of the antiepileptic drug lacosamide. Epilepsy Res., 2015, 110, 189-205.
[] [PMID: 25616473]
Brandt, C.; Heile, A.; Potschka, H.; Stoehr, T.; Löscher, W. Effects of the novel antiepileptic drug lacosamide on the development of amygdala kindling in rats. Epilepsia, 2006, 47(11), 1803-1809.
[] [PMID: 17116018]
Stöhr, T.; Kupferberg, H.J.; Stables, J.P.; Choi, D.; Harris, R.H.; Kohn, H.; Walton, N.; White, H.S. Lacosamide, a novel anti-convulsant drug, shows efficacy with a wide safety margin in rodent models for epilepsy. Epilepsy Res., 2007, 74(2-3), 147-154.
[] [PMID: 17433624]
Licko, T.; Seeger, N.; Zellinger, C.; Russmann, V.; Matagne, A.; Potschka, H. Lacosamide treatment following status epilepticus attenuates neuronal cell loss and alterations in hippocampal neurogenesis in a rat electrical status epilepticus model. Epilepsia, 2013, 54(7), 1176-1185.
[] [PMID: 23614482]
Behr, C.; Lévesque, M.; Ragsdale, D.; Avoli, M. Lacosamide modulates interictal spiking and high-frequency oscillations in a model of mesial temporal lobe epilepsy. Epilepsy Res., 2015, 115, 8-16.
[] [PMID: 26220372]
Wilson, S.M.; Khanna, R. Specific binding of lacosamide to collapsin response mediator protein 2 (CRMP2) and direct impairment of its canonical function: implications for the therapeutic potential of lacosamide. Mol. Neurobiol., 2015, 51(2), 599-609.
[] [PMID: 24944082]
Moutal, A.; François-Moutal, L.; Perez-Miller, S.; Cottier, K.; Chew, L.A.; Yeon, S.K.; Dai, J.; Park, K.D.; Khanna, M.; Khanna, R. (S)-Lacosamide Binding to Collapsin Response Mediator Protein 2 (CRMP2) Regulates CaV2.2 Activity by Subverting Its Phosphorylation by Cdk5. Mol. Neurobiol., 2016, 53(3), 1959-1976.
[] [PMID: 25846820]
Bang, S.R.; Ambavade, S.D.; Jagdale, P.G.; Adkar, P.P.; Waghmare, A.B.; Ambavade, P.D. Lacosamide reduces HDAC levels in the brain and improves memory: Potential for treatment of Alzheimer’s disease. Pharmacol. Biochem. Behav., 2015, 134, 65-69.
[] [PMID: 25931268]
Wilson, S.M.; Xiong, W.; Wang, Y.; Ping, X.; Head, J.D.; Brittain, J.M.; Gagare, P.D.; Ramachandran, P.V.; Jin, X.; Khanna, R. Prevention of posttraumatic axon sprouting by blocking collapsin response mediator protein 2-mediated neurite outgrowth and tubulin polymerization. Neuroscience, 2012, 210, 451-466.
[] [PMID: 22433297]
Reddy, S.D.; Clossen, B.L.; Reddy, D.S. Epigenetic Histone Deacetylation Inhibition Prevents the Development and Persistence of Temporal Lobe Epilepsy. J. Pharmacol. Exp. Ther., 2018, 364(1), 97-109.
[] [PMID: 29101217]
Galanopoulou, A.S. GABA(A) receptors in normal development and seizures: friends or foes? Curr. Neuropharmacol., 2008, 6(1), 1-20.
[] [PMID: 19305785]
Löscher, W. Critical review of current animal models of seizures and epilepsy used in the discovery and development of new antiepileptic drugs. Seizure, 2011, 20(5), 359-368.
[] [PMID: 21292505]
Corda, M.G.; Orlandi, M.; Lecca, D.; Giorgi, O. Decrease in GABAergic function induced by pentylenetetrazol kindling in rats: antagonism by MK-801. J. Pharmacol. Exp. Ther., 1992, 262(2), 792-800.
[PMID: 1323663]
Samokhina, E.; Samokhin, A. Neuropathological profile of the pentylenetetrazol (PTZ) kindling model. Int. J. Neurosci., 2018, 128(11), 1086-1096.
[] [PMID: 29792126]
Davoudi, M.; Shojaei, A.; Palizvan, M.R.; Javan, M.; Mirnajafi-Zadeh, J. Comparison between standard protocol and a novel window protocol for induction of pentylenetetrazol kindled seizures in the rat. Epilepsy Res., 2013, 106(1-2), 54-63.
[] [PMID: 23619005]
Gáll, Z.; Koncz, S.; Gáll, O.; Kolcsár, M. Lacosamide Reduces Seizure Severity but Increases Seizure Frequency in PTZ-Kindled Rats. Acta Med. Marisiensis, 2017, 63(4), 173-177.
Scharfman, H.E.; Goodman, J.H.; Rigoulot, M-A.; Berger, R.E.; Walling, S.G.; Mercurio, T.C.; Stormes, K.; Maclusky, N.J. Seizure susceptibility in intact and ovariectomized female rats treated with the convulsant pilocarpine. Exp. Neurol., 2005, 196(1), 73-86.
[] [PMID: 16084511]
Wasterlain, C.G.C.; Stöhr, T.; Matagne, A. The acute and chronic effects of the novel anticonvulsant lacosamide in an experimental model of status epilepticus. Epilepsy Res., 2011, 94(1-2), 10-17.
[] [PMID: 21277168]
Bonefeld, B.E.; Elfving, B.; Wegener, G. Reference genes for normalization: a study of rat brain tissue. Synapse, 2008, 62(4), 302-309.
[] [PMID: 18241047]
Ruffolo, G.; Di Bonaventura, C.; Cifelli, P.; Roseti, C.; Fattouch, J.; Morano, A.; Limatola, C.; Aronica, E.; Palma, E.; Giallonardo, A.T. A novel action of lacosamide on GABAA currents sets the ground for a synergic interaction with levetiracetam in treatment of epilepsy. Neurobiol. Dis., 2018, 115(115), 59-68.
[] [PMID: 29621596]
Pavlova, T.V.; Yakovlev, A.A.; Stepanichev, M.Y.; Gulyaeva, N.V. Pentylenetetrazol kindling in rats: Is neurodegeneration associated with manifestations of convulsive activity? Neurosci. Behav. Physiol., 2006, 36(7), 741-748.
[] [PMID: 16841155]
Morimoto, K.; Fahnestock, M.; Racine, R.J. Kindling and status epilepticus models of epilepsy: rewiring the brain. Prog. Neurobiol., 2004, 73(1), 1-60.
[] [PMID: 15193778]
Maglóczky, Z.; Wittner, L.; Borhegyi, Z.; Halász, P.; Vajda, J.; Czirják, S.; Freund, T.F. Changes in the distribution and connectivity of interneurons in the epileptic human dentate gyrus. Neuroscience, 2000, 96(1), 7-25.
[] [PMID: 10683405]
Maglóczky, Z.; Freund, T. F. Impaired and Repaired Inhibitory Circuits in the Epileptic Human Hippocampus. Trends Neurosci,, 2005, 28(((6 SPEC. ISS.))), 334-340.
Somogyi, P.; Klausberger, T. Defined types of cortical interneurone structure space and spike timing in the hippocampus. J. Physiol., 2005, 562(Pt 1), 9-26.
[] [PMID: 15539390]
Szilágyi, T.; Orbán-Kis, K.; Horváth, E.; Pap, Z.; Pávai, Z. Laboratory Techniques in Multidisciplinary Research of Epilepsy Tehnici de Laborator În Cercetarea Multidisciplinară a Epilepsiei. Rev. Rom. Med. Lab., 2009, 14(1), 19-24.
Olsen, R.W.; Sieghart, W. GABA A receptors: subtypes provide diversity of function and pharmacology. Neuropharmacology, 2009, 56(1), 141-148.
[] [PMID: 18760291]
Zhu, L-J.; Chen, Z.; Zhang, L-S.; Xu, S-J.; Xu, A-J.; Luo, J-H. Spatiotemporal changes of the N-methyl-D-aspartate receptor subunit levels in rats with pentylenetetrazole-induced seizures. Neurosci. Lett., 2004, 356(1), 53-56.
[] [PMID: 14746900]
Vogel, C.; Marcotte, E.M. Insights into the regulation of protein abundance from proteomic and transcriptomic analyses. Nat. Rev. Genet., 2012, 13(4), 227-232.
[] [PMID: 22411467]
Delcuve, G.P.; Khan, D.H.; Davie, J.R. Roles of histone deacetylases in epigenetic regulation: emerging paradigms from studies with inhibitors. Clin. Epigenetics, 2012, 4(1), 5.
[] [PMID: 22414492]
Bekdash, R.A.; Harrison, N.L. Downregulation of Gabra4 expression during alcohol withdrawal is mediated by specific microRNAs in cultured mouse cortical neurons. Brain Behav., 2015, 5(8)e00355
[] [PMID: 26357588]
Carlson, S.L.; O’Buckley, T.K.; Thomas, R.; Thiele, T.E.; Morrow, A.L. Altered GABAA receptor expression and seizure threshold following acute ethanol challenge in mice lacking the RIIβ subunit of PKA. Neurochem. Res., 2014, 39(6), 1079-1087.
[] [PMID: 24104609]
Palma, E.; Ragozzino, D.; Di Angelantonio, S.; Mascia, A.; Maiolino, F.; Manfredi, M.; Cantore, G.; Esposito, V.; Di Gennaro, G.; Quarato, P.; Miledi, R.; Eusebi, F. The antiepileptic drug levetiracetam stabilizes the human epileptic GABAA receptors upon repetitive activation. Epilepsia, 2007, 48(10), 1842-1849.
[] [PMID: 17521347]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy