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

Abstract

<jats:sec> <jats:title>Background:</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Objective:</jats:title> <jats:p>This study hypothesized that LCM might affect the kindling process by influencing the expression of GABAA receptors in the hippocampus.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods:</jats:title> <jats:p>The gene and protein expression levels of the GABAAg2 were studied using RT-qPCR and immunofluorescent staining.</jats:p> </jats:sec> <jats:sec> <jats:title>Results:</jats:title> <jats:p> 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.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusion:</jats:title> <jats:p> LCM could exhibit modulatory effects on the GABAergic system of the hippocampus that may be independent of the anticonvulsant action.</jats:p> </jats:sec>

Protective effect of lacosamide and topiramate treatment against Pentylenetetrazole-induced kindling and associated cognitive dysfunction in rats

“…Our results regarding lacosamide are in agreement with previous researchers who have found that the drug is effective in the suppression of amygdala kindling at doses 10 and 30 mg/kg while the lowest dose of 3 mg/kg was ineffective (Brandt et al 2006). In addition, there is data that lacosamide reduces the maximal intensity of PTZ-induced seizures and produces modulatory effects on the GABAergyc system (Gáll et al 2020). The results from the current study complete our previous result where we found that lacosamide at a dose of 30 mg/kg has a pronounced antiepileptogenic effect in a model of temporal lobe epilepsy induced by a single injection of pilocarpine (Shishmanova-Doseva et al 2021).…”

Lacosamide improves biochemical, genotoxic, and mitochondrial parameters after PTZ‐kindling model in mice

“…Similar behavior was observed by Gáll et al [34] in which treatment with LCM (10 mg/kg, intraperitoneally) daily for 57 days reduced the maximum intensity of the seizures induced by PTZ, but was unable to prevent kindling. Interestingly, chronic administration of a new hybrid compound (designated C11) synthesized from the drugs lacosamide, ethosuximide (ETS), and levetiracetam (LEV) suppressed the progression of seizures in the model induced by repeated administrations of PTZ in mice [35].…”

Anticonvulsant Action and Long-Term Effects of Chronic Cannabidiol Treatment in the Rat Pentylenetetrazole-Kindling Model of Epilepsy

“…Despite lacking spontaneous seizures, a seizure threshold decrease in kindled animals mimics epilepsy phenotypes through an imbalance between the excitatory and inhibitory neurotransmission systems. [ 31 , 32 , 33 ]. In addition, the PTZ-kindling model has been shown to reflect the cognitive impairments [ 34 , 35 ] and the characteristic cellular changes related to epilepsy in rats, such as astrogliosis [ 18 ] and microglia activation [ 36 ].…”