Cognitive impairment is considered the most common comorbidity in epilepsy. The aim of the present study was to explore the effects of long-term treatment with lacosamide and topiramate on epileptogenesis and related cognitive dysfunction in an experimental model of pentylenetetrazole (PTZ)-induced kindling. The latter was induced by the repeated administration of subconvulsive dose of PTZ (40 mg/kg, s.c.) on every alternate day for 8–9 weeks. Both drugs were applied daily in a dose of 10 mg/kg p.o. 30 min before PTZ injection. To assess behavioral comorbidities all rats underwent one active and one passive avoidance tests. The results show that lacosamide significantly suppressed the progression of kindling, while the effect of topiramate was not so pronounced on seizure development. Long-term treatment with both antiepileptic drugs managed to ameliorate the kindling-associated impairment of learning and memory. Lacosamide and topiramate improved active and passive learning abilities and facilitated the formation of short- and long-term memory traces. Both drugs failed to prevent the hyperactivity associated with epilepsy.

lacosamide, topiramate, kindling, seizures, cognition

Epilepsy is a chronic neurological disorder characterized by the presence of recurrent unprovoked seizures due to an imbalance between cerebral excitatory and inhibitory pathways. It is one of the most common neurological conditions affecting more than 50 million people of all ages worldwide (Abdullahi and Adamu 2017). Epileptogenesis is the process by which parts of a normal healthy brain are converted into hyperexcitant ones leading to the occurrence of recurring epileptiform events and the appearance of the first spontaneous seizure (Pitkänen et al. 2015). This process may be triggered by genetic or different acquired factors. The latter include ischemic stroke, traumatic brain injury, brain tumors or infections, status epilepticus or febrile seizures etc. (Löscher and Brandt 2010). Moreover, epileptogenesis may continue long after the diagnosis of epilepsy and has an impact on seizure severity and frequency (Pitkänen et al. 2015). The most susceptible brain structures to the epileptogenic process are the hippocampus, piriform cortex, and amygdala which are of a great importance for cognitive functions and mood behavior (Aroniadou-Anderjaska et al. 2008).

Different animal models are used to evaluate the epileptogenic process. All of them are associated with synaptic reorganization, astrogliosis, neurogenesis, and neuronal loss (Gupta et al. 2003). One of the models widely used to evaluate epileptogenesis and related mood and cognitive disturbances is the kindling model (Morimoto et al. 2004). The term “kindling” refers to a process in which the periodic application of an initially sub effective dose of a chemical compound or an electrical stimulus induces progressive intensification of brain excitability leading to a seizure disorder. A widely used chemoconvulsant agent to induce kindling is pentylenetetrazole (PTZ) which leads to significant neuronal loss in the CA1 and CA3 hippocampal subfields (Löscher 2011).

A large number of patients with epilepsy suffer from cognitive dysfunction and behavioural alterations such as depression, anxiety and aggressive behaviour which could be associated with morphological and functional alterations in temporal lobe structures (Marcangelo and Ovsiew 2007). Cognitive complications are very heterogeneous and affect different abilities such as language, attention, learning, memory, problem-solving skills etc. The type of deficits depends on the type and location of the underlying neuropathology (Vrinda et al. 2019). Neurocognitive impairment could be a consequence not only of the epileptogenic process but also of the applied antiepileptic treatment. By decreasing neuronal excitability antiepileptic drugs (AEDs) can affect normal neuronal function and therefore produce cognitive adverse effects (Motamedi and Meador 2004). They are most common for the old generations AEDs with a broad spectrum of action whereas newer AEDs with novel mechanisms of action or acting on specific targets have shown lower incidents of behavioural side effects (Vrinda et al. 2019). Lacosamide in a new AED which has a unique mechanism of action. It selectively enhances the slow inactivation of sodium channels and, thus, decreases neuronal hyperexcitability (Licko et al. 2013). Topiramate is a second-generation AED with multiple mechanisms of action including potentiation of γ-aminobutyric acid (GABA)-mediated chloride influx, modulation of voltage-dependent sodium and L-type calcium channels, and blocking glutamatergic α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and kainic acid receptors (Frisch et al. 2007). Although the anticonvulsant activity of TPM is well established, its anti-epileptogenic properties and effects on behavioral responses are still controversial. The data about the effect of lacosamide on cognitive performance and epileptogenesis are still insufficient.

The aim of the present study was to investigate the effects of lacosamide and topiramate treatment on epileptogenesis, cognitive impairment and motor performance in a rat model of PTZ-induced kindling.

PTZ-induced kindling is a widely applied experimental model used for the understanding of epileptogenesis, seizure mechanisms, and associated behavioral comorbidities. It is based on repeated subconvulsant brain stimulation which leads with time to the appearance of tonic-clonic seizures (Zhao et al. 2014). In accordance with other authors, in the present study, we found that repeated administration of subconvulsive doses of PTZ for 63 days (32 injections in total) led to the development of kindling in the control animals evidenced by the presence of convulsions with seizure severity score 5 during three consecutive applications (Agarwal et al. 2011).

In our study, only lacosamide managed to retard the kindling-induced epileptogenesis observed by the reduction of seizure severity score compared to control animals while topiramate failed to fully suppress the development of kindling. 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). Data about the effects of topiramate in different kindling models are still contradictory. Topiramate treatment with a higher than our dose of 80 mg/kg decreases the seizure duration and after-discharge duration in electrical kindling of the basolateral amygdala (Chen et al. 2009) while the drug (200 mg/kg) leads to age-dependent disease-modifying effects under conditions of rapid kindling but failed to block fully epileptogenesis (Mazarati et al. 2007). These data complete our previous research where we found that topiramate has a pronounced antiepileptogeneic effect in a model of TLE but the dose was much higher (80 mg/kg) than the one applied in the current experiment (Shishmanova-Doseva et al. 2022).

PTZ-kindling model also provides opportunities to study the progression of cognitive dysfunction associated with epilepsy. Impairment of learning and memory is one of the most frequently observed comorbidities of epilepsy (Mishra and Goel 2012, 2019). In the current experiment, epileptic animals had impaired active and passive learning abilities, as well as difficulties in the formation of short- and long-term memory traces. These results are in agreement with previous studies which show that PTZ-kindling is represented by loss of spatial and recognition memory and by pronounced impairment of learning and memory consolidation (Mishra and Goel 2012; Ahmadi et al. 2017). All these negative effects on cognition are associated with a significant neuronal loss in the hippocampus, increased acetylcholine esterase activity, and modulation of serotoninergic receptors(Siddharth et al. 2013; Mishra and Goel 2015, 2019; Taiwe et al. 2015). Moreover, recent evidence shows that excessive production of reactive oxygen species and subsequent neuroinflammation play a crucial role not only in the development of epileptogenesis but also have a determining role in the pathogenesis of observed behavior deficits (Ravizza and Vezzani 2018; Kitov et al. 2020; Singh et al. 2021).

In our experiment, we found that both drugs produced different effects in epileptic and naïve rats. Lacosamide and topiramate affected adversely cognitive functions in naïve animals while in the kindled rats they managed to restore them. Both drugs led to improved cognitive performance during epilepsy by improving active and passive learning abilities. Moreover, they facilitated the formation of short- and long term memory traces in both tests - passive and active ones. Lacosamide and topiramate treatment failed to suppress the hyperactivity which was observed with increased number of horizontal and vertical movements in the epileptic animals.

Lacosamide is a new AED and data about its effects on cognitive performance is still insufficient. Our results are consistent with other researchers who have found that the drug improves cognitive performance by decreasing oxidative stress in different brain structures such as the cerebellum and cortex (Abraham et al. 2014). Moreover, a recent study shows that lacosamide has a significant neuroprotective effect against oxidative damage, bioenergetics dysfunction, and DNA damage in a model of PTZ-kindling (Lazzarotto et al. 2021).

Topiramate is a widely used in the clinical practice AED which effects on cognitive functions are still controversial. Our data is in agreement with other studies showing that topiramate improve spatial learning and memory in an experimental model of postoperative cognitive dysfunction (Su et al. 2019). Its neuroprotective effects are related with reduced expression of caspase-3 in the hippocampus, and decreased neuroinflammation as well (Chen et al. 2009; Ye et al. 2014; Su et al. 2019). Contrary, our results differ from other studies showing that topiramate can cause cognitive problems in epileptic patients and some of these effects are related to its pro-oxidant properties (Donegan et al. 2015; Sarangi et al. 2016).

The results from the present study demonstrate that repeated administration of lacosamide managed to mitigate seizure development and produce antiepileptogenic effect in PTZ-kindled rats. Repeated treatment with low doses of either lacosamide or topiramate managed to overcome the cognitive dysfunction associated with epilepsy through improving of passive and active learning abilities and facilitating memory consolidation.