Epilepsy is a chronic neurological condition characterized by recurrent or unexpected seizures, which may be categorized into partial and generalized seizures as well as simple and complicated seizures (Sirven, 2015). On a global scale, around 50 million individuals have epileptic seizures, with an additional 5 million receiving an annual diagnosis of epilepsy. These conditions have a significant impact on their quality of life, leading to various psychological issues (Alimoradi et al., 2023; Pontes Silva and Gama Marques, 2023). Approximately 80% of individuals diagnosed with epilepsy reside in nations classified as low- and middle-income (Minwuyelet et al., 2022). Epilepsy may arise from hereditary factors that can be attributed to other brain injuries, such as head trauma, stroke, vascular abnormalities, congenital brain deformities, or central nervous system infections (Stafstrom and Carmant, 2015). Epileptic seizures are often characterized by transient symptoms such as awareness or loss of consciousness, as well as disruptions in motor function, sensory perception (including hearing, vision, and taste), mood, and other cognitive processes (Akyuz et al., 2023a; Lawal et al., 2018). Moreover, individuals with epilepsy often have comorbid physiological conditions such as anxiety and depression (Reilly et al., 2011). Therefore, epilepsy seizures pose a substantial global burden of disease.

The underlying mechanism of epilepsy involves an imbalance in synaptic activity, namely the interplay between excitatory signaling mediated by glutamate and inhibitory signaling mediated by gamma-aminobutyric acid (GABA) (Fan et al., 2023; Nikolic et al., 2020). Additionally, the modifications of ion channels caused by inherited mutations or acquired changes disturb the accurate control of ion movement across neuronal cell membranes, ultimately leading to excessive activation and the onset of seizures (Akyuz et al., 2023b; Graves, 2006).

The primary mechanism of action of antiepileptic medicines (AEDs) is to promote inhibitory processes over excitatory processes, thus halting or preventing the onset or propagation of seizure activity. The AEDs may be categorized based on their primary mode of operation (Rogawski et al., 2016). The mechanisms encompass various actions, such as the inhibition of sodium-dependent action potentials (e.g., phenytoin and carbamazepine), the inhibition of voltage-gated calcium channels (phenytoin), the blockade of glutamate (lamotrigine and felbamate), the enhancement of GABA (benzodiazepines and barbiturates), the inhibition of GABA reuptake (valproic acid and Tiagabine), and the opening of potassium channels (ezogabine) (Jankovic and Ilickovic, 2013; Messing et al., 1985; Metcalf et al., 2022; Perucca et al., 2023; Qiao et al., 2014; Rana et al., 2023). Numerous studies have provided evidence supporting the frequent recommendation of benzodiazepines and their derivatives as the first choice for anticonvulsant treatment. Benzodiazepines exert their effects by augmenting the activity of GABAA receptors via the promotion of chloride channel opening, hence inducing neuronal hyperpolarization (Kienitz et al., 2022). Approximately 30% of individuals diagnosed with epilepsy exhibit resistance to conventional therapeutic interventions. In addition, individuals are experiencing adverse consequences and interactions that are linked to these conditions (Lima et al., 2022; Sedahmed et al., 2021). Thus, carbamazepine exerts its effects through modulating voltage-gated sodium channels, resulting in the suppression of action potentials and a reduction in synaptic transmission. Carbamazepine has shown a notable elevation in the occurrence of dermatologic responses, including Stevens-Johnson syndrome, systemic symptoms, maculopapular eruptions, toxic epidemic necrolysis, and drug reactions with eosinophilia. Additionally, carbamazepine has teratogenic properties and is classified as a category D medication during pregnancy (Bertilsson, 1978; Wahab, 2010). The exploration of novel antiepileptic medications derived from natural sources is a compelling area of research because of the well-documented antiepileptic properties shown by many phytochemical groups, such as monoterpenoids, diterpenes, and flavonoids (Ali Khan et al., 2023; Arumugam et al., 2016; Shelar et al., 2018).

Citronellal (CIT), also known as (±)-3,7-Dimethyl-6-octenal, is classified as a rhodinal compound and belongs to the class of acyclic monoterpenoid aldehydes. CIT may be isolated from the essential oils of several plant species, including Corymbia citriodora, Cymbopogon nardus, C. citratus, C. winterianus, and Melissa officinalis (Ernst, 2006; Guyo et al., 2021; Quintans-Júnior et al., 2011; Stojanović et al., 2022a). Other plants that contain CIT, such as species belonging to the genera Eucalyptus, Melissa, Mentha, Allium, and Cinnamomum, among others, are recognized for their significant nutritional value and serve as important sources of food spices in numerous regions across the globe (Nerio et al., 2010).

Traditionally, CIT has been used in many applications such as air freshening, cleaning, floor polishing, taste enhancement, masking, general moisturization, hand and body care, as well as adhesive bonding (De Canha et al., 2020; Eden et al., 2020; Jacob et al., 2003). In Asia, CIT is often utilized in the preparation of soups, teas, and curries, as well as in the cooking of various types of fish, meat, and seafood (Simic et al., 2008). In Thailand, lemongrass-infused CIT is used in the creation of a revitalizing cold beverage known as "Nam Takrai." Similarly, in Brazil, infusions with lemongrass are often employed in traditional medicine to regulate the digestive and circulatory systems (Figueirinha et al., 2010). CIT is also commonly taken as tea in England, Brazil, and Southern Europe for both therapeutic and recreational uses as well as a flavoring agent (Aljabr, 2008; Nguefack et al., 2008). Additionally, CIT has been found to elicit pharmacological activities including, antioxidant (Yousefi et al., 2019), anti-inflammatory (Melo et al., 2011), antinociceptive (Melo et al., 2010), anti-bacterial (Guliani et al., 2018), anti-fungal (Aguiar et al., 2014), anthelmintic (Araújo-Filho et al., 2019), sedative (Jäger et al., 1992), antidepressant (Victoria et al., 2014), anesthetic (Hoseini et al., 2022), cardioprotective (Liu et al., 2022), hepatoprotective (Liu et al., 2021), anti-cancer (Ho et al., 2020), antidiabetic (Qiu et al., 2022), lipid-lowering properties (Paul et al., 2022). In addition, recent studies have reported that CIT could also ameliorate the convulsions induced by pentylenetetrazol and strychnine (Stojanović et al., 2022b).

The primary objective of this study is to investigate the anticonvulsant effect of CIT in isoniazid (INH)-induced seizure animals. Subsequently, an in silico study is performed to understand the probable targets responsible for the anticonvulsant mechanisms and predict the pharmacokinetic and toxic properties of CIT compared to two standard drugs (diazepam and carbamazepine).