Essential oils and their constituents have been presented as possible modulators of the central nervous system (CNS) (Figuêredo et al., 2019), and the presence of components such as terpenes in their constitutions is known to have anxiolytic, antidepressant, analgesic, and anticonvulsant activities, and to provoke excitability of the central nervous system (de Sousa et al., 2015; Chen et al., 2020). Rosmarinus officinalis (rosemary), belonging to the Lamiaceae botanical family, is an aromatic plant cultivated in different regions worldwide, with the Mediterranean as its center of origin (Murata et al., 2013; Oliveira et al., 2019). Rosemary is used to accelerate digestion, clear nasal passages, stimulate hair growth, and relieve rheumatic pain, as well as myalgias, neuralgias, and physical and mental fatigue.

Essential oil of R. officinalis (EORO) is also used as a memory and cognition stimulator, have antidiabetic, anti-inflammatory, and hepatoprotective properties, relieve dyslipidemia, and protect against glial cell tumors (Rašković et al., 2014; Rodrigues et al., 2020; Olah et al., 2017; Ozdemir and Goktuk, 2018; Borges et al., 2019; Allegra et al., 2020; Bao et al., 2020; Chen et al., 2020; Zappalà et al., 2021). According to Bellumori et al. (2021), Ahmed and Babakir-Mina (2020) and Paixão and de Carvalho (2021), rosemary has immunomodulatory and antimicrobial activity against bacteria (Staphylococcus epidermidis, S. aureus, Bacillus subtilis, Proteus vulgaris, Pseudomonas aeruginosa, and Escherichia coli) and fungi (Candida albicans and Aspergillus niger). Several studies have demonstrated the interactive relationship of EORO with the CNS, having activity in the cholinergic and dopaminergic pathways (Park et al., 2010; Sasaki et al., 2012; Borrás-Linares et al., 2014; Kayashima et al., 2020). Studies of stimulant effects are related to the components 1,8-cineole (oxide) and α-pinene (monoterpene) which, through sympathetic activity, stimulate the autonomic nervous system and increase blood pressure and respiratory rate measurements (Howes and Houghton, 2003; Sasaki et al., 2012; Kayashima et al., 2020). In line with these studies, Schriever et al., 2017 and DeGuzman et al., 2020 recorded by electroencephalography a significant decrease in the power of alpha waves in the bilateral middle frontal regions; they associated this result with increased alertness they clinically observed.

It is known that despite advances in the understanding of epilepsy, the mechanisms responsible for the epileptic phenomenon and its cellular bases are still not fully understood, although existing studies indicate that EORO interacts with the CNS. The behavioral and electrocorticographic characterization during these interactions caused by EORO have never been described and can help us understand the pathophysiological mechanisms that underlie epilepsies.

Many substances contained in essential oils have anticonvulsant effects and may benefit people with epilepsy. Compounds such as carvone, citral, eugenol, or linalool are present as promising agents with antiepileptic activity. However, some essential oils are proconvulsant or are even present anticonvulsant and proconvulsant compounds in the same essential oil (Filho et al., 2006; Lopes et al., 2008; Quintans-Júnior et al., 2008; Sousa et al., 2008; Subhan et al., 2008; Bahr et al., 2019; de Oliveira et al., 2020; Mathew et al., 2021; de Oliveira et al., 2022; de Araújo et al., 2023). The behavior of the animals after the application of EORO initially showed depression of the central nervous system with the presence of intense myorelaxation that characterized the first phase of the behavior. However, a phase of excitability was revealed with the appearance of convulsive crises in the second phase, which demonstrated to the same components of the essential oil a decrease of excitability in the initial period and then an increase of excitability. A similar behavior was observed in the ethanolic extract of Nerium oleander, but with different components—in this case oleandrin, which corresponds to a digitaloid (de Melo et al., 2020). Figuêredo et al. (2019) studied the effects of 1,8-cineol (eucalyptol 50 mg/kg)—the key phytochemical component of EORO—in the CNS of mice through the analysis of a behavioral model, finding that the latency of death was significantly prolonged in the groups which were submitted to convulsion induced by PTZ, which is a power stimulant of CNS due to its inhibitory capacity of the receptor GABAA in the control group. This corroborates our phase 1 results that EORO seems to act as a depressor of CNS. A study on the essential oil of Ocimum basilicum also suggested the hypnotic and anticonvulsant activities of this oil in the presence of terpene like the 1,8—cineole and linalool (Ismail, 2006). Camphor, the second biggest key phytochemical component of EORO, was studied by Ferreira et al. (2020) through electrocardiographic analysis where moderate neuronal hyperexcitability, fast evolution to tonic-clonic convulsion, and alterations in the electrocardiographic registers presented characters of epileptiform activity with an increase in the total power of the wave, revealing an increase in the delta and theta waves. This corroborated our phase 2 results that the EORO was a CNS exciter, and therefore a proconvulsant. In the phytochemical analysis of the oil used in the study, the compound linalool was identified. This is an acyclic monoterpene that is well-known for its potential in aromatherapy and cosmetics. It is a compound that has anxiolytic potential in animal models capable of potentiating the function of GABA in the GABA A receptor (Milano et al., 2017) and inhibiting the excitatory action of glutamate receptors (Elisabetsky et al., 1999; Kessler et al., 2012, Ohkuma et al., 2002). Linalool derivatives and metabolites including linalool oxide, linalyl acetate, eight-oxolinalyl acetate, 8-carboxylinalyl acetate, and 8-oxolinalool also increase GABAergic activity and may have anticonvulsant effects (Linck et al., 2009; Vatanparast et al., 2017; Bahr et al., 2019) (Table 1). Hydroxylation at C8 of linalyl acetate led to reduced GABAergic responses (Granger et al., 2005; Milanos et al., 2017). The possible oxidation of linalool by P450 system oxidases may have contributed to the formation of different oxygenated byproducts that express distinct affinities and properties regarding the activation of GABA receptors (Boachon et al., 2015). The hydrophobicity of linalool favors greater allosteric interaction with GABA, since these receptors are embedded in the hydrophobic lipid bilayer of neurons (Khom et al., 2007). The oxidation of these compounds results in reduced modulation of the GABAA receptor (Khom et al., 2007). The linalool metabolism can thus directly contribute to the onset of seizures, reducing its effects on GABA, since other substances such as camphor and eucalyptol are found in the essential oil. These are known to promote epileptic events in humans, possibly due to their significant presence (Teis and Koren, 1995; Zibrowski et al., 1998; Pearce, 2008; Culić et al., 2009; Ferreira et al., 2020). This context justifies the two antagonistic phases dependent on the time of contact with the EORO, which can be observed in the electrocorticogram. During phase 2, there are characteristic peaks of asynchronous brain activity (Figure 2) with low amplitude patterns and high frequency, low frequency and high amplitude with polypoint wave, and high amplitude and high frequency with similar morphographic elements between shots with an increase in recorded power, demonstrating the intensity of the convulsive condition (Figures 3A,B). The evaluation of brain band oscillations during phase 1 showed a decrease in delta oscillations (1–4 Hz) in relation to the control group. For phase 2, all oscillations up to 40 Hz showed an increase in potency, but beta oscillations showed greater amplitude during seizures. According to Jalilifar et al. (2018) and Hamoy et al. (2018), who studied different pro-convulsant substances, there is an increased preponderance of beta oscillations in the electrocorticogram . All anticonvulsants tested reduced beta oscillations during seizures, although phenobarbital and diazepam performed better, demonstrating the inhibition of the GABAergic pathway by EORO. Research has already described the ability of camphor to induce seizures (Dubovsky, 1995; Pearce, 2008; Burkhard et al., 1999; Ferreira et al., 2020). EORO has components capable of initially depressing and subsequently causing excitability in the central nervous system with characteristic recording patterns that are repeated during the ECoG tracing. The excitability phase is related to the decrease in GABA activity, which can be reversed more effectively with the use of diazepam. EORO has antagonistic effects that can be observed depending on the time of contact with the body.