Eucalyptol prevents pilocarpine-induced seizure and neuronal damage in mice, through the cholinergic, monoaminergic and antioxidant pathways

Current antiepileptic drugs can inhibit seizure occurrence but are not effective in preventing its onset. Moreover, they produce several side effects, which may impact the efficacy of the treatment. In addition, it has been stimulating the prospection of new molecules isolated from aromatic plants, with potential anticonvulsant and neuroprotective activities and less side effects. This study aimed to evaluate, though behavioural and neurochemical methodologies, the anticonvulsant, and neuroprotective effects of eucalyptol on mice subjected to the pilocarpine-induced seizure model. Eucalyptol (100, 200 and 400 mg/kg, p.o.) was administered in mice prior to pilocarpine (350 mg/kg, i.p.) and the following behavioural parameters were assessed: Latency to First Seizure (LFS), Seizure Intensity (SI) and Latency to Death (LD). In addition, an oxotremorine-induced tremors test was performed to evaluate the cholinergic system involvement on the eucalyptol effects. Neurochemical tests were also performed, including determination of hippocampal (HC) concentration of thiobarbituric acid reactive substances (TBARS) and nitrite/nitrate and striatal (ST) concentration of noradrenaline, dopamine, and serotonin. Lastly, histopathological, and morphometric hippocampal analysis were conducted. Eucalyptol increased the latency to first seizure and latency to death, inhibited oxotremorine-induced tremors, decreased hippocampal TBARS and nitrite/nitrate overproduction, increased striatal noradrenaline and dopamine levels and prevented hippocampal neurodegeneration. These results demonstrate the potential anticonvulsant, neuroprotective and antioxidant effects of eucalyptol, probably through a conjunction of mechanisms including muscarinic cholinergic antagonism, oxidative stress mitigation and the monoaminergic system modulation, which appears to effectively control the seizure onset.