Epilepsia do lobo temporal: impacto da desregulação circadiana e alterações metabólicas em modelo experimental

Abstract

Temporal lobe epilepsy (TLE) is a neurological disorder characterized by spontaneous recurrent seizures (SRS). Evidence suggests a bidirectional relationship between TLE and circadian rhythms, with circadian patterns influencing seizure susceptibility and seizures potentially disrupting other biological oscillations. Moreover, studies indicate that seizure severity is associated with alterations in metabolites, which have gained attention as potential biomarkers for the complex diagnosis and management of epilepsy. This thesis is structured into two chapters addressing distinct aspects of TLE. The first chapter explores the effects of circadian rhythm disruption, induced by constant light exposure, on the epileptogenic process. Using a lithium-pilocarpine model, Wistar rats were exposed to constant light (experimental group) or a light-dark cycle (control group) and continuously video-monitored post-status epilepticus (SE). The study evaluated seizure frequency and severity, spontaneous locomotor activity rhythms (SLA), neurodegeneration, and the expression of genes implicated in epileptogenesis. Results demonstrated that constant light exposure prior to SE increased the threshold for SE induction, reduced seizure severity, attenuated neuronal loss, and modulated the expression of Npy and Gad65 transcripts. However, no effects were observed on SRS during the chronic phase. The second chapter investigates the metabolic profile of fecal water in rats subjected to SE, aiming to identify potential biomarkers associated with epileptogenesis. Fecal samples from five experimental groups: Naïve, Post-SE, SRS (epileptic), NS (SE-resistant) and NSRS (without seizures in the chronic phase), were analyzed by Nuclear Magnetic Resonance (NMR) spectroscopy and processed with statistical methods such as PCA, PLS-DA, OPLS-DA and ANOVA. The analysis identified 24 important metabolites, including elevated levels of glutamate and glutamine in the SRS group, reduced butyrate in the Post-SE group and increased branched-chain amino acids (valine, isoleucine and leucine) in the NS and NSRS groups. PCA and PLSDA analyses confirm the separation between the groups, with a total variance of 65%, evidencing greater distinction between the Naïve, SRS and Post-SE groups, while the NS and NSRS groups present similar metabolic patterns. These results indicate that the resistance mechanisms involve adaptive responses distinct from those observed in naïve animals and those that suffered crises, suggesting the presence of specific biological processes that require further investigation. These findings provide novel insights into the metabolic alterations associated with TLE, with potential implications for diagnosis and therapeutic development. Although the chapters address distinct questions due to 9 methodological adaptations during the COVID-19 pandemic, they complement each other by advancing our understanding of TLE from both circadian and metabolic perspectives. Further studies are needed to translate these findings into clinical practice.