Effect of prednisolone in a kindling model of epileptic seizures in rats on cytokine and intestinal microbiota diversity

Amanda Muliterno Domingues Lourenço de Lima; Gabriel de Lima Rosa; Edson Fernando Müller Guzzo; Rafael Bremm Padilha; Milena Conci de Araujo; Rodrigo Costa da Silva; Adriana Simon Coitinho; Sueli Teresinha Van Der Sand

doi:10.1016/j.yebeh.2024.109800

Effect of prednisolone in a kindling model of epileptic seizures in rats on cytokine and intestinal microbiota diversity

Epilepsy Behav. 2024 Apr 23:155:109800. doi: 10.1016/j.yebeh.2024.109800. Online ahead of print.

Authors

Amanda Muliterno Domingues Lourenço de Lima¹, Gabriel de Lima Rosa², Edson Fernando Müller Guzzo², Rafael Bremm Padilha², Milena Conci de Araujo³, Rodrigo Costa da Silva³, Adriana Simon Coitinho⁴, Sueli Teresinha Van Der Sand⁵

Affiliations

¹ Programa de Pós-Graduação em Microbiologia Agrícola e do Ambiente, Universidade Federal do Rio Grande do Sul, Instituto de Ciências Básicas da Saúde, Ramiro Barcelos Street, 2.600, Porto Alegre, RS, Brazil; Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Universidade Federal do Rio Grande do Sul, Instituto de Ciências Básicas da Saúde, Ramiro Barcelos Street, 2.600, Porto Alegre, RS, Brazil; Programa de Pós-Graduação em Ciências Biológicas: Farmacologia e Terapêutica, Universidade Federal do Rio Grande do Sul, Instituto de Ciências Básicas da Saúde, Ramiro Barcelos Street, 2.600, Porto Alegre, RS, Brazil.
² Programa de Pós-Graduação em Ciências Biológicas: Fisiologia, Universidade Federal do Rio Grande do Sul, Instituto de Ciências Básicas da Saúde, Ramiro Barcelos Street, 2.600, Porto Alegre, RS, Brazil.
³ Departamento de Microbiologia, Imunologia e Parasitologia, Universidade Federal do Rio Grande do Sul, Instituto de Ciências Básicas da Saúde, Ramiro Barcelos Street, 2.600, Porto Alegre, RS, Brazil.
⁴ Programa de Pós-Graduação em Ciências Biológicas: Farmacologia e Terapêutica, Universidade Federal do Rio Grande do Sul, Instituto de Ciências Básicas da Saúde, Ramiro Barcelos Street, 2.600, Porto Alegre, RS, Brazil; Programa de Pós-Graduação em Ciências Biológicas: Fisiologia, Universidade Federal do Rio Grande do Sul, Instituto de Ciências Básicas da Saúde, Ramiro Barcelos Street, 2.600, Porto Alegre, RS, Brazil; Departamento de Microbiologia, Imunologia e Parasitologia, Universidade Federal do Rio Grande do Sul, Instituto de Ciências Básicas da Saúde, Ramiro Barcelos Street, 2.600, Porto Alegre, RS, Brazil. Electronic address: adriana.simon@ufrgs.br.
⁵ Programa de Pós-Graduação em Microbiologia Agrícola e do Ambiente, Universidade Federal do Rio Grande do Sul, Instituto de Ciências Básicas da Saúde, Ramiro Barcelos Street, 2.600, Porto Alegre, RS, Brazil; Departamento de Microbiologia, Imunologia e Parasitologia, Universidade Federal do Rio Grande do Sul, Instituto de Ciências Básicas da Saúde, Ramiro Barcelos Street, 2.600, Porto Alegre, RS, Brazil.

PMID: 38657485
DOI: 10.1016/j.yebeh.2024.109800

Abstract

Epilepsy is a neurological disease characterized by spontaneous and recurrent seizures. Epileptic seizures can be initiated and facilitated by inflammatory mechanisms. As the dysregulation of the immune system would be involved in epileptogenesis, it is suggested that anti-inflammatory medications could impact epileptic seizures. These medications could potentially have a side effect by altering the structure and composition of the intestinal microbiota. These changes can disrupt microbial homeostasis, leading to dysbiosis and potentially exacerbating intestinal inflammation. We hypothesize that prednisolone may affect the development of epileptic seizures, potentially influencing the diversity of the intestinal microbiota and the regulation of pro-inflammatory cytokines in intestinal tissue. This study aimed to evaluate the effects of prednisolone treatment on epileptic seizures and investigate the effect of this drug on the bacterial diversity of the intestinal microbiota and markers of inflammatory processes in intestinal tissue. We used Male Wistar rat littermates (n = 31, 90-day-old) divided into four groups: positive control treated with 2 mg/kg of diazepam (n = 6), negative control treated with 0.9 g% sodium chloride (n = 6), and the remaining two groups were subjected to treatment with prednisolone, with one receiving 1 mg/kg (n = 9) and the other 5 mg/kg (n = 10). All administrations were performed intraperitoneally (i.p.) over 14 days. To induce the chronic model of epileptic seizures, we administered pentylenetetrazole (PTZ) 25 mg/kg i.p. on alternate days. Seizure latency (n = 6 - 10) and TNF-α and IL-1β concentrations from intestinal samples were measured by ELISA (n = 6 per group), and intestinal microbiota was evaluated with intergenic ribosomal RNA (rRNA) spacer (RISA) analysis (n = 6 per group). The prednisolone treatment demonstrated an increase in the latency time of epileptic seizures and TNF-α and IL-1β concentrations compared to controls. There was no statistically significant difference in intestinal microbiota diversity between the different treatments. However, there was a strong positive correlation between microbial diversity and TNF-α and IL-1β concentrations. The administration of prednisolone yields comparable results to diazepam on increasing latency between seizures, exhibiting promise for its use in clinical studies. Although there were no changes in intestinal microbial diversity, the increase in the TNF-α and IL-1β cytokines in intestinal tissue may be linked to immune system signaling pathways involving the intestinal microbiota. Additional research is necessary to unravel the intricacies of these pathways and to understand their implications for clinical practice.

Keywords: Cytokine; Epilepsy; Microbiota; Neuroinflammation; Prednisolone; Seizure.