Effect of pioglitazone on the behavior and expression of genes involved in the regulation of epileptogenesis in a lithium-pylocarpine model of temporal lobe epilepsy in rats

Abstract

Epilepsy is a chronic neurological disorder characterized by spontaneous recurrent seizures and various psychoemotional and cognitive impairments [1]. Roughly 30% of patients experience pharmacoresistant epilepsy, and current antiepileptic medications do not prevent the progression of brain epilepsy, necessitating the exploration of novel therapeutics. Recently, the potential involvement of peroxisome proliferator-activated receptors (PPARs) in the development of epilepsy has been examined. PPARs (α, β/δ, γ) are nuclear transcription factors affecting many intracellular cascades, both in the periphery and in the brain. Their agonists were proposed to restrict neuroinflammation, a crucial factor contributing to the pathogenesis of various neuropsychiatric disorders, such as epilepsy [2]. The aim of this study was to investigate the impact of the PPARγ receptor agonist pioglitazone on the regulation of neuroinflammation and epileptogenesis-associated genes, as well as the expression of disorders in research and social behavior in a lithium-pilocarpine model of epilepsy. The lithium-pilocarpine model of temporal lobe epilepsy consists of three phases: 1) induction of an acute epileptic status by administering pilocarpine, 2) a latent period lacking seizures, and 3) a chronic period characterized by spontaneous recurrent seizures. The experiments were conducted on male Wistar rats. At seven to eight weeks of age, the research subjects were administered a LiCl solution (w/w, 127 mg/kg). After 24 hours, they were given methylscopolamine (w/w, 1 mg/kg), followed by pilocarpine (w/w, 20–30 mg/kg, 10 mg/kg until convulsions were pronounced) 30 minutes later. Pilocarpine was not administered to the control rats. Pioglitazone was administered using a biphasic course. The first injection was given at a dose of 7 mg/kg, 75 minutes after pilocarpine-induced status epilepticus. Subsequently, the rats were given a dosage of 1 mg/kg, once daily at 24-hour intervals, for a period of 7 days. The open field test and the foreign object test were performed on days 7 and 8 after pilocarpine administration, respectively. The brain was sampled for further biochemical analysis 12 hours after behavioral testing. The temporal cortex underwent analysis using real-time RT-PCR for the expression of Nlrp3, Aif1, Tnfa, Gfap, Il1b, Il1rn, Bdnf, S100a10, Fgf2, and Tgfb1 genes. The research reveals a surge in the expression of pro-inflammatory proteins and activation markers of glial cell in temporal cortex caused by a lithium-pilocarpine model of epilepsy. This leads to impaired social behavior and hyperactivity in the open field. Pioglitazone successfully decreases the severity of the pilocarpine-induced behavioral disruptions. The PPARg agonist does not have a noteworthy impact on the expression of proinflammatory factors and glia activation markers Aif1 and Gfap. However, it was found to enhance the gene expression of neuroprotective proteins S100A10 and TGFB1 and decrease the expression of growth factors Fgf2 and Bdnf, which worsen epileptogenesis. Overall, these findings suggest that activation of PPARg might provide a protective role in the development of epileptic processes in the brain. Therefore, pioglitazone could be regarded as a possible therapeutic agent for treating epilepsy.