Abstract
BackgroundThe inflammatory process has been described as a crucial mechanism in the pathophysiology of temporal lobe epilepsy. The anti-inflammatory protein annexin A1 (ANXA1) represents an interesting target in the regulation of neuroinflammation through the inhibition of leukocyte transmigration and the release of proinflammatory mediators. In this study, the role of the ANXA1-derived peptide Ac2-26 in an experimental model of status epilepticus (SE) was evaluated.MethodsMale Wistar rats were divided into Naive, Sham, SE and SE+Ac2-26 groups, and SE was induced by intrahippocampal injection of pilocarpine. In Sham animals, saline was applied into the hippocampus, and Naive rats were only handled. Three doses of Ac2-26 (1 mg/kg) were administered intraperitoneally (i.p.) after 2, 8 and 14 h of SE induction. Finally, 24 h after the experiment-onset, rats were euthanized for analyses of neuronal lesion and inflammation.ResultsPilocarpine induced generalised SE in all animals, causing neuronal damage, and systemic treatment with Ac2-26 decreased neuronal degeneration and albumin levels in the hippocampus. Also, both SE groups showed an intense influx of microglia, which was corroborated by high levels of ionised calcium binding adaptor molecule 1(Iba-1) and monocyte chemoattractant protein-1 (MCP-1) in the hippocampus. Ac2-26 reduced the astrocyte marker (glial fibrillary acidic protein; GFAP) levels, as well as interleukin-1β (IL-1β), interleukin-6 (IL-6) and growth-regulated alpha protein (GRO/KC). These effects of the peptide were associated with the modulation of the levels of formyl peptide receptor 2, a G-protein-coupled receptor that binds to Ac2-26, and the phosphorylated extracellular signal-regulated kinase (ERK) in the hippocampal neurons.ConclusionsThe data suggest a neuroprotective effect of Ac2-26 in the epileptogenic processes through downregulation of inflammatory mediators and neuronal loss.
Highlights
The inflammatory process has been described as a crucial mechanism in the pathophysiology of temporal lobe epilepsy
The results show that the number of microglia cells (Iba-1+ cells) increased in the anterior and posterior regions of CA1 and CA3 of status epilepticus (SE) and SE+annexin A1 (ANXA1) N-terminal-derived peptide (Ac2-26) groups compared to that of the controls (Naive and SHAM; Fig. 3b)
Histochemical, biochemical and molecular analyses, the results showed that systemic treatment with Ac2-26 reduced neuronal injury and inflammation related to SE
Summary
The inflammatory process has been described as a crucial mechanism in the pathophysiology of temporal lobe epilepsy. Temporal lobe epilepsy (TLE) is a type of focal epilepsy that has a great clinical relevance due to its high incidence and severity, and the commonest pathology underlying the TLE is unilateral hippocampal sclerosis associated with neuronal loss and gliosis [2]. These characteristics can be reproduced in animals using pilocarpine, a muscarinic receptor agonist [3]. Clinical and experimental evidence support the hypothesis that the inflammatory process in the brain is a common and crucial mechanism of epileptic seizures and epilepsy [10, 11]. The molecular mechanisms by which inflammation can increase the excitability of neurons are still unclear and open new perspectives for the treatment or prevention of these neurological diseases
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