Abstract
Preclinical evidence on the role of glucagon-like peptide-1 receptor (GLP-1r) agonists in the brain led to an increased interest in repurposing these compounds as a therapy for central nervous system (CNS) disorders and associated comorbidities. We aimed to investigate the neuroprotective effects of acute treatment with exendin (EX)-4, a GLP-1r agonist, in an animal model of inflammation. We evaluated the effect of different doses of EX-4 on inflammatory, neurotrophic, and oxidative stress parameters in the hippocampus and serum of lipopolysaccharide (LPS)-injected animals. Male Wistar rats were injected with LPS (0.25 mg/kg i.p.) and treated with different doses of EX-4 (0.1, 0.3, or 0.5 μg/kg i.p.). Sickness behavior was assessed by locomotor activity and body weight, and depressive-like behavior was also evaluated using forced swim test (FST). Brain-derived neurotrophic factor (BDNF), thiobarbituric acid reactive species (TBARS), and interleukin (IL)-6 were quantified in the serum and hippocampus. Glycemia was also analyzed pre- and post-EX-4 treatment. LPS groups exhibited decreased frequency of crossing and reduced body weight (p < 0.001), while alterations on FST were not observed. The higher dose of EX-4 reduced IL-6 in the hippocampus of LPS-injected animals (p = 0.018), and EX-4 per se reduced TBARS serum levels with a modest antioxidant effect in the LPS groups (p ≤ 0.005). BDNF hippocampal levels seemed to be increased in the LPS+EX-4 0.5 group compared with LPS+Saline (p > 0.05). Our study provides evidence on acute anti-inflammatory effects of EX-4 in the hippocampus of rats injected with LPS, contributing to future studies on repurposing compounds with potential neuroprotective properties.
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Funding
LPG is a scholarship recipient from the National Council for Scientific and Technological Development (CNPq). RG receives a Research Productivity Scholarship (PQ2) from CNPq. This work was supported by the Research Incentive Fund of Hospital de Clínicas de Porto Alegre (grant number 15-0002, ARR) and the National Council for Scientific and Technological Development - CNPq (grant numbers 401162/2016-8 and 302800/2017-4, AP).
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LPG, AP, RG, RC, and ARR designed and wrote the protocol. LPG, EDR, BSP, EZA, LFO, and PF performed the experiments, behavior, and biochemical analysis. LPG, AP, and ARR performed the statistical analysis. LPG and ARR wrote the manuscript draft, and all authors contributed and approved the final article.
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This study was approved by the institutional animal care and use committee from the Hospital de Clínicas de Porto Alegre (HCPA, project number 15-0002) and all experimental procedures were performed in accordance with national (DBCA no. 30/2016 – CONCEA 2016) and international (Guide for the care and use of laboratory animals – NIH 2011) ethical standards.
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Géa, L.P., da Rosa, E.D., Panizzutti, B.S. et al. Reduction of hippocampal IL-6 levels in LPS-injected rats following acute exendin-4 treatment. Naunyn-Schmiedeberg's Arch Pharmacol 393, 1303–1311 (2020). https://doi.org/10.1007/s00210-020-01867-5
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DOI: https://doi.org/10.1007/s00210-020-01867-5