Lipoic Acid and Fish Oil Combination Potentiates Neuroinflammation and Oxidative Stress Regulation and Prevents Cognitive Decline of Rats After Sepsis

Abstract

Sepsis causes organ dysfunction due to an infection, and it may impact the central nervous system. Neuroinflammation and oxidative stress are related to brain dysfunction after sepsis. Both processes affect microglia activation, neurotrophin production, and long-term cognition. Fish oil (FO) is an anti-inflammatory compound, and lipoic acid (LA) is a universal antioxidant substance. They exert neuroprotective roles when administered alone. We aimed at determining the effect of FO+LA combination on microglia activation and brain dysfunction after sepsis. Microglia cells from neonatal pups were co-treated with lipopolysaccharide (LPS) and FO or LA, alone or combined, for 24 h. Cytokine levels were measured. Wistar rats were subjected to sepsis by cecal ligation and perforation (CLP) and treated orally with FO, LA, or FO+LA. At 24 h after surgery, the hippocampus, prefrontal cortex, and total cortex were obtained and assayed for levels of cytokines, myeloperoxidase (MPO) activity, protein carbonyls, superoxide dismutase (SOD), and catalase (CAT) activity. At 10 days after surgery, brain-derived neurotrophic factor (BDNF) levels were determined and behavioral tests were performed. The combination diminished in vitro levels of pro-inflammatory cytokines. The combination reduced TNF-α in the cortex, IL-1β in the prefrontal cortex, as well as MPO activity, and decreased protein carbonyls formation in all structures. The combination enhanced catalase activity in the prefrontal cortex and hippocampus, elevated BDNF levels in all structures, and prevented behavioral impairment. In summary, the combination was effective in preventing cognitive damage by reducing neuroinflammation and oxidative stress and increasing BDNF levels.

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Funding

This research was supported by grants from the National Council for Scientific and Technological Development (Conselho Nacional de Desenvolvimento Científico e Tecnológico - CNPq) (FP) and the Coordination for the Improvement of Higher Education Personnel (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES) (ADG). FP and TB are CNPq Research Fellows. The funding sources were not involved in the conduction of the research, preparation of the article nor in the decision to submit the article for publication.

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Contributions

FB and ADG conceived, designed, and coordinated the in vivo study. TB and ADG conceived, designed, and coordinated the in vitro study. ADG and VVG prepared microglia cell culture. ADG, GS, and GC performed microglia cell treatment and cytokine analysis. ADG, MPSG, LGD, and AON performed sepsis induction and treatments. AON, LG, and TC ensured and provided animal care throughout the in vivo study. JP, BHO, DFM, and FB performed neurotrophin determinations. MG, TB-S, and JB performed cytokine measurements. ADG, LG, TD, TC, and SB performed oxidative stress and myeloperoxidase determinations. NR and JJF performed behavioral evaluations. ADG analyzed the data, prepared the figures, and wrote the manuscript. FP, TB, and ADG revised and edited the manuscript.

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Correspondence to Fabricia Petronilho.

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The authors declare that they have no conflict of interest.

Ethical Approval

All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted (Animal Welfare Committee Animal Research of University of Texas Health Science Center at Houston – United States, protocol number AWC-15-0056; Animal Research Ethic Committee of the Universidade do Sul de Santa Catarina - Brazil, protocol number 15.043.4.01.IV). All efforts were made to minimize the number of animals used and their suffering.

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Giustina, A.D., de Souza Goldim, M.P., Danielski, L.G. et al. Lipoic Acid and Fish Oil Combination Potentiates Neuroinflammation and Oxidative Stress Regulation and Prevents Cognitive Decline of Rats After Sepsis. Mol Neurobiol (2020). https://doi.org/10.1007/s12035-020-02032-y

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Keywords

  • Sepsis
  • Fish oil
  • Lipoic acid
  • Microglia
  • Oxidative stress