Indole-3-guanylhydrazone hydrochloride mitigates long-term cognitive impairment in a neonatal sepsis model with involvement of MAPK and NFκB pathways.

Autor: Heimfarth L; Laboratory of Neuroscience and Pharmacological Assay (LANEF), Graduate Program in Pharmaceutical Sciences, Federal University of Sergipe, São Cristóvão, Sergipe, Brazil. Electronic address: luahei@yahoo.com.br., Carvalho AMS; Laboratory of Neuroscience and Pharmacological Assay (LANEF), Graduate Program in Pharmaceutical Sciences, Federal University of Sergipe, São Cristóvão, Sergipe, Brazil., Quintans JSS; Laboratory of Neuroscience and Pharmacological Assay (LANEF), Graduate Program in Pharmaceutical Sciences, Federal University of Sergipe, São Cristóvão, Sergipe, Brazil., Pereira EWM; Laboratory of Neuroscience and Pharmacological Assay (LANEF), Graduate Program in Pharmaceutical Sciences, Federal University of Sergipe, São Cristóvão, Sergipe, Brazil., Lima NT; Laboratory of Neuroscience and Pharmacological Assay (LANEF), Graduate Program in Pharmaceutical Sciences, Federal University of Sergipe, São Cristóvão, Sergipe, Brazil., Bezerra Carvalho MT; Laboratory of Neuroscience and Pharmacological Assay (LANEF), Graduate Program in Pharmaceutical Sciences, Federal University of Sergipe, São Cristóvão, Sergipe, Brazil., Barreto RSS; Laboratory of Neuroscience and Pharmacological Assay (LANEF), Graduate Program in Pharmaceutical Sciences, Federal University of Sergipe, São Cristóvão, Sergipe, Brazil., Moreira JCF; Biochemistry Department, Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil., da Silva-Júnior EF; Chemistry and Biotechnology Institute, Federal University of Alagoas, Maceió, Alagoas, Brazil., Schmitt M; Département de Pharmacochimie Moléculaire, Centre de Neurochimie, Strasbourg University, Strasbourg, France., Bourguignon JJ; Département de Pharmacochimie Moléculaire, Centre de Neurochimie, Strasbourg University, Strasbourg, France., de Aquino TM; Chemistry and Biotechnology Institute, Federal University of Alagoas, Maceió, Alagoas, Brazil., Araújo-Júnior JX; Laboratory of Medicinal Chemistry, Institure of Pharmaceutical Sciences, Federal University of Alagoas, Maceio, Alagoas, Brazil., Quintans-Júnior LJ; Laboratory of Neuroscience and Pharmacological Assay (LANEF), Graduate Program in Pharmaceutical Sciences, Federal University of Sergipe, São Cristóvão, Sergipe, Brazil. Electronic address: lucindojr@gmail.com.
Jazyk: angličtina
Zdroj: Neurochemistry international [Neurochem Int] 2020 Mar; Vol. 134, pp. 104647. Date of Electronic Publication: 2019 Dec 23.
DOI: 10.1016/j.neuint.2019.104647
Abstrakt: Background: Neonatal sepsis is defined as a systemic inflammatory response caused by a suspected or proven infection, occurring in the first month of life, and remains one of the main causes of morbidity and mortality in newborn and preterm infants. Frequently, survivors of neonatal sepsis have serious long-term cognitive impairment and adverse neurologic outcomes. There is currently no specific drug treatment for sepsis. Indole-3-guanylhydrazone hydrochloride (LQM01) is an aminoguanidine derivative that has been described as an anti-inflammatory, antihypertensive and antioxidant with potential applicability in inflammatory diseases.
Methods: We used a LPS-challenged neonatal sepsis rodent model to investigate the effect of LQM01 on cognitive impairment and anxiety-like behavior in sepsis mice survivors, and examined the possible molecular mechanisms involved.
Results: It was found that LQM01 exposure during the neonatal period reduces anxiety-like behavior and cognitive impairment caused by lipopolysaccharides (LPS) in adult life. Additionally, treatment with LQM01 decreased pro-inflammatory cytokine levels and reduced NFκB, COX-2, MAPK and microglia activation in hippocampus of neonatal mice. Furthermore, LQM01 was also able to prevent oxidative damage in hippocampus of neonatal mice and preserve brain barrier integrity.
Conclusions: LQM01 attenuated inflammatory reactions in an LPS-challenged neonatal sepsis mice model through the MAPK and NFκB signaling pathways and microglia activation suppression. All these findings are associated with mitigated cognitive impairment in 70 days-old LQM01 treated-mice.
General Significance: We revealed the effect of LQM01 as an anti-septic agent, and the role of crucial molecular pathways in mitigating the potential damage caused by neonatal sepsis.
(Copyright © 2019. Published by Elsevier Ltd.)
Databáze: MEDLINE
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