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

Autor: José Cláudio Fonseca Moreira, Luana Heimfarth, Alexandra M.S. Carvalho, Edeildo Ferreira da Silva-Júnior, Martine Schmitt, Thiago Mendonça de Aquino, Rosana S.S. Barreto, Jean-Jacques Bourguignon, Erik Willyame Menezes Pereira, João Xavier de Araújo-Júnior, Jullyana S.S. Quintans, Lucindo José Quintans-Júnior, Mikaella Tuanny Bezerra Carvalho, Natália Teles Lima
Přispěvatelé: Federal University of Sergipe (UFS), Universidade Federal do Rio Grande do Sul [Porto Alegre] (UFRGS), Universidade Federal de Alagoas = Federal University of Alagoas (UFAL), Laboratoire d'Innovation Thérapeutique (LIT), Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC)
Rok vydání: 2020
Předmět:
Lipopolysaccharides
Male
0301 basic medicine
MAPK/ERK pathway
Indoles
[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology
medicine.medical_treatment
Anti-Inflammatory Agents
Hippocampus
chemistry.chemical_compound
0302 clinical medicine
[SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases
Aminoguanidine
Microglia
Neonatal sepsis
endotoxemia
NF-kappa B
3. Good health
Cytokine
medicine.anatomical_structure
Cytokines
Female
Neonatal Sepsis
Signal transduction
Hydrochloride
Sepsis
03 medical and health sciences
Cellular and Molecular Neuroscience
[SDV.SP.MED]Life Sciences [q-bio]/Pharmaceutical sciences/Medication
Oxidative damage
medicine
Animals
Cognitive Dysfunction
Guanidine
Inflammation
Mitogen-Activated Protein Kinase Kinases
[SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics
business.industry
Cell Biology
medicine.disease
Guanylhydrazone
Mice
Inbred C57BL
Disease Models
Animal
030104 developmental biology
chemistry
Immunology
business
030217 neurology & neurosurgery
Zdroj: Neurochemistry International
Neurochemistry International, Elsevier, 2020, 134, pp.104647. ⟨10.1016/j.neuint.2019.104647⟩
ISSN: 0197-0186
DOI: 10.1016/j.neuint.2019.104647
Popis: International audience; 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 antiseptic agent, and the role of crucial molecular pathways in mitigating the potential damage caused by neonatal sepsis.
Databáze: OpenAIRE
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