In vitro 6-hydroxydopamine-induced neurotoxicity: New insights on NFκB modulation

PABLO IGLESIAS GONZÁLEZ; MELISA CONDE; VERÓNICA GONZÁLEZ-PARDO; ROMINA URANGA; GABRIELA SALVADOR

TOXICOLOGY IN VITRO : AN INTERNATIONAL JOURNAL PUBLISHED IN ASSOCIATION WITH BIBRA.

PERGAMON-ELSEVIER SCIENCE LTD

Lugar: Amsterdam; Año: 2019 vol. 60 p. 400 - 411

0887-2333

Neuronal exposure to 6-hydroxydopamine (6-OHDA), a hydroxylated analog of dopamine, constitutes a veryuseful strategy for studying the molecular events associated with neuronal death in Parkinson´s disease. 6-OHDAincreases oxidant levels and impairs mitochondrial respiratory chain, thus promoting neuronal injury and death.Despite the extensive use of 6-OHDA in animal models, the exact molecular events triggered by this neurotoxicantat the neuronal level have not been yet fully understood.Human IMR-32 neuroblastoma cells exposed to increasing concentrations of 6-OHDA displayed high levels ofreactive oxygen species and increased plasma membrane permeability with concomitant cell viability diminution.As part of the neuronal response to 6-OHDA exposure, the nuclear translocation of nuclear factor kappalight-chain-enhancer of activated B cells (NFκB) p65 subunit was observed. NFκB nuclear localization was alsoaccompanied by an increase of IκB phosphorylation as well as a rise in cyclooxygenase-2 (COX-2) and theprostaglandin receptor, EP4, mRNA levels.Even though the canonical pathways participating in the modulation of NFκB have been extensively described,here we tested the hypothesis that 6-OHDA-induced injury can activate lipid signaling and, in turn,modulate the transcriptional response. 6-OHDA challenge triggered the activation of lipid signaling pathwaysand increased phosphatidic acid (PA), diacylglycerol and free fatty acid levels in human neuroblastoma cells.The inhibition of PA production was able to prevent the decrease in cell viability triggered by 6-OHDA, thenuclear translocation of NFκB p65 subunit and the rise in COX-2 mRNA expression. Our results indicate that theonset of the inflammatory process triggered by 6-OHDA involves the activation of PA signaling that, in turn,governs NFκB subcellular localization and COX-2 expression