Bioquímica e Farmacologia: Acesso Aberto
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Sex-specific Gene Expression in Flupirtine-Treated Cln3Δex7/8 Mouse Brain

Rose-Mary Boustany1,6*, Joelle Makoukji1, Sara Saab1, Katia Maalouf1, Nadine J. Makhoul1, Angelica V. Carmona2, Nihar Kinarivala3, Paul C. Trippier2,4,5

Gene expression is a powerful tool to understand structure-function relationships in the nervous system. This study reports global gene expression changes induced by flupirtine in brain of male and female Cln3Δex7/8 mice, exposing potential flupirtine targets at the molecular level. Gene expression analysis of male and female Cln3Δex7/8 mouse brain was determined following oral administration of flupirtine for 14 weeks, using Mouse Genome 430 2.0 array Chips and an Affymetrix platform. Fifty-six genes in males and 79 in females were differentially expressed in flupirtine-versus vehicle-treated Cln3Δex7/8 mouse brain. Flupirtine altered several pathways in Cln3Δex7/8 mouse brain: apoptosis, the complement cascade, NF-kB, and p38α MAPK signaling pathways. Gene-gene network analysis highlighted networks and processes functionally pertinent to flupirtine treatment. These encompassed neurodegeneration, neuro-inflammation, and implicated neurological disorders such as Alzheimer and Parkinson disease. Flupirtine mediates its action in males and females through distinctive actionable targets in the same pathways. This work consolidates the groundwork for considering flupirtine as a treatment option in human CLN3 disease.