L-carnitine modulates molecular responses associated with inflammation, endoplasmic reticulum stress, and neurotrophic signaling in cerebral cortex of neonatal Gcdh−/− mice exposed to glutaric and quinolinic acids

Abstract

Abstract Glutaric acidemia type 1 (GA I) is caused by deficient activity of glutaryl-CoA dehydrogenase, leading to predominant accumulation of glutaric acid (GA) in the brain. GA I patients present progressive neurological deterioration whose pathophysiology is only partially elucidated. We investigated whether intracerebral GA administration, alone or combined with quinolinic acid (QA), a pro-inflammatory intermediate of the kynurenine pathway, could alter the expression of genes associated with inflammatory signaling, endoplasmic reticulum (ER) stress, and neurotrophic support in cerebral cortex of wild-type (WT) and Gcdh −/− mice. We also tested the effects of L-carnitine (Carn) on these parameters. GA alone increased mRNA levels of the genes encoding NF-κB ( NFKB1 ), COX-2 ( PTGS2 ), iNOS ( NOS2 ), and TLR2 ( TLR2 ) in both genotypes, while reducing those of IL-10 ( IL10 ) and VEGF-A ( VEGFA ) only in Gcdh −/− mice. Combined QA + GA treatment produced a larger response, including increased TNF-α ( TNF ), IL-1β ( IL1B ), IL-6 ( IL6 ) , NLRP3 ( NLRP3 ), CHOP ( DDIT3 ) and PERK ( EIF2AK3 ) mRNA levels in the Gcdh −/− mice, besides reducing IκBα ( NFKBIA ), IL-10 ( IL10 ) and BDNF ( BDNF ) expression in both genotypes, and VEGF-A ( VEGFA ) in the Gcdh −/− mice. We also found that lysine (Lys) and QA treatment elevated TNF-α, IL-1β, and IL-6 protein levels in Gcdh −/− mice. Carn prevented or attenuated most transcriptional alterations induced by QA + GA and reduced cytokine protein elevations elicited by Lys + QA administration. These findings indicate that Carn modulates acute molecular responses related to inflammation, ER stress, and neurotrophic factors in the cerebral cortex of the GAI mouse model.