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.

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.