L-Carnitine Prevents Lipopolysaccharide-Induced Inflammatory Response, Microglia Activation and Neuronal Damage in Cerebral Cortex, as Well as Neuromotor Development Delay in Neonatal Glutaryl-CoA Dehydrogenase Deficient (Gcdh-/-) Mice.

Patients with glutaric acidemia type I (GA I) frequently manifest with acute encephalopathy usually triggered by infections and by progressive neurological deterioration. Since the pathogenesis of the brain damage in GA I during inflammatory processes is poorly established, we investigated biomarkers of inflammatory response and neural damage in the cerebral cortex of wild type (WT) and glutaryl-CoA dehydrogenase (GCDH) deficient mice (Gcdh-/-) receiving acute lysine and lipopolysaccharide (LPS) administration to induce inflammation. Neuromotor development reflexes and the neuroprotective effects of L-carnitine (Carn), whose potent anti-inflammatory properties have been recently described, were also evaluated. LPS increased the gene expression of most parameters of the inflammatory response, which were normalized or attenuated by Carn both in WT and Gcdh-/- mice. Importantly, gene expression of TNF-α, IL-6, NFkB, IκBα, COX-2 and VEGF, and heme oxygenase-1 content were significantly increased in LPS-treated Gcdh-/- relatively to the WT mice. Furthermore, the neuronal biomarker protein NeuN was reduced, whereas the number of vacuoles and neurodegenerative cells were increased in the LPS-treated Gcdh-/- mice, indicating neuronal damage and loss in these animals. Furthermore, the righting and the gait reflexes were altered in the Gcdh-/- mice, reflecting impairment of neuromotor development. Finally, Carn prevented LPS-induced inflammation, neuronal damage, vacuolation, increased neurodegenerative cells and the righting reflex. Our findings suggest that inflammation plays an important role in the pathogenesis of the neurological alterations following infectious/inflammatory processes in GA I patients and that higher doses of Carn should be considered during these episodes.