l-Carnitine prevents oxidative stress in striatum of glutaryl-CoA dehydrogenase deficient mice submitted to lysine overload

• Published in: Biochimica et biophysica acta. Molecular basis of disease 2019-09, Vol.1865 (9), p.2420-2427
• Main Authors: Guerreiro, Gilian, Amaral, Alexandre U., Ribeiro, Rafael Teixeira, Faverzani, Jéssica, Groehs, Ana Carolina, Sitta, Angela, Deon, Marion, Wajner, Moacir, Vargas, Carmen Regla
• Format: Article
• Language: English
• Subjects: Amino Acid Metabolism, Inborn Errors - metabolism; Amino Acid Metabolism, Inborn Errors - pathology; Amino Acid Metabolism, Inborn Errors - veterinary; Animals; Brain Diseases, Metabolic - metabolism; Brain Diseases, Metabolic - pathology; Brain Diseases, Metabolic - veterinary; Carnitine - analogs & derivatives; Carnitine - metabolism; Carnitine - pharmacology; Corpus Striatum - metabolism; Diet - veterinary; Disease Models, Animal; Glutaric aciduria type I; Glutaryl-CoA dehydrogenase; Glutaryl-CoA Dehydrogenase - deficiency; Glutaryl-CoA Dehydrogenase - genetics; Glutaryl-CoA Dehydrogenase - metabolism; Glutathione Peroxidase - metabolism; Knockout model Gcdh; l-Carnitine; Lysine - blood; Lysine - pharmacology; Mice; Mice, Knockout; Oxidative stress; Oxidative Stress - drug effects; Reactive Oxygen Species - metabolism; Superoxide Dismutase - metabolism
• ISSN: 0925-4439; 1879-260X
• DOI: 10.1016/j.bbadis.2019.06.007

The deficiency of the enzyme glutaryl-CoA dehydrogenase leads to predominant accumulation of glutaric acid (GA) in the organism and is known as glutaric acidemia type I (GA1). Despite the mechanisms of brain damage involved in GA1 are not fully understood, oxidative stress may be involved in this process. Treatment is based on protein/lysine (Lys) restriction and l-carnitine (L-car) supplementation. L-car was recently shown to have an important antioxidant role. A knockout mice model (Gcdh−/−) submitted to a dietary overload of Lys was developed to better understand the GA1 pathogenesis. In this study, we evaluated L-car and glutarylcarnitine levels, the lipid and protein damage, reactive oxygen species (ROS) production and antioxidant enzymes activities in striatum of Gcdh−/− and wild-type (WT) mice. We also determined the effect of the L-car treatment on these parameters. Thirty-day-old Gcdh−/− and WT mice were fed a normal chow (0.9% Lys) or submitted to a high Lys diet (4.7%) for 72 h. Additionally, these animals were administered with three intraperitoneal injections of saline or L-car in different times. Gcdh−/− mice were deficient in L-car and presented a higher glutarylcarnitine levels. They also presented lipid and protein damage, an increased ROS production and altered antioxidant enzymes compared to WT mice. Additionally, mice exposed to Lys overload presented higher alterations in these parameters than mice under normal diet, which were significantly decreased or normalized in those receiving L-car. Thus, we demonstrated a new beneficial effect of the L-car treatment attenuating or abolishing the oxidative stress process in Gcdh−/− mice. •L-car treatment attenuated l-carnitine deficiency and decreased glutarylcarnitine levels in Gcdh−/− mice.•Gcdh−/− mice presented higher ROS levels than WT animals.•Gcdh−/− mice presented higher lipid and protein damage than WT mice.•L-car treatment was able to decrease protein and lipid oxidation.•Antioxidant enzyme activities were increased in Gcdh−/− in relation to WT mice.