ABSTRACT
Medium-chain fatty acids and acylcarnitines accumulate in medium-chain acyl-CoA dehydrogenase deficiency (MCADD), the most frequent fatty acid oxidation defect clinically characterized by episodic crises with vomiting, seizures and coma. Considering that the pathophysiology of the neurological symptoms observed in MCADD is poorly known and, to our knowledge, there is no report on the involvement of acylcarnitines in the brain damage presented by the affected patients, the objective of the present study was to investigate the in vitro effects of hexanoylcarnitine (HC), octanoylcarnitine, decanoylcarnitine (DC) and cis-4-decenoylcarnitine (cDC) at concentrations varying from 0.01 to 1.0mM on important oxidative stress parameters in cerebral cortex of young rats. HC, DC and cDC significantly induced lipid peroxidation, as determined by increased thiobarbituric acid-reactive substances (TBA-RS) values. In addition, carbonyl formation was significantly augmented and sulfhydryl content diminished by DC, reflecting induction of protein oxidative damage. HC, DC and cDC also decreased glutathione (GSH) levels, the most important brain antioxidant defense. Furthermore, DC-induced elevation of TBA-RS values and decrease of GSH levels were prevented by the free radical scavengers melatonin and α-tocopherol, indicating the involvement of reactive oxygen species in these effects. We also found that l-carnitine itself did not induce lipid and protein oxidative damage, neither reduced the antioxidant defenses. Our present data show that the major medium-chain acylcarnitines accumulating in MCADD elicit oxidative stress in rat brain. It is therefore presumed that these compounds may be involved to a certain extent in the pathogenesis of the neurologic dysfunction of MCADD.
Subject(s)
Cerebral Cortex/physiopathology , Homeostasis/physiology , Lipid Metabolism, Inborn Errors/pathology , Acyl-CoA Dehydrogenase/deficiency , Animals , Carnitine/analogs & derivatives , Carnitine/toxicity , Cerebral Cortex/drug effects , Cerebral Cortex/metabolism , Glutathione/metabolism , Homeostasis/drug effects , Homeostasis/ethics , Lipid Metabolism, Inborn Errors/chemically induced , Lipid Metabolism, Inborn Errors/prevention & control , Lipid Peroxidation/drug effects , Male , Melatonin/administration & dosage , Oxidative Stress/drug effects , Oxidative Stress/physiology , Protein Carbonylation/drug effects , Rats , Rats, Wistar , Statistics, Nonparametric , Thiobarbituric Acid Reactive Substances/metabolism , alpha-Tocopherol/administration & dosageABSTRACT
AIM: To evaluate the efficacy and safety of 2 analogs of L-carnitine on rats made insulin resistant by a high-fructose diet. METHODS: Using rats made insulin resistant by a high-fructose diet, we investigated the impact of 2 analogs of L-carnitine (25 mg/kg) and L-carnitine (250 mg/kg) on glucose, triglycerides and cholesterol blood levels, and liver glycogen. We also evaluated the safety of both analogs by the assessment of some biochemical and hematological parameters, a histological analysis and a study of embryotoxicity. RESULTS: Both analogs reduced the levels of triglycerides in the liver and plasma, but only analog 2 reduced the cholesterol levels in insulin-resistant rats. No changes were observed in glycogen content. Safety evaluations revealed alterations in blood lymphocytes and embryotoxicity data. CONCLUSION: This study demonstrated that the 2 analogs maintain the pharmacological properties of L-carnitine but have a different efficacy, potency and toxicity.