Disruption of redox homeostasis in cerebral cortex of developing rats by acylcarnitines accumulating in medium-chain acyl-CoA dehydrogenase deficiency.

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.

Neurochemical evidence that phytanic acid induces oxidative damage and reduces the antioxidant defenses in cerebellum and cerebral cortex of rats.

AIMS: In the present work we investigated the in vitro effects of phytanic acid (Phyt), that accumulates in Refsum disease and other peroxisomal diseases, on important parameters of oxidative stress in cerebellum and cerebral cortex from young rats. MAIN METHODS: The parameters thiobarbituric acid-reactive substances levels (TBA-RS; lipid peroxidation), carbonyl formation and sulfhydryl oxidation (protein oxidative damage) and the concentrations of the most important nonenzymatic antioxidant defense reduced glutathione (GSH) were determined. KEY FINDINGS: It was observed that Phyt significantly increased TBA-RS levels in both cerebral structures. This effect was prevented by the antioxidants alpha-tocopherol and melatonin, suggesting the involvement of free radicals. Phyt also provoked protein oxidative damage in both cerebellum and cerebral cortex, as determined by increased carbonyl content and sulfhydryl oxidation. Furthermore, Phyt significantly diminished the concentrations of GSH, while melatonin and alpha-tocopherol treatment totally blocked this effect. We also verified that Phyt does not behave as a direct acting oxidant, since Phyt did not oxidize commercial solutions of GSH and reduced cytochrome c to Phyt in a free cell medium. SIGNIFICANCE: Our data indicate that oxidative stress is elicited in vitro by Phyt, a mechanism that may contribute at least in part to the pathophysiology of Refsum disease and other peroxisomal disorders where Phyt is accumulated.