Role of Catalase and Superoxide Dismutase Activities on Oxidative Stress in the Brain of a Phenylketonuria Animal Model and the Effect of Lipoic Acid

Abstract

Phenylketonuria (PKU) is an inherited metabolic disorder caused by deficiency of phenylalanine hydroxylase which leads to accumulation of phenylalanine and its metabolites in tissues of patients with severe neurological involvement. Recently, many studies in animal models or patients have reported the role of oxidative stress in PKU. In the present work we studied the effect of lipoic acid against oxidative stress in rat brain provoked by an animal model of hyperphenylalaninemia (HPA), induced by repetitive injections of phenylalanine and α-methylphenylalanine (a phenylalanine hydroxylase inhibitor) for 7 days, on some oxidative stress parameters. Lipoic acid prevented alterations on catalase (CAT) and superoxide dismutase (SOD), and the oxidative damage of lipids, proteins, and DNA observed in HPA rats. In addition, lipoic acid diminished reactive species generation compared to HPA group which was positively correlated to SOD/CAT ratio. We also observed that in vitro Phe inhibited CAT activity while phenyllactic and phenylacetic acids stimulated superoxide dismutase activity. These results demonstrate the efficacy of lipoic acid to prevent oxidative stress induced by HPA model in rats. The possible benefits of lipoic acid administration to PKU patients should be considered.

Prooxidant-antioxidant balance in patients with phenylketonuria and its correlation to biochemical and hematological parameters

“…A modified PAB was applied based on a previously described method [24]. Briefly, a standard curve was plotted using varying proportions (0%-100%) of 250 μM hydrogen peroxide with 3 mM uric acid (in 10 mM NaOH).…”

“…Phenylalanine directly suppresses GPx production or advances GPx degradation in a rat model of hyperphenylalaninemia [24]. Conversely, GPx activity levels express a tight negative connection with the serum Phe level, which suggests that Phe per Se inhibits GPx activity [25].…”

Phenylketonuria Pathophysiology: on the Role of Metabolic Alterations

“…While PLA and PAA increase SOD activity in rat brain tissue, PPA decreases glucose-6-phosphate dehydrogenase (EC # 1.1.1.49) in the same tissue [43,46], indicating a possible indirect mechanism by which Phe leads to oxidative stress in PKU. The main findings on disruption of redox homeostasis reported in patients and animal models of PKU are summarized in Table 1.…”

“…In this scenario, high Phe concentrations also increases sulfhydryl oxidation, TBA-RS and MDA levels, and 2',7'-dichlorofluorescein (DCFH) oxidation, indicating protein and lipid oxidative damage and increased production of reactive species of oxygen, respectively [38][39][40][41][42][43]. Most of these findings were prevented by supplementation with lipoic acid, melatonin, alpha-tocopherol and/or ascorbic acid, which are potent and well-known antioxidants [22].…”

Role of α-Lipoid Acid and Acetyl-L-Carnitine in Dementia

“…In controlled experiments in an animal model of hyperphenylalaninemia, LA prevents the oxidative stress associated with PKU, in vitro and in vivo, by decreasing the ROS and thereby attenuating oxidative damage of proteins, lipids, and DNA [23,24]. The metabolites of phenylalanine and its oxidative degradation products cause increased risk for neurological complications.…”