Experimental hyperphenylalaninemia provokes oxidative stress in rat brain

Abstract

Tissue accumulation of L-phenylalanine (Phe) is the biochemical hallmark of human phenylketonuria (PKU), an inherited metabolic disorder clinically characterized by mental retardation and other neurological features. The mechanisms of brain damage observed in this disorder are poorly understood. In the present study we investigated some oxidative stress parameters in the brain of rats with experimental hyperphenylalaninemia. Chemiluminescence, total radical-trapping antioxidant potential (TRAP), superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) activities were measured in the brain of the animals. We observed that chemiluminescence is increased and TRAP is reduced in the brain of hyperphenylalaninemic rats. Similar data were obtained in the in vitro experiments using Phe at various concentrations. CAT activity was significantly inhibited by Phe in vitro and in vivo, whereas GSH-Px activity was reduced in vivo but not in vitro and SOD activity was not altered by any treatment. The results indicate that oxidative stress may be involved in the neuropathology of PKU. However, further studies are necessary to confirm and extend our findings to the human condition and also to determine whether an antioxidant therapy may be of benefit to these patients.

Parsing the life-shortening effects of dietary protein: effects of individual amino acids

“…Methionine is proposed to be related to oxidative stress processes [56]. Interestingly, injections of phenylalanine in rats induce metabolic disorders also associated with oxidative stress [57] and, in the African honeybee, the use of an antioxidant reduces the life-shortening effect of foods with an excess of free essential amino acids [58]. Despite their toxicity at high concentrations, these amino acids are essential (Met, Thr, Phe) or conditionally essential (Ser) for insects [59].…”

L‐dopa–responsive Parkinson's syndrome in association with phenylketonuria: In vivo dopamine transporter and D2 receptor findings

“…Exposure to high serum phenylalanine concentrations in infancy is thought to have an adverse effect during vulnerable periods of brain development,40 e.g., during arborization of cortical dendrites, myelination of forebrain structures,23 and development of brain dopamine, which largely takes place in the first postnatal year 4, 41. Moreover, ongoing hyperphenylalaninemia has been linked to a state of neuronal oxidative stress that may contribute to late neurological deterioration in PKU 42, 43. Such processes could preferentially involve dorsal striatal projections.…”

DNA damage induced by phenylalanine and its analogue p-chlorophenylalanine in blood and brain of rats subjected to a model of hyperphenylalaninemia

“…In this context, previous studies showed that experimental HPA provokes increased lipid peroxidation in the brain, whereas the ratio of glutathione/ glutathione disulfide was decreased and glucose-6-phosphate dehydrogenase and catalase activities were increased in the erythrocytes of a PKU animal model (Sierra et al 1998;Hagen et al 2002;Schulpis et al 2003;Faust et al 2004). Additionally, PKU patients show a significant increase in plasma thiobarbituric acid-reactive substances (TBA-RS), as well as a decrease in plasma total antioxidant reactivity, reflecting an impaired capacity to rapidly handle an increase in reactive species generation or a decrease in antioxidant enzyme activities (Colomé et al 2003;Sirtori et al 2005;Sitta et al 2006Sitta et al , 2009aSitta et al , 2009bGassió et al 2008).…”

“…Phe also influences neural excitability (Iarosh et al 1987), while experimental hyperphenylalaninemia (HPA) in newborn rats leads to reduced myelinogenesis (Burri et al 1990) and decreased axonal conduction velocity, as well as decreased Na + /K + -ATPase activity in synaptic plasma membranes (Wyse et al 1994(Wyse et al , 1999. Furthermore, in vitro and in vivo evidence from both animal and human studies have emphasized a role for oxidative stress in the pathogenesis of brain dysfunction in PKU (Wilke et al 1992;Sierra et al 1998;Ercal et al 2002;Hagen et al 2002;Martinez-Cruz et al 2002;Sirtori et al 2005;Sitta et al 2006Sitta et al , 2009aSitta et al , 2009b.…”