Oxidative stress induced by phenylketonuria in the rat: Prevention by melatonin, vitamin E, and vitamin C

Abstract

Phenylketonuria (PKU) is an autosomal recessive disorder caused by a deficiency of the phenylalanine hydroxylation system and is characterized by a block in the conversion of phenylalanine (PHE) to tyrosine. We examined the effects of maternal hyperphenylalaninemia on the morphological and biochemical development of pup rat brain and cerebellum. In our model of PKU we evaluated a number of markers of oxidative stress such as Ehrlich adducts formation, lipid peroxidation, as well as the levels of reduced and oxidized glutathione, and the activities of the enzymes glutathione peroxidase and glutathione reductase. We also studied the expression of heme-oxigenase-1 and mitogen-activated protein kinase 1/2 (MAPK 1/2) as additional markers of oxidative stress. We demonstrate that PKU strongly increased most of the oxidative stress markers studied and induced significant morphological damage. We also showed that daily administration of melatonin (20 mg/kg BW), vitamin E (30 mg/kg BW), and vitamin C (30 mg/kg BW) until delivery prevented the oxidative biomolecular damage in the rat brain and cerebellum. Although no significant differences were observed among the antioxidants studied, it should be noted that the doses of melatonin were less than those for vitamins E and C. We conclude that PKU induces a clear state of oxidative stress that is somehow involved in the brain and body damage occurring in this inborn error. Moreover, melatonin and other antioxidants are capable of preventing completely the damage induced by PKU.

PKU is a reversible neurodegenerative process within the nigrostriatum that begins as early as 4 weeks of age in Pahenu2 mice

“…Numerous studies have provided experimental evidence demonstrating oxidative stress in human PKU patients and animal models (Artuch et al, 2001(Artuch et al, ,2004Colome et al, 2003;Ercal et al, 2002;Martinez-Cruz et al, 2002;Sierra et al, 1998;Sirtori et al, 2005). Our laboratory previously demonstrated increased inducible nitric oxide synthase production by infiltrative cd11b macrophage cells in the mesencephalon and hypothalamus of PKU mice (Embury et al, 2005), providing further evidence of oxidative processes occurring in these regions.…”

“…Sirtori et al (2005) demonstrated the involvement of oxidative stress in human PKU patients through increased levels of thiobarbituric acid reactive species (indicative of lipid peroxidation) and decreased total antioxidant reactivity, suggestive of deficient capacity to handle increases in reactive species. Martinez-Cruz et al (2002) determined that in an experimentally induced rat model of maternal PKU, oxidative stress parameters were increased and adversely influenced morphologic and biochemical development in rat pup brain and cerebellum.…”

An IκBα phosphorylation inhibitor induces heme oxygenase-1(HO-1) expression through the activation of reactive oxygen species (ROS)–Nrf2–ARE signaling and ROS–PI3K/Akt signaling in an NF-κB-independent mechanism

“…HO degrades heme, which produces equimolar quantities of biliverdin, which is then converted to bilirubin by biliverdin reductase, iron, and carbon monoxide [1]. HO exists in three isoforms: HO-1 is an inducible form that is increased by a variety of stimuli, such as oxidative stress, lipopolysaccharides, melatonin, transforming growth factor-beta1, and adenosine [2][3][4][5][6]. HO-2 and HO-3 are constitutive forms.…”

Phenylketonuria Pathophysiology: on the Role of Metabolic Alterations

“…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].…”