Mitochondrial damage induced by fetal hyperphenylalaninemia in the rat brain and liver: its prevention by melatonin, Vitamin E, and Vitamin C.

Abnormal oxidative stress was observed in hyperphenylalaninemia and other inborn errors of intermediary metabolism, owing to the accumulation of toxic metabolites, free radical production and increased LPO products. In our model of maternal hyperphenylalaninemia, pregnant rats were injected with 300 mg/kg BW l-phenylalanine (PHE) and 50 mg/kg BW p-chlorophenylalanine (PCPA) dissolved in saline. In this research study, we measured LPO-by-products, i.e., malonaldehyde (MDA) and 4-hydroxynonenal (4-HNE) and we demonstrated that maternal hyperphenylalaninemia increased both markers of oxidative stress in the brain and liver mitochondria of the pups. We also demonstrated that administration of melatonin, Vitamin E, and Vitamin C, in this order of potency, prevented the oxidative damage to the mitochondria, especially in the brain. We therefore conclude that maternal hyperphenylalaninemia induces a clear state of oxidative stress that is somehow directly involved in brain and liver impairment, which can be prevented by melatonin, Vitamin E, and Vitamin C.

Melatonin prevents hyperhomocysteinemia and neural lipid peroxidation induced by methionine intake.

This study was designed to determine the protective effect of melatonin treatment against oxidative damage in rat brain induced by hyperhomocysteinemia (Hhcy). Oral administration of methionine and its degradation product, homocysteine (hcy), causes mild to moderate Hhcy. The major end-point of oxidative damage measured in this report was lipid peroxidation (LPO). The levels of malondialdehyde (MDA) were assayed as index of lipid peroxidation. The increase in lipid peroxidation was inhibited by melatonin. Rats were divided into seven groups: one was used as control and each remaining group was supplemented with methionine dissolved and added to the drinking water daily for 4 weeks (0.5, 1, 1.5, 2, 3 g /kg BW). Additional groups of rats were given both melatonin (30 mg/kg BW) and methionine in drinking water daily. At the conclusion of the study, MDA levels were significantly increased in the brains of methionine-treated rats compared with control rats, whereas melatonin prevented the increases in MDA levels. Plasma hcy levels in animals treated with melatonin were significantly lower than those of controls. Melatonin lowered plasma hcy levels and could potentially be beneficial in prevention of neurodegeneration caused by mild hyperhomocysteinemia.

Melatonin prevents focal rat cerebellum injury as assessed by induction of heat shock protein (HO-1) following subarachnoid injections of lysed blood.

The present paper studies a marker of oxidative stress such as heme oxygenase-1 (HO-1), the main heat shock protein. HO-1 expression was induced in the focal region of the cerebellum following experimental subarachnoid hemorrhage (SAH). Lysed blood was injected into the subarachnoid space or cisterna magna region of adult rats. The experimental groups used were: (1) animals injected with lysed blood alone; (2) animals injected with saline alone; (3) lysed blood plus melatonin (10 mg/kg body weight(BW)); (4) lysed blood plus melatonin (10 mg/kg BW injected 1 h before SAH); (5) lysed blood plus melatonin (5 mg/kg BW injected 1 h before SAH); (6) lysed blood plus vitamin E (Trolox; 30 mg/kg BW injected simultaneously); (7) lysed blood plus vitamin E (30 mg/kg BW injected 1 h before SAH); and (8) lysed blood plus vitamin E (15 mg/kg BW injected 1 h before SAH). Animals were sacrificed 24 h later. Injection of lysed blood induced an overexpression of HO-1. Both, melatonin and vitamin E were able to prevent the expression of the heat shock protein. However, in terms of efficiency, the antioxidant capability of melatonin was clearly higher than that exhibited by vitamin E. The results presented in this study show that antioxidants, especially melatonin, prevent focal regions of injury as assessed by heat shock protein expression in a rat model of SAH.

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

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.

Melatonin prevents the formation of pyrrolized proteins in human plasma induced by hydrogen peroxide.

This report presents a model of oxidative stress, which includes formation of pyrrolized proteins in human plasma. Pyrroles were determined using Ehrlich's reagent under acid conditions. Adduct formation in plasma proteins was induced by hydrogen peroxide (H(2)O(2)) in a dose-dependent manner. The simultaneous addition of melatonin to the incubation medium with 100 mM H(2)O(2) prevented the formation of Ehrlich adducts. This inhibitory effect of melatonin on adduct formation was significant at concentrations higher than 10 nM melatonin. When melatonin was added to the medium 60 min before adding H(2)O(2), no significant difference was observed. The effect of melatonin was also compared with other known antioxidants such as vitamin E (Trolox) and vitamin C; the order of potency of the antioxidants was melatonin>vitamin E>vitamin C. In conclusion, the results presented in this paper add new perspectives to other well known antioxidant properties of melatonin such as prevention of protein pyrrolization.

Dosificacion y Validacion de Aspirina (ASA) y Derivados en Orina / Dosification and validation of aspirin (ASA) and derivates in urine

Se estudiron 131 casos de ninos con diferentes edades, sexo y raza, aparentemente sanos, procedentes de los servicios de consulta externa del Hospital Pediatrico Docente "Juan Manuel Marquez", con el fin de conocer concentraciones basales de salicilatos en orina. Posteriormente se estudiaron 20 casos voluntarios con el objetivo de establecer valores de referencia y por ultimo se procesaron 10 casos de ninos con intoxicacion por salicilato con el proposito de conocer rango toxico de este parametro en orina

Dosificación y Validación de Aspirina (ASA) y Derivados en Orina / Dosification and validation of aspirin (ASA) and derivates in urine

Se estudiron 131 casos de niños con diferentes edades, sexo y raza, aparentemente sanos, procedentes de los servicios de consulta externa del Hospital Pediátrico Docente "Juan Manuel Marquéz", con el fin de conocer concentraciones basales de salicilatos en orina. Posteriormente se estudiaron 20 casos voluntarios con el objetivo de establecer valores de referencia y por último se procesaron 10 casos de niños con intoxicación por salicilato con el propósito de conocer rango tóxico de este parámetro en orina(AU)