Effect of phenylalanine and its metabolites on ATP diphosphohydrolase activity in synaptosomes from rat cerebral cortex

Wyse, Ângela Terezinha de Souza; Sarkis, João José Freitas; Cunha-Filho, João Sabino; Teixeira, Marcio Vieira; Schetinger, Maria Rosa Chitolina; Wajner, Moaçir; Wannmacher, Clóvis Milton Duval

doi:10.1007/bf00965152

Cited by 23 publications

(1 citation statement)

References 38 publications

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“…In this scenario, Phe is thought to be the main neurotoxic metabolite in PKU, due to interference with the production of the neurotransmitters dopamine and noradrenaline, decrease of the availability of tryptophan and tyrosine, as well as serotonin and catecholamine depletion (Aragon et al 1982;Herrero et al 1983). 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.…”

Section: Introductionmentioning

confidence: 97%

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

Simon

Santos

Scaini

et al. 2013

Biochem. Cell Biol.

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Phenylketonuria (PKU) is a disease caused by a deficiency of phenylalanine hydroxylase (PAH), resulting in an accumulation of phenylalanine (Phe) in the brain tissue, cerebrospinal fluid, and other tissues of PKU patients. Considering that high levels of Phe are associated with neurological dysfunction and that the mechanisms underlying the neurotoxicity in PKU remain poorly understood, the main objective of this study was to investigate the in vivo and in vitro effects of Phe on DNA damage, as determined by the alkaline comet assay. The results showed that, compared to control group, the levels of DNA migration were significantly greater after acute administration of Phe, p-chlorophenylalanine (p-Cl-Phe, an inhibitor of PAH), or a combination thereof in cerebral cortex and blood, indicating DNA damage. These treatments also provoked increase of carbonyl content. Additionally, when Phe or p-Cl-Phe was present in the incubation medium, we observed an increase in the frequency and index of DNA damage in the cerebral cortex and blood, without affecting lactate dehydrogenase (LDH) release. Our in vitro and in vivo findings indicate that DNA damage occurs in the cerebral cortex and blood of rats receiving Phe, suggesting that this mechanism could be, at least in part, responsible for the neurological dysfunction in PKU patients.

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Section: Introductionmentioning

confidence: 97%

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

Simon

Santos

Scaini

et al. 2013

Biochem. Cell Biol.

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NTPDase and 5'‐nucleotidase activities in physiological and disease conditions: New perspectives for human health

et al. 2007

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Abstract. Extracellular nucleotides and nucleosides act as signaling molecules involved in a wide spectrum of biological effects. Their levels are controlled by a complex cell surface-located group of enzymes called ectonucleotidases. There are four major families of ectonucleotidases, nucleoside triphosphate diphosphohydrolases (NTPDases/CD39), ectonucleotide pyrophosphatase/phosphodiesterases (E-NPPs), alkaline phosphatases and ecto-5'-nucleotidase. In the last few years, substantial progress has been made toward the molecular identification of members of the ectonucleotidase families and their enzyme structures and functions. In this review, there is an emphasis on the involvement of NTPDase and 5'-nucleotidase activities in disease processes in several tissues and cell types. Brief background information is given about the general characteristics of these enzymes, followed by a discussion of their roles in thromboregulatory events in diabetes, hypertension, hypercholesterolemia and cancer, as well as in pathological conditions where platelets are less responsive, such as in chronic renal failure. In addition, immunomodulation and cell-cell interactions involving these enzymes are considered, as well as ATP and ADP hydrolysis under different clinical conditions related with alterations in the immune system, such as acute lymphoblastic leukemia (ALL), Bchronic lymphocytic leukemia (B-CLL) and infections associated with human immunodeficiency virus (HIV). Finally, changes in ATP, ADP and AMP hydrolysis induced by inborn errors of metabolism, seizures and epilepsy are discussed in order to highlight the importance of these enzymes in the control of neuronal activity in pathological conditions. Despite advances made toward understanding the molecular structure of ectonucleotidases, much more investigation will be necessary to entirely grasp their role in physiological and pathological conditions.

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Ectonucleotidases and synaptic plasticity: Implications in physiological and pathological conditions

Bonan

Schetinger

Battastini

et al. 2001

Drug Development Research

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Several studies have suggested a role of extracellular ATP in synaptic plasticity. The signaling actions induced by extracellular ATP are directly correlated to the activity of a group of ectonucleotidases, which includes an ecto-ATPase (EC 3.6.1.3), an ATP diphosphohydrolase (apyrase, EC 3.6.1.5), and a 5′-nucleotidase (EC 3.1.3.5). These ectoenzymes trigger enzymatic conversion of ATP to adenosine, an important neuromodulator. Our studies have shown that ectonucleotidase activities are modulated in physiological and pathological situations able to induce synaptic plasticity, such as memory, epilepsy, and ischemia. Synaptosomal ectonucleotidase activities from hippocampus and entorhinal cortex were inhibited after the training session in a step-down inhibitory avoidance task in rats. Considering that adenosine has anticonvulsant effects, ectonucleotidase activities were determined after the induction of epilepsy by several animal models, such as pilocarpine, kainic acid, and kindling models. ATP diphosphohydrolase and 5′-nucleotidase activities from synaptosomes of hippocampus and cerebral cortex of rats significantly and differently increased after induction of status epilepticus by pilocarpine, kainic acid, or kindling models. Furthermore, significant changes have been observed in ATP diphosphohydrolase and 5′-nucleotidase after ischemia and reperfusion in hippocampal synaptosomes of rats. The demonstration that ectonucleotidases presented the activities altered after a memory task, or the induction of animal models of epilepsy or ischemia-reperfusion, suggests that these enzymes can act in the regulation of synaptic activity, controlling ATP and adenosine levels, depending on the synaptic plasticity developed, in physiological or pathological conditions. Drug Dev. Res. 52:57-65, 2001.

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Effect of phenylalanine and its metabolites on ATP diphosphohydrolase activity in synaptosomes from rat cerebral cortex

Cited by 23 publications

References 38 publications

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

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

NTPDase and 5'‐nucleotidase activities in physiological and disease conditions: New perspectives for human health

Ectonucleotidases and synaptic plasticity: Implications in physiological and pathological conditions

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