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Carolina Maso Viegas - One of the best experts on this subject based on the ideXlab platform.
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Chronic postnatal ornithine administration to rats provokes learning deficit in the open field task
Metabolic Brain Disease, 2012Co-Authors: Carolina Maso Viegas, Estela Natacha Brandt Busanello, Anelise Miotti Tonin, Mateus Grings, Alana Pimentel Moura, Luciana Ritter, Ângela Zanatta, Lisiane Aurélio Knebel, Vannessa Araujo Lobato, Letícia Ferreira PettenuzzoAbstract:Hyperornithinemia is the biochemical hallmark of Hyperornithinemia–hyperammonemia–homocitrullinuria (HHH) syndrome, an inherited metabolic disease clinically characterized by mental retardation whose pathogenesis is still poorly known. In the present work, we produced a chemical animal model of Hyperornithinemia induced by a subcutaneous injection of saline-buffered Orn (2–5 μmol/g body weight) to rats. High brain Orn concentrations were achieved, indicating that Orn is permeable to the blood brain barrier. We then investigated the effect of early chronic postnatal administration of Orn on physical development and on the performance of adult rats in the open field, the Morris water maze and in the step down inhibitory avoidance tasks. Chronic Orn treatment had no effect on the appearance of coat, eye opening or upper incisor eruption, nor on the free-fall righting reflex and on the adult rat performance in the Morris water maze and in the inhibitory avoidance tasks, suggesting that physical development, aversive and spatial localization were not changed by Orn. However, Orn-treated rats did not habituate to the open field apparatus, implying a deficit of learning/memory. Motor activity was the same for Orn- and saline- injected animals. We also verified that Orn subcutaneous injections provoked lipid peroxidation in the brain, as determined by a significant increase of thiobarbituric acid-reactive substances levels. Our results indicate that chronic early postnatal Hyperornithinemia may impair the central nervous system, causing minor disabilities which result in specific learning deficiencies.
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Impairment of brain redox homeostasis caused by the major metabolites accumulating in Hyperornithinemia–hyperammonemia–homocitrullinuria syndrome in vivo
Metabolic brain disease, 2012Co-Authors: Carolina Maso Viegas, Estela Natacha Brandt Busanello, Anelise Miotti Tonin, Alana Pimentel Moura, Ângela Zanatta, Guilhian Leipnitz, Carolina Gonçalves Fernandes, Bianca Seminotti, Moacir WajnerAbstract:Ornithine, ammonia and homocitrulline are the major metabolites accumulating in Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome, a genetic disorder characterized by neurological regression whose pathogenesis is still not understood. The present work investigated the in vivo effects of intracerebroventricular administration of ornithine and homocitrulline in the presence or absence of hyperammonemia induced by intraperitoneal urease treatment on a large spectrum of oxidative stress parameters in cerebral cortex from young rats in order to better understand the role of these metabolites on brain damage. Ornithine increased thiobarbituric acid-reactive substances (TBA-RS) levels and carbonyl formation and decreased total antioxidant status (TAS) levels. We also observed that the combination of hyperammonemia with ornithine resulted in significant decreases of sulfhydryl levels, reduced glutathione (GSH) concentrations and the activities of catalase (CAT) and glutathione peroxidase (GPx), highlighting a synergistic effect of ornithine and ammonia. Furthermore, homocitrulline caused increases of TBA-RS values and carbonyl formation, as well as decreases of GSH concentrations and GPx activity. Hcit with hyperammonemia (urease treatment) decreased TAS and CAT activity. We also showed that urease treatment per se was able to enhance TBA-RS levels. Finally, nitric oxide production was not altered by Orn and Hcit alone or in combination with hyperammonemia. Our data indicate that the major metabolites accumulating in Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome provoke lipid and protein oxidative damage and a reduction of the antioxidant defenses in the brain. Therefore, it is presumed that oxidative stress may represent a relevant pathomechanism involved in the brain damage found in patients affected by this disease.
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impairment of brain redox homeostasis caused by the major metabolites accumulating in Hyperornithinemia hyperammonemia homocitrullinuria syndrome in vivo
Metabolic Brain Disease, 2012Co-Authors: Carolina Maso Viegas, Estela Natacha Brandt Busanello, Anelise Miotti Tonin, Alana Pimentel Moura, Ângela Zanatta, Guilhian Leipnitz, Carolina Gonçalves Fernandes, Bianca Seminotti, Moacir WajnerAbstract:Ornithine, ammonia and homocitrulline are the major metabolites accumulating in Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome, a genetic disorder characterized by neurological regression whose pathogenesis is still not understood. The present work investigated the in vivo effects of intracerebroventricular administration of ornithine and homocitrulline in the presence or absence of hyperammonemia induced by intraperitoneal urease treatment on a large spectrum of oxidative stress parameters in cerebral cortex from young rats in order to better understand the role of these metabolites on brain damage. Ornithine increased thiobarbituric acid-reactive substances (TBA-RS) levels and carbonyl formation and decreased total antioxidant status (TAS) levels. We also observed that the combination of hyperammonemia with ornithine resulted in significant decreases of sulfhydryl levels, reduced glutathione (GSH) concentrations and the activities of catalase (CAT) and glutathione peroxidase (GPx), highlighting a synergistic effect of ornithine and ammonia. Furthermore, homocitrulline caused increases of TBA-RS values and carbonyl formation, as well as decreases of GSH concentrations and GPx activity. Hcit with hyperammonemia (urease treatment) decreased TAS and CAT activity. We also showed that urease treatment per se was able to enhance TBA-RS levels. Finally, nitric oxide production was not altered by Orn and Hcit alone or in combination with hyperammonemia. Our data indicate that the major metabolites accumulating in Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome provoke lipid and protein oxidative damage and a reduction of the antioxidant defenses in the brain. Therefore, it is presumed that oxidative stress may represent a relevant pathomechanism involved in the brain damage found in patients affected by this disease.
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Evidence that the major metabolites accumulating in Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome induce oxidative stress in brain of young rats.
International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience, 2009Co-Authors: Alexandre Umpierrez Amaral, Carolina Maso Viegas, Ângela Zanatta, Guilhian Leipnitz, Carolina Gonçalves Fernandes, Bianca Seminotti, Carlos Severo Dutra-filho, Moacir WajnerAbstract:Ornithine and homocitrulline are the major metabolites accumulating in Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome, a genetic disorder characterized by neurological regression whose pathogenesis is still not understood. The present work investigated the in vitro effects of ornithine and homocitrulline on important parameters of oxidative stress in cerebral cortex from young rats. Ornithine significantly increased chemiluminescence and thiobarbituric acid-reactive substances levels, indicators of lipid peroxidation, while homocitrulline only augmented chemiluminescence values. Furthermore, ornithine-induced increase of thiobarbituric acid-reactive substances levels was attenuated (melatonin and reduced glutathione) or totally prevented (alpha-tocopherol) by free radical scavengers, suggesting that reactive species were involved in the lipid oxidative damage. We also observed that ornithine and homocitrulline significantly decreased the tissue antioxidant defenses, determined by reduced glutathione concentrations, the major non-enzymatic antioxidant defense found in the brain. Homocitrulline reduction of glutathione levels was completely prevented by melatonin and alpha-tocopherol, whereas ornithine-induced decrease of glutathione levels was only attenuated by these free radical scavengers. Ornithine and homocitrulline also induced protein oxidative damage, increasing carbonyl formation and sulfhydryl oxidation. In contrast, these amino acids did not affect nitric oxide production, indicating that nitrogen reactive species were not implicated in the lipid and oxidative damage provoked by ornithine and homocitrulline. Therefore, it is presumed that the major metabolites accumulating in Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome elicit oxidative stress and that this pathomechanism may possibly be involved in the brain damage found in patients affected by this disorder.
Moacir Wajner - One of the best experts on this subject based on the ideXlab platform.
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impairment of brain redox homeostasis caused by the major metabolites accumulating in Hyperornithinemia hyperammonemia homocitrullinuria syndrome in vivo
Metabolic Brain Disease, 2012Co-Authors: Carolina Maso Viegas, Estela Natacha Brandt Busanello, Anelise Miotti Tonin, Alana Pimentel Moura, Ângela Zanatta, Guilhian Leipnitz, Carolina Gonçalves Fernandes, Bianca Seminotti, Moacir WajnerAbstract:Ornithine, ammonia and homocitrulline are the major metabolites accumulating in Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome, a genetic disorder characterized by neurological regression whose pathogenesis is still not understood. The present work investigated the in vivo effects of intracerebroventricular administration of ornithine and homocitrulline in the presence or absence of hyperammonemia induced by intraperitoneal urease treatment on a large spectrum of oxidative stress parameters in cerebral cortex from young rats in order to better understand the role of these metabolites on brain damage. Ornithine increased thiobarbituric acid-reactive substances (TBA-RS) levels and carbonyl formation and decreased total antioxidant status (TAS) levels. We also observed that the combination of hyperammonemia with ornithine resulted in significant decreases of sulfhydryl levels, reduced glutathione (GSH) concentrations and the activities of catalase (CAT) and glutathione peroxidase (GPx), highlighting a synergistic effect of ornithine and ammonia. Furthermore, homocitrulline caused increases of TBA-RS values and carbonyl formation, as well as decreases of GSH concentrations and GPx activity. Hcit with hyperammonemia (urease treatment) decreased TAS and CAT activity. We also showed that urease treatment per se was able to enhance TBA-RS levels. Finally, nitric oxide production was not altered by Orn and Hcit alone or in combination with hyperammonemia. Our data indicate that the major metabolites accumulating in Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome provoke lipid and protein oxidative damage and a reduction of the antioxidant defenses in the brain. Therefore, it is presumed that oxidative stress may represent a relevant pathomechanism involved in the brain damage found in patients affected by this disease.
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Impairment of brain redox homeostasis caused by the major metabolites accumulating in Hyperornithinemia–hyperammonemia–homocitrullinuria syndrome in vivo
Metabolic brain disease, 2012Co-Authors: Carolina Maso Viegas, Estela Natacha Brandt Busanello, Anelise Miotti Tonin, Alana Pimentel Moura, Ângela Zanatta, Guilhian Leipnitz, Carolina Gonçalves Fernandes, Bianca Seminotti, Moacir WajnerAbstract:Ornithine, ammonia and homocitrulline are the major metabolites accumulating in Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome, a genetic disorder characterized by neurological regression whose pathogenesis is still not understood. The present work investigated the in vivo effects of intracerebroventricular administration of ornithine and homocitrulline in the presence or absence of hyperammonemia induced by intraperitoneal urease treatment on a large spectrum of oxidative stress parameters in cerebral cortex from young rats in order to better understand the role of these metabolites on brain damage. Ornithine increased thiobarbituric acid-reactive substances (TBA-RS) levels and carbonyl formation and decreased total antioxidant status (TAS) levels. We also observed that the combination of hyperammonemia with ornithine resulted in significant decreases of sulfhydryl levels, reduced glutathione (GSH) concentrations and the activities of catalase (CAT) and glutathione peroxidase (GPx), highlighting a synergistic effect of ornithine and ammonia. Furthermore, homocitrulline caused increases of TBA-RS values and carbonyl formation, as well as decreases of GSH concentrations and GPx activity. Hcit with hyperammonemia (urease treatment) decreased TAS and CAT activity. We also showed that urease treatment per se was able to enhance TBA-RS levels. Finally, nitric oxide production was not altered by Orn and Hcit alone or in combination with hyperammonemia. Our data indicate that the major metabolites accumulating in Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome provoke lipid and protein oxidative damage and a reduction of the antioxidant defenses in the brain. Therefore, it is presumed that oxidative stress may represent a relevant pathomechanism involved in the brain damage found in patients affected by this disease.
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Evidence that the major metabolites accumulating in Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome induce oxidative stress in brain of young rats.
International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience, 2009Co-Authors: Alexandre Umpierrez Amaral, Carolina Maso Viegas, Ângela Zanatta, Guilhian Leipnitz, Carolina Gonçalves Fernandes, Bianca Seminotti, Carlos Severo Dutra-filho, Moacir WajnerAbstract:Ornithine and homocitrulline are the major metabolites accumulating in Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome, a genetic disorder characterized by neurological regression whose pathogenesis is still not understood. The present work investigated the in vitro effects of ornithine and homocitrulline on important parameters of oxidative stress in cerebral cortex from young rats. Ornithine significantly increased chemiluminescence and thiobarbituric acid-reactive substances levels, indicators of lipid peroxidation, while homocitrulline only augmented chemiluminescence values. Furthermore, ornithine-induced increase of thiobarbituric acid-reactive substances levels was attenuated (melatonin and reduced glutathione) or totally prevented (alpha-tocopherol) by free radical scavengers, suggesting that reactive species were involved in the lipid oxidative damage. We also observed that ornithine and homocitrulline significantly decreased the tissue antioxidant defenses, determined by reduced glutathione concentrations, the major non-enzymatic antioxidant defense found in the brain. Homocitrulline reduction of glutathione levels was completely prevented by melatonin and alpha-tocopherol, whereas ornithine-induced decrease of glutathione levels was only attenuated by these free radical scavengers. Ornithine and homocitrulline also induced protein oxidative damage, increasing carbonyl formation and sulfhydryl oxidation. In contrast, these amino acids did not affect nitric oxide production, indicating that nitrogen reactive species were not implicated in the lipid and oxidative damage provoked by ornithine and homocitrulline. Therefore, it is presumed that the major metabolites accumulating in Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome elicit oxidative stress and that this pathomechanism may possibly be involved in the brain damage found in patients affected by this disorder.
Carlo Dionisi-vici - One of the best experts on this subject based on the ideXlab platform.
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The Hyperornithinemia-hyperammonemia- homocitrullinuria syndrome
Orphanet journal of rare diseases, 2015Co-Authors: Diego Martinelli, Emanuela Ponzi, Giuseppe Fiermonte, Daria Diodato, Enrico Bertini, Sara Boenzi, Magnus Monne, Carlo Dionisi-viciAbstract:Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is a rare autosomal recessive disorder of the urea cycle. HHH has a panethnic distribution, with a major prevalence in Canada, Italy and Japan. Acute clinical signs include intermittent episodes of vomiting, confusion or coma and hepatitis-like attacks. Alternatively, patients show a chronic course with aversion for protein rich foods, developmental delay/intellectual disability, myoclonic seizures, ataxia and pyramidal dysfunction. HHH syndrome is caused by impaired ornithine transport across the inner mitochondrial membrane due to mutations in SLC25A15 gene, which encodes for the mitochondrial ornithine carrier ORC1. The diagnosis relies on clinical signs and the peculiar metabolic triad of hyperammonemia, Hyperornithinemia, and urinary excretion of homocitrulline. HHH syndrome enters in the differential diagnosis with other inherited or acquired conditions presenting with hyperammonemia. A systematic review of publications reporting patients with HHH syndrome was performed. We retrospectively evaluated the clinical, biochemical and genetic profile of 111 HHH syndrome patients, 109 reported in 61 published articles, and two unpublished cases. Lethargy and coma are frequent at disease onset, whereas pyramidal dysfunction and cognitive/behavioural abnormalities represent the most common clinical features in late-onset cases or during the disease course. Two common mutations, F188del and R179* account respectively for about 30% and 15% of patients with the HHH syndrome. Interestingly, the majority of mutations are located in residues that have side chains protruding into the internal pore of ORC1, suggesting their possible interference with substrate translocation. Acute and chronic management consists in the control of hyperammonemia with protein-restricted diet supplemented with citrulline/arginine and ammonia scavengers. Prognosis of HHH syndrome is variable, ranging from a severe course with disabling manifestations to milder variants compatible with an almost normal life. This paper provides detailed information on the clinical, metabolic and genetic profiles of all HHH syndrome patients published to date. The clinical phenotype is extremely variable and its severity does not correlate with the genotype or with recorded ammonium/ornithine plasma levels. Early intervention allows almost normal life span but the prognosis is variable, suggesting the need for a better understanding of the still unsolved pathophysiology of the disease.
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The Hyperornithinemia–hyperammonemia-homocitrullinuria syndrome
Orphanet Journal of Rare Diseases, 2015Co-Authors: David Martinelli, Emanuela Ponzi, Giuseppe Fiermonte, Daria Diodato, Enrico Bertini, Sara Boenzi, Magnus Monne, Carlo Dionisi-viciAbstract:BACKGROUND Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is a rare autosomal recessive disorder of the urea cycle. HHH has a panethnic distribution, with a major prevalence in Canada, Italy and Japan. Acute clinical signs include intermittent episodes of vomiting, confusion or coma and hepatitis-like attacks. Alternatively, patients show a chronic course with aversion for protein rich foods, developmental delay/intellectual disability, myoclonic seizures, ataxia and pyramidal dysfunction. HHH syndrome is caused by impaired ornithine transport across the inner mitochondrial membrane due to mutations in SLC25A15 gene, which encodes for the mitochondrial ornithine carrier ORC1. The diagnosis relies on clinical signs and the peculiar metabolic triad of hyperammonemia, Hyperornithinemia, and urinary excretion of homocitrulline. HHH syndrome enters in the differential diagnosis with other inherited or acquired conditions presenting with hyperammonemia. METHODS A systematic review of publications reporting patients with HHH syndrome was performed. RESULTS We retrospectively evaluated the clinical, biochemical and genetic profile of 111 HHH syndrome patients, 109 reported in 61 published articles, and two unpublished cases. Lethargy and coma are frequent at disease onset, whereas pyramidal dysfunction and cognitive/behavioural abnormalities represent the most common clinical features in late-onset cases or during the disease course. Two common mutations, F188del and R179* account respectively for about 30% and 15% of patients with the HHH syndrome. Interestingly, the majority of mutations are located in residues that have side chains protruding into the internal pore of ORC1, suggesting their possible interference with substrate translocation. Acute and chronic management consists in the control of hyperammonemia with protein-restricted diet supplemented with citrulline/arginine and ammonia scavengers. Prognosis of HHH syndrome is variable, ranging from a severe course with disabling manifestations to milder variants compatible with an almost normal life. CONCLUSIONS This paper provides detailed information on the clinical, metabolic and genetic profiles of all HHH syndrome patients published to date. The clinical phenotype is extremely variable and its severity does not correlate with the genotype or with recorded ammonium/ornithine plasma levels. Early intervention allows almost normal life span but the prognosis is variable, suggesting the need for a better understanding of the still unsolved pathophysiology of the disease.
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The Mitochondrial Ornithine Transporter BACTERIAL EXPRESSION, RECONSTITUTION, FUNCTIONAL CHARACTERIZATION, AND TISSUE DISTRIBUTION OF TWO HUMAN ISOFORMS
The Journal of biological chemistry, 2003Co-Authors: Guiseppe Fiermonte, Carlo Dionisi-vici, Filippo M Santorelli, Vincenza Dolce, Laura David, Ferdinando Palmieri, John E. WalkerAbstract:Two isoforms of the human ornithine carrier, ORC1 and ORC2, have been identified by overexpression of the proteins in bacteria and by study of the transport properties of the purified proteins reconstituted into liposomes. Both transport L-isomers of ornithine, lysine, arginine, and citrulline by exchange and by unidirectional mechanisms, and they are inactivated by the same inhibitors. ORC2 has a broader specificity than ORC1, and L- and D-histidine, L-homoarginine, and D-isomers of ornithine, lysine, and ornithine are all substrates. Both proteins are expressed in a wide range of human tissues, but ORC1 is the predominant form. The highest levels of expression of both isoforms are in the liver. Five mutant forms of ORC1 associated with the human disease Hyperornithinemia-hyperammonemia-homocitrullinuria were also made. The mutations abolish the transport properties of the protein. In patients with Hyperornithinemia-hyperammonemia-homocitrullinuria, isoform ORC2 is unmodified, and its presence compensates partially for defective ORC1.
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BACTERIAL EXPRESSION, RECONSTITUTION, FUNCTIONAL CHARACTERIZATION, AND TISSUE DISTRIBUTION OF TWO HUMAN ISOFORMS*
2003Co-Authors: Giuseppe Fiermonte, Carlo Dionisi-vici, Filippo M Santorelli, Vincenza Dolce, Laura David, Ferdinando Palmieri, John E. WalkerAbstract:Two isoforms of the human ornithine carrier, ORC1 and ORC2, have been identified by overexpression of the proteins in bacteria and by study of the transport properties of the purified proteins reconstituted into liposomes. Both transport L-isomers of ornithine, lysine, arginine, and citrulline by exchange and by unidirectional mechanisms, and they are inactivated by the same inhibitors. ORC2 has a broader specificity than ORC1, and L- and D-histidine, L-homoarginine, and D-isomers of ornithine, lysine, and ornithine are all substrates. Both proteins are expressed in a wide range of human tissues, but ORC1 is the predominant form. The highest levels of expression of both isoforms are in the liver. Five mutant forms of ORC1 associated with the human disease Hyperornithinemia-hyperammonemia-homocitrullinuria were also made. The mutations abolish the transport properties of the protein. In patients with Hyperornithinemia-hyperammonemia-homocitrullinuria, isoform ORC2 is unmodified, and its presence compensates partially for defective ORC1. Rat liver mitochondria contain an ornithine-citrulline transport protein, often known as the ornithine carrier (ORC) 1 (1–5). The reconstituted purified protein is highly active in ornithinecitrulline exchange and is somewhat less active in unidirectional transport of ornithine. It transports lysine and arginine also but does not transport histidine. The positive charges of ornithine and lysine are compensated by cotransport of a proton with citrulline in exchange. Its affinity for ornithine is lower than for other substrates, and under saturating internal concentrations it is not dependent on the nature of the countersubstrate. The exchange reaction operates by a simultaneous (sequential) mechanism, and the unidirectional transport of
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Seven novel mutations in the ORNT1 gene (SLC25A15) in patients with Hyperornithinemia, hyperammonemia, and homocitrullinuria syndrome.
Human mutation, 2001Co-Authors: S. Salvi, Enrico Bertini, Carlo Dionisi-vici, Margherita Verardo, Filippo M SantorelliAbstract:Eight unrelated Italian patients with the Hyperornithinemia, hyperammonemia, and homocitrullinuria (HHH) syndrome were analyzed for mutations in the ORNT1 gene. Seven novel mutations were identified (Q89X, G27R, G190D, R275Q, c.861insG, c.164insA, and IVS5+1G→ A). Other previously described variants were a heterozygous deletion of a phenylalanine residue (F188del) in one allele and the R179X in two. The G27R mutation was carried by two patients. Analyses of ORNT1 mRNA in four patients showed that mutant alleles were stable and of the predicted size. The current study expands the spectrum of mutations in ORNT1 gene. © 2001 Wiley-Liss, Inc.
Alana Pimentel Moura - One of the best experts on this subject based on the ideXlab platform.
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Chronic postnatal ornithine administration to rats provokes learning deficit in the open field task
Metabolic Brain Disease, 2012Co-Authors: Carolina Maso Viegas, Estela Natacha Brandt Busanello, Anelise Miotti Tonin, Mateus Grings, Alana Pimentel Moura, Luciana Ritter, Ângela Zanatta, Lisiane Aurélio Knebel, Vannessa Araujo Lobato, Letícia Ferreira PettenuzzoAbstract:Hyperornithinemia is the biochemical hallmark of Hyperornithinemia–hyperammonemia–homocitrullinuria (HHH) syndrome, an inherited metabolic disease clinically characterized by mental retardation whose pathogenesis is still poorly known. In the present work, we produced a chemical animal model of Hyperornithinemia induced by a subcutaneous injection of saline-buffered Orn (2–5 μmol/g body weight) to rats. High brain Orn concentrations were achieved, indicating that Orn is permeable to the blood brain barrier. We then investigated the effect of early chronic postnatal administration of Orn on physical development and on the performance of adult rats in the open field, the Morris water maze and in the step down inhibitory avoidance tasks. Chronic Orn treatment had no effect on the appearance of coat, eye opening or upper incisor eruption, nor on the free-fall righting reflex and on the adult rat performance in the Morris water maze and in the inhibitory avoidance tasks, suggesting that physical development, aversive and spatial localization were not changed by Orn. However, Orn-treated rats did not habituate to the open field apparatus, implying a deficit of learning/memory. Motor activity was the same for Orn- and saline- injected animals. We also verified that Orn subcutaneous injections provoked lipid peroxidation in the brain, as determined by a significant increase of thiobarbituric acid-reactive substances levels. Our results indicate that chronic early postnatal Hyperornithinemia may impair the central nervous system, causing minor disabilities which result in specific learning deficiencies.
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Impairment of brain redox homeostasis caused by the major metabolites accumulating in Hyperornithinemia–hyperammonemia–homocitrullinuria syndrome in vivo
Metabolic brain disease, 2012Co-Authors: Carolina Maso Viegas, Estela Natacha Brandt Busanello, Anelise Miotti Tonin, Alana Pimentel Moura, Ângela Zanatta, Guilhian Leipnitz, Carolina Gonçalves Fernandes, Bianca Seminotti, Moacir WajnerAbstract:Ornithine, ammonia and homocitrulline are the major metabolites accumulating in Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome, a genetic disorder characterized by neurological regression whose pathogenesis is still not understood. The present work investigated the in vivo effects of intracerebroventricular administration of ornithine and homocitrulline in the presence or absence of hyperammonemia induced by intraperitoneal urease treatment on a large spectrum of oxidative stress parameters in cerebral cortex from young rats in order to better understand the role of these metabolites on brain damage. Ornithine increased thiobarbituric acid-reactive substances (TBA-RS) levels and carbonyl formation and decreased total antioxidant status (TAS) levels. We also observed that the combination of hyperammonemia with ornithine resulted in significant decreases of sulfhydryl levels, reduced glutathione (GSH) concentrations and the activities of catalase (CAT) and glutathione peroxidase (GPx), highlighting a synergistic effect of ornithine and ammonia. Furthermore, homocitrulline caused increases of TBA-RS values and carbonyl formation, as well as decreases of GSH concentrations and GPx activity. Hcit with hyperammonemia (urease treatment) decreased TAS and CAT activity. We also showed that urease treatment per se was able to enhance TBA-RS levels. Finally, nitric oxide production was not altered by Orn and Hcit alone or in combination with hyperammonemia. Our data indicate that the major metabolites accumulating in Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome provoke lipid and protein oxidative damage and a reduction of the antioxidant defenses in the brain. Therefore, it is presumed that oxidative stress may represent a relevant pathomechanism involved in the brain damage found in patients affected by this disease.
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impairment of brain redox homeostasis caused by the major metabolites accumulating in Hyperornithinemia hyperammonemia homocitrullinuria syndrome in vivo
Metabolic Brain Disease, 2012Co-Authors: Carolina Maso Viegas, Estela Natacha Brandt Busanello, Anelise Miotti Tonin, Alana Pimentel Moura, Ângela Zanatta, Guilhian Leipnitz, Carolina Gonçalves Fernandes, Bianca Seminotti, Moacir WajnerAbstract:Ornithine, ammonia and homocitrulline are the major metabolites accumulating in Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome, a genetic disorder characterized by neurological regression whose pathogenesis is still not understood. The present work investigated the in vivo effects of intracerebroventricular administration of ornithine and homocitrulline in the presence or absence of hyperammonemia induced by intraperitoneal urease treatment on a large spectrum of oxidative stress parameters in cerebral cortex from young rats in order to better understand the role of these metabolites on brain damage. Ornithine increased thiobarbituric acid-reactive substances (TBA-RS) levels and carbonyl formation and decreased total antioxidant status (TAS) levels. We also observed that the combination of hyperammonemia with ornithine resulted in significant decreases of sulfhydryl levels, reduced glutathione (GSH) concentrations and the activities of catalase (CAT) and glutathione peroxidase (GPx), highlighting a synergistic effect of ornithine and ammonia. Furthermore, homocitrulline caused increases of TBA-RS values and carbonyl formation, as well as decreases of GSH concentrations and GPx activity. Hcit with hyperammonemia (urease treatment) decreased TAS and CAT activity. We also showed that urease treatment per se was able to enhance TBA-RS levels. Finally, nitric oxide production was not altered by Orn and Hcit alone or in combination with hyperammonemia. Our data indicate that the major metabolites accumulating in Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome provoke lipid and protein oxidative damage and a reduction of the antioxidant defenses in the brain. Therefore, it is presumed that oxidative stress may represent a relevant pathomechanism involved in the brain damage found in patients affected by this disease.
Anelise Miotti Tonin - One of the best experts on this subject based on the ideXlab platform.
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Chronic postnatal ornithine administration to rats provokes learning deficit in the open field task
Metabolic Brain Disease, 2012Co-Authors: Carolina Maso Viegas, Estela Natacha Brandt Busanello, Anelise Miotti Tonin, Mateus Grings, Alana Pimentel Moura, Luciana Ritter, Ângela Zanatta, Lisiane Aurélio Knebel, Vannessa Araujo Lobato, Letícia Ferreira PettenuzzoAbstract:Hyperornithinemia is the biochemical hallmark of Hyperornithinemia–hyperammonemia–homocitrullinuria (HHH) syndrome, an inherited metabolic disease clinically characterized by mental retardation whose pathogenesis is still poorly known. In the present work, we produced a chemical animal model of Hyperornithinemia induced by a subcutaneous injection of saline-buffered Orn (2–5 μmol/g body weight) to rats. High brain Orn concentrations were achieved, indicating that Orn is permeable to the blood brain barrier. We then investigated the effect of early chronic postnatal administration of Orn on physical development and on the performance of adult rats in the open field, the Morris water maze and in the step down inhibitory avoidance tasks. Chronic Orn treatment had no effect on the appearance of coat, eye opening or upper incisor eruption, nor on the free-fall righting reflex and on the adult rat performance in the Morris water maze and in the inhibitory avoidance tasks, suggesting that physical development, aversive and spatial localization were not changed by Orn. However, Orn-treated rats did not habituate to the open field apparatus, implying a deficit of learning/memory. Motor activity was the same for Orn- and saline- injected animals. We also verified that Orn subcutaneous injections provoked lipid peroxidation in the brain, as determined by a significant increase of thiobarbituric acid-reactive substances levels. Our results indicate that chronic early postnatal Hyperornithinemia may impair the central nervous system, causing minor disabilities which result in specific learning deficiencies.
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Impairment of brain redox homeostasis caused by the major metabolites accumulating in Hyperornithinemia–hyperammonemia–homocitrullinuria syndrome in vivo
Metabolic brain disease, 2012Co-Authors: Carolina Maso Viegas, Estela Natacha Brandt Busanello, Anelise Miotti Tonin, Alana Pimentel Moura, Ângela Zanatta, Guilhian Leipnitz, Carolina Gonçalves Fernandes, Bianca Seminotti, Moacir WajnerAbstract:Ornithine, ammonia and homocitrulline are the major metabolites accumulating in Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome, a genetic disorder characterized by neurological regression whose pathogenesis is still not understood. The present work investigated the in vivo effects of intracerebroventricular administration of ornithine and homocitrulline in the presence or absence of hyperammonemia induced by intraperitoneal urease treatment on a large spectrum of oxidative stress parameters in cerebral cortex from young rats in order to better understand the role of these metabolites on brain damage. Ornithine increased thiobarbituric acid-reactive substances (TBA-RS) levels and carbonyl formation and decreased total antioxidant status (TAS) levels. We also observed that the combination of hyperammonemia with ornithine resulted in significant decreases of sulfhydryl levels, reduced glutathione (GSH) concentrations and the activities of catalase (CAT) and glutathione peroxidase (GPx), highlighting a synergistic effect of ornithine and ammonia. Furthermore, homocitrulline caused increases of TBA-RS values and carbonyl formation, as well as decreases of GSH concentrations and GPx activity. Hcit with hyperammonemia (urease treatment) decreased TAS and CAT activity. We also showed that urease treatment per se was able to enhance TBA-RS levels. Finally, nitric oxide production was not altered by Orn and Hcit alone or in combination with hyperammonemia. Our data indicate that the major metabolites accumulating in Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome provoke lipid and protein oxidative damage and a reduction of the antioxidant defenses in the brain. Therefore, it is presumed that oxidative stress may represent a relevant pathomechanism involved in the brain damage found in patients affected by this disease.
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impairment of brain redox homeostasis caused by the major metabolites accumulating in Hyperornithinemia hyperammonemia homocitrullinuria syndrome in vivo
Metabolic Brain Disease, 2012Co-Authors: Carolina Maso Viegas, Estela Natacha Brandt Busanello, Anelise Miotti Tonin, Alana Pimentel Moura, Ângela Zanatta, Guilhian Leipnitz, Carolina Gonçalves Fernandes, Bianca Seminotti, Moacir WajnerAbstract:Ornithine, ammonia and homocitrulline are the major metabolites accumulating in Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome, a genetic disorder characterized by neurological regression whose pathogenesis is still not understood. The present work investigated the in vivo effects of intracerebroventricular administration of ornithine and homocitrulline in the presence or absence of hyperammonemia induced by intraperitoneal urease treatment on a large spectrum of oxidative stress parameters in cerebral cortex from young rats in order to better understand the role of these metabolites on brain damage. Ornithine increased thiobarbituric acid-reactive substances (TBA-RS) levels and carbonyl formation and decreased total antioxidant status (TAS) levels. We also observed that the combination of hyperammonemia with ornithine resulted in significant decreases of sulfhydryl levels, reduced glutathione (GSH) concentrations and the activities of catalase (CAT) and glutathione peroxidase (GPx), highlighting a synergistic effect of ornithine and ammonia. Furthermore, homocitrulline caused increases of TBA-RS values and carbonyl formation, as well as decreases of GSH concentrations and GPx activity. Hcit with hyperammonemia (urease treatment) decreased TAS and CAT activity. We also showed that urease treatment per se was able to enhance TBA-RS levels. Finally, nitric oxide production was not altered by Orn and Hcit alone or in combination with hyperammonemia. Our data indicate that the major metabolites accumulating in Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome provoke lipid and protein oxidative damage and a reduction of the antioxidant defenses in the brain. Therefore, it is presumed that oxidative stress may represent a relevant pathomechanism involved in the brain damage found in patients affected by this disease.