Long-term enzyme replacement therapy in Fabry patients protects against oxidative and inflammatory process.

Fabry disease (FD) is an X-linked recessive lysosomal storage disorder, characterized by a deficiency of α-galactosidase, which causes the progressive accumulation of glycosphingolipids, especially globotriaosylsphingosine (Gb3), in lysosomes across multiple organs. Substrate deposition, associated with tissue damage in FD, also contributes to the emergence of a pro-inflammatory state presented by some patients. We investigated pro- and anti-inflammatory cytokines, and the expression of inflammation-associated genes in treated FD patients, as well as oxidative parameters.

Protective effects of L-carnitine on behavioral alterations and neuroinflammation in striatum of glutaryl-COA dehydrogenase deficient mice.

Glutaric acidemia type 1 (GA1) is caused by glutaryl-CoA dehydrogenase deficiency that leads to a blockage in the metabolic route of the amino acids lysine and tryptophan and subsequent accumulation of glutaric acid (GA), 3-hydroxyglutaric acids and glutarylcarnitine (C5DC). Patients predominantly manifest neurological symptoms, associated with acute striatal degeneration, as well as progressive cortical and striatum injury whose pathogenesis is not yet fully established. Current treatment includes protein/lysine restriction and l-carnitine supplementation of (L-car).

Evidence that Thiosulfate Inhibits Creatine Kinase Activity in Rat Striatum via Thiol Group Oxidation.

Sulfite oxidase, molybdenum cofactor, and ETHE1 deficiencies are autosomal recessive disorders that affect the metabolism of sulfur-containing amino acids. Patients with these disorders present severe neurological dysfunction and basal ganglia abnormalities, accompanied by high levels of thiosulfate in biological fluids and tissues. Aiming to better elucidate the pathophysiology of basal ganglia damage in these disorders, we evaluated the in vivo effects of thiosulfate administration on bioenergetics, oxidative stress, and neural damage in rat striatum.

Investigation of correlation of urinary globotriaosylceramide (Gb3) levels with markers of renal function in patients with Fabry disease.

Fabry disease (FD) is a disorder that results from mutations of hydrolase α-galactosidase A. The enzymatic defect leads to accumulation of globotriaosylceramide (Gb3) in the kidney. Substrate deposition is related to tissue damage in FD, but the relation of urinary Gb3 levels in patients and the renal function markers remain not completely understood.

Bezafibrate prevents mitochondrial dysfunction, antioxidant system disturbance, glial reactivity and neuronal damage induced by sulfite administration in striatum of rats: Implications for a possible therapeutic strategy for sulfite oxidase deficiency.

Sulfite accumulates in tissues of patients affected by sulfite oxidase (SO) deficiency, a neurometabolic disease characterized by seizures and progressive encephalopathy, often resulting in early death. We investigated the effects of sulfite on mitochondrial function, antioxidant system, glial reactivity and neuronal damage in rat striatum, as well as the potential protective effects of bezafibrate on sulfite-induced toxicity. Thirty-day-old rats were intrastriatally administered with sulfite (2μmol) or NaCl (2μmol; control) and euthanized 30min after injection for evaluation of biochemical parameters and western blotting, or 7days after injection for analysis of glial reactivity and neuronal damage.

Glycine Administration Alters MAPK Signaling Pathways and Causes Neuronal Damage in Rat Brain: Putative Mechanisms Involved in the Neurological Dysfunction in Nonketotic Hyperglycinemia.

High glycine (GLY) levels have been suggested to induce neurotoxic effects in the central nervous system of patients with nonketotic hyperglycinemia (NKH). Since the mechanisms involved in the neuropathophysiology of NKH are not totally established, we evaluated the effect of a single intracerebroventricular administration of GLY on the content of proteins involved in neuronal damage and inflammatory response, as well as on the phosphorylation of the MAPK p38, ERK1/2, and JNK in rat striatum and cerebral cortex. We also examined glial fibrillary acidic protein (GFAP) staining, a marker of glial reactivity.

Intracerebral Glycine Administration Impairs Energy and Redox Homeostasis and Induces Glial Reactivity in Cerebral Cortex of Newborn Rats.

Accumulation of glycine (GLY) is the biochemical hallmark of glycine encephalopathy (GE), an aminoacidopathy characterized by severe neurological dysfunction that may lead to early death. In the present study, we evaluated the effect of a single intracerebroventricular administration of GLY on bioenergetics, redox homeostasis, and histopathology in brain of neonatal rats. Our results demonstrated that GLY decreased the activities of the respiratory chain complex IV and creatine kinase, induced reactive species generation, and diminished glutathione (GSH) levels 1, 5, and 10 days after GLY injection in cerebral cortex of 1-day-old rats.

Higher susceptibility of cerebral cortex and striatum to sulfite neurotoxicity in sulfite oxidase-deficient rats.

Patients affected by sulfite oxidase (SO) deficiency present severe seizures early in infancy and progressive neurological damage, as well as tissue accumulation of sulfite, thiosulfate and S-sulfocysteine. Since the pathomechanisms involved in the neuropathology of SO deficiency are still poorly established, we evaluated the effects of sulfite on redox homeostasis and bioenergetics in cerebral cortex, striatum, cerebellum and hippocampus of rats with chemically induced SO deficiency. The deficiency was induced in 21-day-old rats by adding 200ppm of tungsten, a molybdenum competitor, in their drinking water for 9weeks.

In vitro evidence that sulfite impairs glutamatergic neurotransmission and inhibits glutathione metabolism-related enzymes in rat cerebral cortex.

Sulfite oxidase (SOX) deficiency is an inherited neurometabolic disorder biochemically characterized by tissue accumulation and high urinary excretion of sulfite and thiosulfate. Affected patients present severe neurological dysfunction accompanied by seizures, whose pathophysiology is poorly known. In the present study we evaluated the in vitro effects of sulfite and thiosulfate on important parameters of glutamatergic neurotransmission and redox homeostasis in rat cerebral cortex slices.

Evidence that glycine induces lipid peroxidation and decreases glutathione concentrations in rat cerebellum.

Patients with non-ketotic hyperglycinemia (NKH) present severe neurological symptoms and brain abnormalities involving cerebellum. Although the pathomechanisms underlying the cerebellum damage have not been studied, high tissue levels of glycine (GLY), the biochemical hallmark of this disorder have been suggested to contribute to the neuropathology of this disease. We investigated the in vitro effects of GLY on important parameters of oxidative stress and energy metabolism in cerebellum of 30-day-old rats.

Disturbance of brain energy and redox homeostasis provoked by sulfite and thiosulfate: potential pathomechanisms involved in the neuropathology of sulfite oxidase deficiency.

Sulfite oxidase (SO) deficiency is biochemically characterized by tissue accumulation and high urinary excretion of sulfite, thiosulfate and S-sulfocysteine. Affected patients present severe neurological symptoms and cortical atrophy, whose pathophysiology is still poorly established. Therefore, in the present work we investigated the in vitro effects of sulfite and thiosulfate on important parameters of energy metabolism in the brain of young rats.

Disturbance of redox homeostasis by ornithine and homocitrulline in rat cerebellum: a possible mechanism of cerebellar dysfunction in HHH syndrome.

Aims: Cerebellar ataxia is commonly observed in hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome, an inherited metabolic disorder biochemically characterized by ornithine (Orn), homocitrulline (Hcit) and ammonia accumulation. Since the pathophysiology of cerebellum damage in this disorder is still unknown, we investigated the effects of Hcit and Orn on important parameters of redox and energy homeostasis in cerebellum of young rats.

Material And Methods: We determined thiobarbituric acid-reactive substance (TBA-RS) levels, carbonyl content, nitrate and nitrite production, hydrogen peroxide production, GSH concentrations, sulfhydryl content, as well as activities of respiratory chain complexes I-IV, creatine kinase, Na(+),K(+)-ATPase, aconitase and α-ketoglutarate dehydrogenase.

Glycine intracerebroventricular administration disrupts mitochondrial energy homeostasis in cerebral cortex and striatum of young rats.

High tissue levels of glycine (GLY) are the biochemical hallmark of nonketotic hyperglycinemia (NKH), an inherited metabolic disease clinically characterized by severe neurological symptoms and brain abnormalities. Considering that the mechanisms underlying the neuropathology of this disease are not fully established, the present work investigated the in vivo effects of intracerebroventricular administration of GLY on important parameters of energy metabolism in cerebral cortex and striatum from young rats. Our results show that GLY reduced CO₂ production using glucose as substrate and inhibited the activities of citrate synthase and isocitrate dehydrogenase in striatum, whereas no alterations of these parameters were verified in cerebral cortex 30 min after GLY injection.

Neurochemical evidence that the metabolites accumulating in 3-methylcrotonyl-CoA carboxylase deficiency induce oxidative damage in cerebral cortex of young rats.

Isolated 3-methylcrotonyl-CoA carboxylase deficiency (3MCCD) is an autosomal recessive disorder of leucine metabolism biochemically characterized by accumulation of 3-methylcrotonylglycine (3MCG), 3-methylcrotonic acid (3MCA) and 3-hydroxyisovaleric acid. A considerable number of affected individuals present neurological symptoms with or without precedent crises of metabolic decompensation and brain abnormalities whose pathogenesis is poorly known. We investigated the in vitro effects of 3MCG and 3MCA on important parameters of oxidative stress in cerebral cortex of young rats.

Impairment of brain redox homeostasis caused by the major metabolites accumulating in hyperornithinemia-hyperammonemia-homocitrullinuria syndrome in vivo.

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.

Chronic postnatal ornithine administration to rats provokes learning deficit in the open field task.

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.

Phytanic acid disturbs mitochondrial homeostasis in heart of young rats: a possible pathomechanism of cardiomyopathy in Refsum disease.

Phytanic acid (Phyt) accumulates in tissues and biological fluids of patients affected by Refsum disease. Although cardiomyopathy is an important clinical manifestation of this disorder, the mechanisms of heart damage are poorly known. In the present study, we investigated the in vitro effects of Phyt on important parameters of oxidative stress in heart of young rats.

Experimental evidence that pristanic acid disrupts mitochondrial homeostasis in brain of young rats.

Patients affected by peroxisomal disorders commonly present neurologic dysfunction and brain abnormalities, whose neuropathology is poorly understood. Given that high sustained concentrations of pristanic acid (Prist) are found in the brain of these patients, it is conceivable that this complex branched-chain fatty acid is neurotoxic. Therefore, the present work investigated the in vitro effects of Prist at similar concentrations found in plasma of affected patients with some peroxisomal disorders on important parameters of energy homeostasis, including respiratory parameters determined by oxygen consumption, membrane potential (ΔΨm), NAD(P)H content, and swelling in mitochondrial preparations obtained from brain of young rats using glutamate plus malate or succinate as respiratory substrates.

3-Methylcrotonylglycine disrupts mitochondrial energy homeostasis and inhibits synaptic Na(+),K (+)-ATPase activity in brain of young rats.

Deficiency of 3-methylcrotonyl-CoA carboxylase activity is an inherited metabolic disease biochemically characterized by accumulation and high urinary excretion of 3-methylcrotonylglycine (3MCG), and also of 3-hydroisovalerate in lesser amounts. Affected patients usually have neurologic dysfunction, brain abnormalities and cardiomyopathy, whose pathogenesis is still unknown. The present study investigated the in vitro effects of 3MCG on important parameters of energy metabolism, including CO(2) production from labeled acetate, enzyme activities of the citric acid cycle, as well as of the respiratory chain complexes I-IV (oxidative phosphorylation), creatine kinase (intracellular ATP transfer), and synaptic Na(+),K(+)-ATPase (neurotransmission) in brain cortex of young rats.

Neurochemical evidence that pristanic acid impairs energy production and inhibits synaptic Na(+), K(+)-ATPase activity in brain of young rats.

Pristanic acid (Prist) accumulates in some peroxisomal disorders characterized by neurologic dysfunction and brain abnormalities. The present work investigated the in vitro effects of Prist on important parameters of energy metabolism in brain cortex of young rats. CO(2) production from labeled acetate and the activities of the respiratory chain complexes I-IV, creatine kinase and synaptic Na(+), K(+)-ATPase were measured.

Dual mechanism of brain damage induced in vivo by the major metabolites accumulating in hyperornithinemia-hyperammonemia-homocitrullinuria syndrome.

Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is an autosomal recessive disorder caused by a defect in the mitochondrial ornithine transporter, leading to accumulation of ornithine (Orn), homocitrulline (Hcit) and ammonia. Progressive neurological regression whose pathogenesis is not well established is common in this disease. The present work investigated the in vivo effects of intracerebroventricular administration of Orn and Hcit on important parameters of oxidative stress and energy metabolism in cerebral cortex from young rats.

In vitro evidence that phytanic acid compromises Na(+),K(+)-ATPase activity and the electron flow through the respiratory chain in brain cortex from young rats.

Phytanic acid (Phyt) tissue concentrations are increased in Refsum disease and other peroxisomal disorders characterized by neurologic damage and brain abnormalities. The present work investigated the in vitro effects of Phyt, at concentrations found in these peroxisomal disorders, on important parameters of energy metabolism in brain cortex of young rats. The parameters analyzed were CO(2) production from labeled acetate and glucose, the activities of the citric acid cycle enzymes citrate synthase, aconitase, isocitrate dehydrogenase, alpha-ketoglutarate dehydrogenase, succinate dehydrogenase, fumarase and malate dehydrogenase, as well as of the respiratory chain complexes I-IV, creatine kinase and Na(+),K(+)-ATPase.

Neurochemical evidence that glycine induces bioenergetical dysfunction.

Glycine tissue concentrations are increased particularly in nonketotic and ketotic hyperglycinemia, inherited metabolic disorders characterized by severe neurologic damage and brain abnormalities. The present work investigated the in vitro effects of glycine on important parameters of energy metabolism in the brain of young rats. The parameters analyzed were CO2 generated from glucose, acetate and citrate and the activities of the respiratory chain complexes I-IV, of the citric acid cycle enzymes citrate synthase, aconitase, isocitrate dehydrogenase, alpha-ketoglutarate dehydrogenase, succinate dehydrogenase, fumarase and malate dehydrogenase, of creatine kinase and Na+,K+-ATPase.

Promotion of lipid and protein oxidative damage in rat brain by ethylmalonic acid.

High concentrations of ethylmalonic acid are found in tissues and biological fluids of patients affected by ethylmalonic encephalopathy, deficiency of short-chain acyl-CoA dehydrogenase activity and other illnesses characterized by developmental delay and neuromuscular symptoms. The pathophysiological mechanisms responsible for the brain damage in these patients are virtually unknown. Therefore, in the present work we investigated the in vitro effect of EMA on oxidative stress parameters in rat cerebral cortex.

In vitro evidence that D-serine disturbs the citric acid cycle through inhibition of citrate synthase activity in rat cerebral cortex.

The present work investigated the in vitro effects of D-serine (D-Ser) on important parameters of energy metabolism in cerebral cortex of young rats. The parameters analyzed were CO(2) generation from glucose and acetate, glucose uptake and the activities of the respiratory chain complexes I-IV, of the citric acid cycle enzymes citrate synthase, aconitase, isocitrate dehydrogenase, alpha-ketoglutarate dehydrogenase, succinate dehydrogenase, fumarase and malate dehydrogenase and of creatine kinase and Na(+),K(+)-ATPase. Our results show that D-Ser significantly reduced CO(2) production from acetate, but not from glucose, reflecting an impairment of the citric acid cycle function.