ABSTRACT
Introduction: Recent evidence shows that oxidative stress seems to be related with the pathophysiology of X-linked adrenoleukodystrophy (X-ALD), a neurodegenerative disorder. Methods: In the present study, the in vitro effect of N-acetyl-L-cysteine (NAC) on glutathione (GSH) and sulfhydryl levels in X-ALD patients was evaluated. Results: A significant reduction of GSH and sulfhydryl content was observed in X-ALD patients compared to the control group. Furthermore, 5 mM of NAC, in vitro, led to an increase in GSH content and sulfhydryl groups in these patients. Conclusion: These data probably indicate that an adjuvant therapy with the antioxidant NAC could improve the oxidative imbalance in X-ALD patients(AU)
Subject(s)
Humans , Male , Female , Child , Adolescent , Adult , Middle Aged , Acetylcysteine/pharmacology , Adrenoleukodystrophy/physiopathology , Glutathione/deficiency , Sulfhydryl Compounds/metabolism , Adrenoleukodystrophy/drug therapy , Oxidation-Reduction/drug effects , Oxidative StressABSTRACT
X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal disorder biochemically characterized by the accumulation of very long chain fatty acids (VLCFA), particularly hexacosanoic acid (C(26:0)) and tetracosanoic acid (C(24:0)), in tissues and biological fluids. Although patients affected by this disorder predominantly present central and peripheral demyelination as well as adrenal insufficiency, the mechanisms underlying the brain damage in X-ALD are poorly known. The current treatment of X-ALD with glyceroltrioleate (C(18:1))/glyceroltrierucate (C(22:1)) (Lorenzo's oil, LO) combined with a VLCFA-poor diet normalizes VLCFA concentrations, but the neurological symptoms persist or even progress in symptomatic patients. Considering that free radical generation is involved in various neurodegenerative disorders and that in a previous study we showed evidence that oxidative stress is probably involved in the pathophysiology of X-ALD symptomatic patients, in the present study we evaluated various oxidative stress parameters, namely thiobarbituric acid reactive species (TBA-RS) and total antioxidant reactivity (TAR) in plasma, as well as the activities of the antioxidant enzymes catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx) in erythrocytes from symptomatic and asymptomatic X-ALD patients and verified whether LO treatment and a VLCFA restricted diet could change these parameters. We observed a significant increase of plasma TBA-RS in symptomatic and asymptomatic X-ALD patients, reflecting induction of lipid peroxidation even before the disease was manifested. In addition, LO treatment did not alter this profile. Furthermore, plasma TAR measurement of X-ALD patients was not different from that of controls. Similarly, the antioxidant enzyme activities CAT, SOD and GPx were not altered in erythrocyte from X-ALD patients as compared to controls. We also examined the in vitro effects of hexacosanoic acid (C(26:0)) and tetracosanoic acid (C(24:0)) alone or combined with oleic (C(18:1))/erucic (C(22:1)) acids on various oxidative stress parameters in cerebral cortex of young rats, namely chemiluminescence, TBA-RS, TAR, CAT, SOD and GPx in order to investigate whether those fatty acids were able to induce oxidative stress. We found that there was a significant increase of TBARS and of chemiluminescence in rat cerebral cortex exposed to C(26:0)/C(24:0), and that the addition of C(18:1)and C(22:1) to the assays did not prevent this effect. Furthermore, TAR measurement was not altered by C(26:0) and C(24:0) acids in rat cerebral cortex. Taken together, our results indicate that lipid peroxidation occurs in X-ALD and that LO treatment does not attenuate or prevent free radical generation in these patients. Therefore, it may be presumed that antioxidants should be considered as an adjuvant therapy for X-ALD patients.
Subject(s)
Adrenoleukodystrophy/physiopathology , Erucic Acids/pharmacology , Oxidative Stress/drug effects , Triolein/pharmacology , Adrenoleukodystrophy/drug therapy , Adrenoleukodystrophy/metabolism , Analysis of Variance , Animals , Cerebral Cortex/drug effects , Cerebral Cortex/metabolism , Child , Drug Combinations , Fatty Acids, Unsaturated/metabolism , Humans , Lipid Peroxidation/drug effects , Male , Rats , Rats, Wistar , Superoxide Dismutase/metabolism , Thiobarbituric Acid Reactive Substances/analysisABSTRACT
X-linked adrenoleukodystrophy (X-ALD) is a hereditary disorder of peroxisomal metabolism biochemically characterized by the accumulation of very long chain fatty acids (VLCFA), particularly hexacosanoic acid (C26:0) and tetracosanoic acid (C24:0) in different tissues and in biological fluids. The disease is clinically characterized by central and peripheral demyelination and adrenal insufficiency, which is closely related to the increased concentrations of these fatty acids. However, the mechanisms underlying the brain damage in X-ALD are poorly known. Considering that free radical generation is involved in various neurodegenerative disorders, like Parkinson disease, multiple sclerosis and Alzheimer's disease, in the present study we evaluated various oxidative stress parameters, namely chemiluminescence, thiobarbituric acid reactive species (TBA-RS), total radical-trapping antioxidant potential (TRAP), and total antioxidant reactivity (TAR) in plasma of X-ALD patients, as well as the activities of the antioxidant enzymes catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx) in erythrocytes and fibroblasts from these patients. It was verified a significant increase of plasma chemiluminescence and TBA-RS, reflecting induction of lipid peroxidation, as well as a decrease of plasma TAR, indicating a deficient capacity to rapidly handle an increase of reactive species. We also observed a significant increase of erythrocytes GPx activity and of catalase and SOD activities in fibroblasts from the patients studied. It is therefore proposed that oxidative stress may be involved in pathophysiology of X-ALD.
Subject(s)
Adrenoleukodystrophy/physiopathology , Oxidative Stress/physiology , Adrenoleukodystrophy/blood , Adult , Antioxidants/metabolism , Catalase/blood , Cells, Cultured , Child , Erythrocytes/enzymology , Erythrocytes/metabolism , Free Radicals/metabolism , Glutathione Peroxidase/blood , Humans , Superoxide Dismutase/blood , Thiobarbituric Acid Reactive Substances/analysisSubject(s)
Adrenoleukodystrophy , Adrenoleukodystrophy/diagnosis , Adrenoleukodystrophy/diagnostic imaging , Adrenoleukodystrophy/genetics , Adrenoleukodystrophy/physiopathology , Adult , Evoked Potentials, Somatosensory , Fatty Acids/metabolism , Gait , Humans , Male , Neural Conduction , Neuropsychological Tests , Radiography , Tomography, Emission-Computed, Single-Photon , UrodynamicsABSTRACT
La adrenoleucodistrofia (ADLD) es una enfermedad hereditaria rara y de expresión clínica variable según la edad de inicio. La forma infantil, motivo de la presente publicación, se caracteriza por la asociación de insuficiencia adrenal y deterioro neurológico progresivo secundario a desmielinización. A propósito de dos casos, los autores destacan el valor diagnóstico de las lesiones desmielinizantes visibles en RM que, en forma característica, adoptan una distribución en alas de mariposa pues interesan el esplenio del cuerpo calloso y la sustancia blanca parietooccipital bihemisférica adyacente. El refuerzo en bandas visibles, luego de inyectado el godolinio, en la periferia de áreas de señal anormal (hipointensa en T1 e hipertensa en T2), resulta casi patognomónico y delimita el sector de ruptura de la barrera hematoencefálica secundaria a desmielinización activa
Subject(s)
Humans , Child , Adrenoleukodystrophy/diagnosis , Demyelinating Diseases/diagnosis , Magnetic Resonance Spectroscopy , Adrenoleukodystrophy/history , Adrenoleukodystrophy/physiopathology , Gadolinium , Adrenal Glands/pathologyABSTRACT
La adrenoleucodistrofia (ADLD) es una enfermedad hereditaria rara y de expresión clínica variable según la edad de inicio. La forma infantil, motivo de la presente publicación, se caracteriza por la asociación de insuficiencia adrenal y deterioro neurológico progresivo secundario a desmielinización. A propósito de dos casos, los autores destacan el valor diagnóstico de las lesiones desmielinizantes visibles en RM que, en forma característica, adoptan una distribución en alas de mariposa pues interesan el esplenio del cuerpo calloso y la sustancia blanca parietooccipital bihemisférica adyacente. El refuerzo en bandas visibles, luego de inyectado el godolinio, en la periferia de áreas de señal anormal (hipointensa en T1 e hipertensa en T2), resulta casi patognomónico y delimita el sector de ruptura de la barrera hematoencefálica secundaria a desmielinización activa (AU)
Subject(s)
Humans , Child , Adrenoleukodystrophy/diagnosis , Magnetic Resonance Spectroscopy/diagnosis , Demyelinating Diseases/diagnosis , Adrenoleukodystrophy/physiopathology , Adrenoleukodystrophy/history , Adrenal Glands/pathology , Gadolinium/diagnosisABSTRACT
A case of a two and a half year old boy with unexplained repeated episodes of hyponatremic dehydration and hyperkalemia, as well as noticeable psychomotor retardation and hyperpigmentation is presented. His neurologic development was considered normal until he was two, when he progressively began to regress. Magnetic resonance imaging of the brain showed white matter demyelination and cortical atrophy as well as primary adrenal insufficiency when stimulated with ACTH. Both magnetic resonance imaging and the ACTH stimulation test are useful for the diagnosis of adrenoleukodystrophy. Adrenoleukodystrophy; hyponatremic dehydration; cutaneous hyperpigmentation; white matter degenerative disease; magnetic resonance imaging.