3-nitrotyrosine and Brain-Diseases

Butyl paraben is a preservative used in food, drugs and cosmetics. Neurotoxic effect was reported recently beside the potential estrogenic activity of parabens. There is controversy as to the potential harmful effects of butyl parabens, which are suspected to contribute to autism and learning disabilities. The purpose of this study was to examine the similarities between paraben intoxication signs in the rat brain and brain markers in an autistic like rat model. This study provides evidence of many parallels between the two, including (1) oxidative stress, (2) decreased reduced glutathione levels and elevated oxidised glutathione, (3) mitochondrial dysfunction, and (4) neuroinflammation and increased pro-inflammatory cytokine levels in the brain (tumour necrosis factor-alpha, interleukin-1-beta, and interleukin-6). (5) Increased protein oxidation reported by a significant increase in 3-nitrotyrosine (3-NT)/tyrosine ratio. (6) A marked disturbance was found in the production of energy carriers (AMP, ATP and AMP/ATP ratio) in comparison with the control. The evidence suggests that paraben may, to some extent, either cause or contribute to the brain physiopathology in ASDs or pathogens that produce the brain pathology observed in the diagnosed rat model of ASD.

Topics: Adenosine Monophosphate; Adenosine Triphosphate; Animals; Autistic Disorder; Biomarkers; Brain; Brain Diseases; Chromatography, High Pressure Liquid; Female; Glutathione; Glutathione Disulfide; Inflammation Mediators; Interleukin-1beta; Interleukin-6; Male; Mitochondria; Oxidative Stress; Parabens; Pregnancy; Rats, Wistar; Tumor Necrosis Factor-alpha; Tyrosine; Valproic Acid

The cervical spinal cords of 2 horses with equine degenerative myeloencephalopathy (EDM) were evaluated for evidence of oxidative damage to the central nervous system (CNS) using immunohistochemical staining for 3-nitrotyrosine (3-NT) and 4-hydroxynonenol (4-HNE). Neurons of the CNS from horses with EDM had positive immunohistochemical staining, whereas control samples did not, thus supporting the theory that oxidative damage is a potential underlying factor in horses with EDM. In addition, serum vitamin E concentration was low in both EDM-affected horses, and vitamin E concentration was also deficient in the cerebrospinal fluid in 1 EDM horse, further supporting the association between low vitamin E concentrations and oxidative damage to the CNS. Continued research is necessary to further define the pathophysiologic mechanisms of EDM.

Topics: Aldehydes; Animals; Ataxia; Brain Diseases; Central Nervous System; Female; Horse Diseases; Horses; Immunohistochemistry; Neurodegenerative Diseases; Oxidative Stress; Spinal Cord Diseases; Tyrosine; Vitamin E; Vitamin E Deficiency

Superoxide mediated oxidative stress is a key neuropathologic mechanism in acute central nervous system injuries. We have analyzed the neuroprotective efficacy of the transient overexpression of antioxidant enzyme Cu/Zn Superoxide dismutase (SOD) after excitotoxic injury to the immature rat brain by using a recently constructed modular protein vector for non-viral gene delivery termed NLSCt. For this purpose, animals were injected with the NLSCt vector carrying the Cu/Zn SOD or the control GFP transgenes 2 hours after intracortical N-methyl-D-aspartate (NMDA) administration, and daily functional evaluation was performed. Moreover, 3 days after, lesion volume, neuronal degeneration and nitrotyrosine immunoreactivity were evaluated.. Overexpression of Cu/Zn SOD transgene after NMDA administration showed improved functional outcome and a reduced lesion volume at 3 days post lesion. In secondary degenerative areas, increased neuronal survival as well as decreased numbers of degenerating neurons and nitrotyrosine immunoreactivity was seen. Interestingly, injection of the NLSCt vector carrying the control GFP transgene also displayed a significant neuroprotective effect but less pronounced.. When the appropriate levels of Cu/Zn SOD are expressed transiently after injury using the non-viral modular protein vector NLSCt a neuroprotective effect is seen. Thus recombinant modular protein vectors may be suitable for in vivo gene therapy, and Cu/Zn SOD should be considered as an interesting therapeutic transgene.

Topics: Animals; Animals, Newborn; Brain; Brain Diseases; Cell Death; Female; Gene Expression; Gene Transfer Techniques; Genetic Vectors; Male; N-Methylaspartate; Neurons; Neuroprotective Agents; Neurotoxins; Rats; Rats, Long-Evans; Superoxide Dismutase; Transgenes; Tyrosine

Topics: Animals; Antioxidants; Brain Diseases; Corpus Striatum; Iron; Male; Metalloporphyrins; Neurotoxins; Nitrogen; Oxidative Stress; Peroxynitrous Acid; Quinolinic Acid; Rats; Rats, Wistar; Tyrosine

Relative hyperoxia is a condition frequently encountered in premature infants, either spontaneously or during treatment in the Neonatal Intensive Care Unit. The effects of high inspiratory oxygen concentrations on immature brain cells and their signaling cascades are largely unknown. The aim of the study was to investigate the effect of hyperoxia on the amount and topographic distribution of iNOS-expression (inducible nitric oxide synthase) in the immature rat brain, and to localize hyperoxia-induced formation of peroxynitrite as a potential marker of cellular damage to immature cerebral structures. Seven-day-old Wistar rat pups were exposed to >80% oxygen for 24 h and were then transcardially perfused. Following paraformaldehyde fixation, brains were paraffin-embedded and immunohistochemically stained for iNOS and nitrotyrosine. iNOS protein was quantified by Western blot; iNOS mRNA expression was studied by RT-PCR. Total brain iNOS mRNA was up-regulated, demonstrating a peak at 6 h following the onset of hyperoxia. Immunohistochemical staining was predominantly observed in microglial cells of hippocampus and frontal cortex with some iNOS reactivity in endothelial and perivascular cells. Nitrotyrosine staining was positive in apical dendrites of neurons in the frontal cortex. There was no positive staining for iNOS or nitrotyrosine in control animals. Hyperoxia causes iNOS mRNA and protein up-regulation in microglial cells of the immature rat brain. Positive neuronal nitrotyrosine staining indicates formation of peroxynitrite with potential deleterious effects for immature cellular structures in the neonatal brain.

Topics: Animals; Blotting, Western; Brain; Brain Diseases; Hyperoxia; Immunohistochemistry; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; Tyrosine

Oxidative stress has been shown to be implicated in the pathogenesis of central nervous system injuries such as cerebral ischemia and trauma, and chronic neurodegenerative diseases. In vitro studies show that oxidative stress, particularly peroxynitrite, could trigger DNA strand breaks, which lead to the activation of repairing enzymes including Poly(ADP-ribose) Polymerase-1 (PARP-1). As excessive activation of this enzyme induces cell death, we examined whether such a cascade also occurs in vivo in a model of oxidative stress in rat brain. For this purpose, the mitochondrial toxin malonate, which promotes free radical production, was infused into the left striatum of rats. Immunohistochemistry showed that 3-nitrotyrosine, an indicator of nitrosative stress, and poly(ADP-ribose), a marker of poly(ADP-ribose)polymerase-1 activation, were present as early as 1 h after malonate, and that they persisted for 24 h. The PARP inhibitor, 3-aminobenzamide, significantly reduced the lesion and inhibited PARP-1 activation induced by malonate. These results demonstrate that oxidative stress induced in vivo in the central nervous system leads to the activation of poly(ADP-ribose)polymerase-1, which contributes to neuronal cell death.

Topics: Animals; Apoptosis; Benzamides; Brain; Brain Diseases; Enzyme Activation; Immunohistochemistry; Male; Malonates; Oxidative Stress; Poly Adenosine Diphosphate Ribose; Poly(ADP-ribose) Polymerases; Rats; Rats, Sprague-Dawley; Substantia Nigra; Tyrosine

Topics: Animals; Antioxidants; Brain Diseases; Humans; Kidney Failure, Chronic; Oxidative Stress; Rats; Tyrosine

To determine whether, and if so how, iNOS expresses and affects brain injury induced by hypoxia-ischemia in an immature brain.. Seven-day-old Wistar rat pups were exposed to right common carotid artery ligation followed by 1.5 hours of hypoxia. The time course of iNOS mRNA expression, enzymatic activity, and protein production in the cerebral cortex were determined. The extent of the infarct area in the cerebral cortex and the production of 3-nitrotyrosine (a biomarker of peroxynitrite) were compared between the control pups and pups treated with S-methyl-isothiourea (a selective iNOS inhibitor).. In the cortex ipsilateral to carotid ligation, iNOS mRNA appeared from 6 hours to 24 hours after hypoxia-ischemia and disappeared at 48 hours. The iNOS protein and its activity also increased at 12 hours and reached a maximum level at 48 hours after the insult. The percentage of damage in the cerebral cortex was significantly higher in the control pups than in treated pups (31.9 vs 10.6%). Tri-nitrotyrosine following iNOS expression-positive cells were located predominantly at the infarct and peri-infarct regions.. iNOS expression might be an important determinant of ischemic immature brain injury.

Topics: Animals; Animals, Newborn; Brain Diseases; Carotid Arteries; Hypoxia-Ischemia, Brain; Kinetics; Ligation; Nitrates; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Rats; Rats, Wistar; RNA, Messenger; Tyrosine

Reactive nitrogen species may play a mechanistic role in neurodegenerative diseases by posttranslationally altering normal brain proteins. In support of this hypothesis, we demonstrate that an anti-3-nitrotyrosine polyclonal antibody stains all of the major hallmark lesions of synucleinopathies including Lewy bodies, Lewy neurites and neuraxonal spheroids in dementia with Lewy bodies, the Lewy body variant of Alzheimer's disease, and neurodegeneration with brain iron accumulation type 1, as well as glial and neuronal cytoplasmic inclusions in multiple system atrophy. This antibody predominantly recognized nitrated alpha-synuclein when compared to other in vitro nitrated constituents of these pathological lesions, such as neurofilament subunits and microtubules. Collectively, these findings imply that alpha-synuclein is nitrated in pathological lesions. The widespread presence of nitrated alpha-synuclein in diverse intracellular inclusions suggests that oxidation/nitration is involved in the onset and/or progression of neurodegenerative diseases.

Topics: Adult; Aged; Aged, 80 and over; alpha-Synuclein; Antibodies; Blotting, Western; Brain Diseases; Female; Humans; Immunohistochemistry; Inclusion Bodies; Lewy Bodies; Male; Middle Aged; Nerve Tissue Proteins; Neurodegenerative Diseases; Neuroglia; Nitrates; Synucleins; Tissue Distribution; Tyrosine

To evaluate whether an intact respiratory burst exists within the orbit of diabetics with rhinocerebral mucormycosis.. Immunohistochemical detection of nitrotyrosine in the orbital tissue of diabetics requiring exenteration due to rhinocerebral mucormycosis. Nitrotyrosine is the stable product of the nitration of tyrosine residues by peroxynitrite. Peroxynitrite is a potent oxidant produced by the combination of superoxide and nitric oxide during the respiratory burst.. Four specimens were analyzed. All showed focal areas of specific staining against nitrotyrosine of the walls and internal structures of fungal organisms.. An intact respiratory burst is present in the orbit of diabetics during infection with rhinocerebral mucormycosis. Possible mechanisms of peroxynitrite's microbicidal effects and reasons for a deficiency in diabetics are discussed.

Topics: Adolescent; Adult; Aged; Brain Diseases; Diabetes Mellitus; Eye Infections, Fungal; Female; Humans; Immunoenzyme Techniques; Male; Middle Aged; Mucormycosis; Nitrates; Orbital Diseases; Paranasal Sinus Diseases; Respiratory Burst; Tyrosine