3-nitrotyrosine and Parkinson-Disease--Secondary

Heterocyclic amines (HCAs) are primarily formed during cooking of meat at high temperature. HCAs have been extensively studied as mutagens and possible carcinogens. Emerging data suggest that HCAs are neurotoxic and may be relevant to Parkinson's disease (PD) etiology. However, the majority of HCAs have not been evaluated for in vivo neurotoxicity. Here, we investigated acute in vivo neurotoxicity of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). PhIP is the most prevalent genotoxin in many types of meats. Adult, male Sprague-Dawley rats were subjected to acute, systemic PhIP at doses and time-points that have been extensively utilized in cancer studies (100 and 200 mg/kg for 8, 24 h) and evaluated for changes in dopaminergic, serotoninergic, GABAergic, and glutamatergic neurotransmission. PhIP exposure resulted in decreased striatal dopamine metabolite levels and dopamine turnover in the absence of changes to vesicular monoamine transporter 2 levels; other neurotransmitter systems were unaffected. Quantification of intracellular nitrotyrosine revealed higher levels of oxidative damage in dopaminergic neurons in the substantia nigra after PhIP exposure, while other neuronal populations were less sensitive. These changes occurred in the absence of an overt lesion to the nigrostriatal dopamine system. Collectively, our study suggests that acute PhIP treatment in vivo targets the nigrostriatal dopaminergic system and that PhIP should be further examined in chronic, low-dose studies for PD relevance.

Topics: Animals; Corpus Striatum; Dopamine; Dopaminergic Neurons; Dose-Response Relationship, Drug; Imidazoles; Male; Neurotoxicity Syndromes; Oxidative Stress; Parkinson Disease, Secondary; Rats, Sprague-Dawley; Substantia Nigra; Time Factors; Tyrosine

Serofendic acid was recently identified as a neuroprotective factor from fetal calf serum. This study was designed to evaluate the neuroprotective effects of an intranigral microinjection of serofendic acid based on behavioral, neurochemical and histochemical studies in hemi-parkinsonian rats using 6-hydroxydopamine (6-OHDA). Rats were injected with 6-OHDA in the presence or absence of serofendic acid, or were treated with serofendic acid on the same lateral side, at 12, 24 or 72 h after 6-OHDA lesion. Intranigral injection of 6-OHDA alone induced a massive loss of tyrosine hydroxylase (TH)-immunopositive neurons in the substantia nigra pars compacta (SNpc). Either simultaneous or 12 h post-administration of serofendic acid significantly prevented both dopaminergic neurodegeneration and drug-induced rotational asymmetry. Immunoreactivities for oxidative stress markers, such as 3-nitrotyrosine (3-NT) and 4-hydroxy-2-nonenal (4-HNE), were markedly detected in the SNpc of rats injected with 6-OHDA alone. These immunoreactivities were markedly suppressed by the co-administration of serofendic acid, similar to the results in vehicle-treated control rats. In addition, serofendic acid inhibited 6-OHDA-induced alpha-synuclein expression and glial activation in the SNpc. These results suggest that serofendic acid protects against 6-OHDA-induced SNpc dopaminergic neurodegeneration in a rat model of Parkinson's disease.

Topics: Adrenergic Agents; Aldehydes; alpha-Synuclein; Animals; Behavior, Animal; Blotting, Western; CD11b Antigen; Cell Count; Cell Line; Disease Models, Animal; Diterpenes; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Interactions; Functional Laterality; Glial Fibrillary Acidic Protein; Humans; Immunohistochemistry; Male; Neurodegenerative Diseases; Neuroprotective Agents; Oxidopamine; Parkinson Disease, Secondary; Parkinsonian Disorders; Rats; Rats, Wistar; Reactive Oxygen Species; Rotarod Performance Test; Rotation; Substantia Nigra; Synaptophysin; Time Factors; Tyrosine; Tyrosine 3-Monooxygenase

Oxidation of catecholamines is suggested to contribute to oxidative stress in Parkinson's disease. Nitric oxide (*NO) is able to oxidize cyclic compounds like ubiquinol; moreover, recent lines of evidence proposed a direct role of *NO and its by-product peroxynitrite in the pathophysiology of Parkinson's disease. The aim of this study was to analyze the potential reaction between 6-hydroxydopamine, a classic inducer of Parkinson's disease, and *NO. The results showed that *NO reacts with the deprotonated form of 6-hydroxydopamine at pH 7 and 37 degrees C with a second-order rate constant of 1.5 x 10(3) M(-1) x s(-1) as calculated by the rate of *NO decay measured with an amperometric sensor. Accordingly, the rates of formation of 6-hydroxy-dopamine quinone were dependent on *NO concentration. The coincubation of *NO and 6-hydroxydopamine with either bovine serum albumin or alpha-synuclein led to tyrosine nitration of the protein, in a concentration dependent-manner and sensitive to superoxide dismutase. These findings suggest the formation of peroxynitrite during the redox reactions following the interaction of 6-hydroxydopamine with *NO. The implications of this reaction for in vivo models are discussed in terms of the generation of reactive nitrogen and oxygen species within a propagation process that may play a significant role in neurodegenerative diseases.

Topics: alpha-Synuclein; Animals; Cattle; Nerve Tissue Proteins; Nitric Oxide; Oxidation-Reduction; Oxidopamine; Parkinson Disease; Parkinson Disease, Secondary; Peroxynitrous Acid; Serum Albumin, Bovine; Superoxide Dismutase; Synucleins; Tyrosine

Glutathione peroxidase (GSHPx) is a critical intracellular enzyme involved in detoxification of hydrogen peroxide (H(2)O(2)) to water. In the present study we examined the susceptibility of mice with a disruption of the glutathione peroxidase gene to the neurotoxic effects of malonate, 3-nitropropionic acid (3-NP), and 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP). Glutathione peroxidase knock-out mice showed no evidence of neuropathological or behavioral abnormalities at 2-3 months of age. Intrastriatal injections of malonate resulted in a significant twofold increase in lesion volume in homozygote GSHPx knock-out mice as compared to both heterozygote GSHPx knock-out and wild-type control mice. Malonate-induced increases in conversion of salicylate to 2,3- and 2, 5-dihydroxybenzoic acid, an index of hydroxyl radical generation, were greater in homozygote GSHPx knock-out mice as compared with both heterozygote GSHPx knock-out and wild-type control mice. Administration of MPTP resulted in significantly greater depletions of dopamine, 3,4-dihydroxybenzoic acid, and homovanillic acid in GSHPx knock-out mice than those seen in wild-type control mice. Striatal 3-nitrotyrosine (3-NT) concentrations after MPTP were significantly increased in GSHPx knock-out mice as compared with wild-type control mice. Systemic 3-NP administration resulted in significantly greater striatal damage and increases in 3-NT in GSHPx knock-out mice as compared to wild-type control mice. The present results indicate that a knock-out of GSHPx may be adequately compensated under nonstressed conditions, but that after administration of mitochondrial toxins GSHPx plays an important role in detoxifying increases in oxygen radicals.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; 3,4-Dihydroxyphenylacetic Acid; Animals; Brain Chemistry; Catechols; Convulsants; Corpus Striatum; Disease Models, Animal; Dopamine Agents; Female; Free Radicals; Glutathione; Glutathione Peroxidase; Heterozygote; Homovanillic Acid; Homozygote; Huntington Disease; Male; Malonates; Mice; Mice, Inbred Strains; Mice, Knockout; MPTP Poisoning; Nitro Compounds; Oxidative Stress; Parkinson Disease, Secondary; Propionates; Tyrosine