4-hydroxy-2-nonenal and Parkinsonian-Disorders

Although the etiology of Parkinson's disease (PD) is unknown, a common element of most theories is the involvement of oxidative stress, either as a cause or effect of the disease. There have been relatively few studies that have characterized oxidative stress in animal models of PD. In the present study a 6-hydroxydopamine (6-OHDA) rodent model of PD was used to investigate the in vivo production of oxidative stress after administration of the neurotoxin. 6-OHDA was injected into the striatum of young adult rats and the production of protein carbonyls and 4-hydroxynonenal (HNE) was measured at 1, 3, 7, and 14 days after administration. A significant increase in both markers was found in the striatum 1 day after neurotoxin administration, and this increase declined to basal levels by day 7. There was no significant increase found in the substantia nigra at any of the time points investigated. This same lesion paradigm produced dopamine depletions of 90-95% in the striatum and 63-80% in the substantia nigra by 14-28 days post-6-OHDA. Protein carbonyl and HNE levels were also measured in middle-aged and aged animals 1 day after striatal 6-OHDA. Both protein carbonyl and HNE levels were increased in the striatum of middle-aged and aged animals treated with 6-OHDA, but the increases were not as great as those observed in the young adult animals. Similar to the young animals, there were no increases in either marker in the substantia nigra of the middle-aged and aged animals. There was a trend for an age-dependent increase in basal amounts of oxidative stress markers when comparing the non-lesioned side of the brains of the three age groups. These results support that an early event in the course of dopamine depletion following intrastriatal 6-OHDA administration is the generation of oxidative stress.

Topics: Age Factors; Aging; Aldehydes; Animals; Corpus Striatum; Dopamine; Male; Oxidative Stress; Oxidopamine; Parkinsonian Disorders; Rats; Rats, Inbred F344; Reactive Oxygen Species; Substantia Nigra

Mutations in parkin are involved in some cases of autosomal recessive juvenile parkinsonism (AR-JP), but it is not known how they result in nigral cell death. We examined the effect of parkin overexpression on the response of cells to various insults. Wild-type and AR-JP-associated mutant parkins (Del3-5, T240R, and Q311X) were overexpressed in NT-2 and SK-N-MC cells. Overexpressed wild-type parkin delayed cell death induced by serum withdrawal, H(2)O(2), 1-methyl-4-phenylpyridinium (MPP(+)), or 4-hydroxy-2-trans-nonenal (HNE) but did not delay cell death caused by the proteasome inhibitor lactacystin. Increases in damage to proteins (protein carbonyls and 3-nitrotyrosine) were attenuated by wild-type parkin after serum withdrawal or exposure to H(2)O(2), MPP(+), or HNE but not after exposure to lactacystin. The mutant parkins (of all types) markedly accelerated cell death in response to all the insults, accompanied by increased levels of 8-hydroxyguanine, protein carbonyls, lipid peroxidation, and 3-nitrotyrosine and decreased levels of GSH. The viability loss induced by all the insults showed apoptotic features. The presence of parkin mutations in substantia nigra in Parkinson's disease may increase neuronal vulnerability to a range of toxic insults.

Topics: 1-Methyl-4-phenylpyridinium; Acetylcysteine; Aldehydes; Apoptosis; Cell Death; Cell Line, Tumor; Drug Resistance; Enzyme Inhibitors; Genetic Predisposition to Disease; Glutamic Acid; Guanine; Humans; Hydrogen Peroxide; Mutation; Nerve Degeneration; Neurons; Neurotoxins; Oxidative Stress; Parkinsonian Disorders; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Substantia Nigra; Tyrosine; Ubiquitin-Protein Ligases

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

Mutations in alpha-synuclein (A30P and A53T) are involved in some cases of familial Parkinson's disease (FPD), but it is not known how they result in nigral cell death. We examined the effect of alpha-synuclein overexpression on the response of cells to various insults. Wild-type alpha-synuclein and alpha-synuclein mutations associated with FPD were overexpressed in NT-2/D1 and SK-N-MC cells. Overexpression of wild-type alpha-synuclein delayed cell death induced by serum withdrawal or H(2)O(2), but did not delay cell death induced by 1-methyl-4-phenylpyridinium ion (MPP(+)). By contrast, wild-type alpha-synuclein transfectants were sensitive to viability loss induced by staurosporine, lactacystin or 4-hydroxy-2-trans-nonenal (HNE). Decreases in glutathione (GSH) levels were attenuated by wild-type alpha-synuclein after serum deprivation, but were aggravated following lactacystin or staurosporine treatment. Mutant alpha-synucleins increased levels of 8-hydroxyguanine, protein carbonyls, lipid peroxidation and 3-nitrotyrosine, and markedly accelerated cell death in response to all the insults examined. The decrease in GSH levels was enhanced in mutant alpha-synuclein transfectants. The loss of viability induced by toxic insults was by apoptosic mechanism. The presence of abnormal alpha-synucleins in substantia nigra in PD may increase neuronal vulnerability to a range of toxic agents.

Topics: 1-Methyl-4-phenylpyridinium; Aldehydes; alpha-Synuclein; Cell Division; Cell Line; Cell Survival; Clone Cells; Culture Media, Serum-Free; Enzyme Inhibitors; Gene Expression; Glutathione; Guanine; Humans; Hydrogen Peroxide; Ketones; Lipid Peroxidation; Mitochondria; Mutation; Nerve Tissue Proteins; Neuroblastoma; Oxidants; Oxidative Stress; Parkinsonian Disorders; Synucleins; Teratocarcinoma; Transfection; Tyrosine