dinoprost and Parkinson-Disease

Early phases of Parkinson's disease (PD) are characterized by a mild reduction of dopamine (DA) in striatum and by emergence of psychiatric disturbances that precede overt motor symptoms. In order to characterize the neurochemical re-arrangements induced by such striatal impairment, we used a mouse model in which a low dose of 6-hydroxydopamine (6-OHDA) was bilaterally injected into the dorsal striatum. These mice showed a DA reduction of about 40% that remained stable up to 12 weeks after injection. This reduction was accompanied by changes in DA metabolite levels, such as HVA, transiently reduced at 4 weeks, and DOPAC, decreased at 12 weeks. No change in the 5-hydroxytryptamine (5-HT) levels was found but the 5-hydroxyindoleacetic acid (5-HIAA)/5-HT ratio was increased at 4 weeks. In addition, at the same time-point, the levels of 15-F(2t)-IsoP, an index of oxidative stress, and of PGE(2), a major product of cyclooxygenase-2, were decreased in different brain areas while BDNF levels were increased. These neurochemical changes were accompanied by altered behavioral responses concerning the emotional reactivity. Overall, the present findings suggest that a change of 5-HT metabolism and a modification of oxidative stress levels may play a role in the early PD degeneration phases.

Topics: Adrenergic Agents; Animals; Behavior, Animal; Biogenic Monoamines; Brain Chemistry; Brain-Derived Neurotrophic Factor; Corpus Striatum; Dinoprost; Dinoprostone; Disease Models, Animal; Exploratory Behavior; Locomotion; Male; Maze Learning; Mice; Mice, Inbred C57BL; Oxidopamine; Parkinson Disease; Swimming

To determine the utility of 8,12-isoprostaneF2alpha-VI (iP), a specific and sensitive index of lipid peroxidation, as a biomarker for dementia in Parkinson disease (PD).. iP is a member of the F2-isoprostanes family that has been shown to be promising biomarker for Alzheimer disease. However, iP levels have not been studied in patients with clinical diagnosis of PD or Parkinson disease with dementia (PDD).. PD and PDD patient plasma and urine iP levels were compared with age-matched and sex-matched controls. Clinical measures including demographics and tests of motor function, affect, and cognition were assessed and compared with iP levels.. There were no differences in plasma iP levels between PD subjects and controls (299 vs. 306 pg/mL; P=0.6). Urine iP levels were higher in cases than controls (2.8 vs. 2.1 ng/mg Cr; P=0.003), but levels were lower than those seen in Alzheimer disease patients in prior studies. Within PD subjects, there was no association of iP levels in either the plasma or urine with performance on any clinical measure.. Plasma and urine iP levels do not seem to be substantially elevated in PD and are not associated with severity of cognitive impairment in PDD.

Topics: Aged; Aged, 80 and over; Biomarkers; Cognition Disorders; Dementia; Dinoprost; Disability Evaluation; Female; Humans; Lipid Peroxidation; Male; Mental Status Schedule; Middle Aged; Parkinson Disease; Prognosis; Reference Values

Guam parkinsonism-dementia complex (PDC) is a neurodegenerative tauopathy in ethnic Chamorro residents of the Mariana Islands that manifests clinically with parkinsonism as well as dementia and is characterized neuropathologically by prominent cortical neuron loss in association with extensive telencephalic neurofibrillary tau pathology. To further characterize cortical gray and white matter tau, alpha-synuclein and lipid peroxidation pathologies in Guam PDC, we examined the brains of 17 Chamorro PDC and control subjects using biochemical and immunohistological techniques. We observed insoluble tau pathology in both gray and white matter of PDC and Guam control cases, with frontal and temporal lobes being most severely affected. Using phosphorylation dependent anti-tau antibodies, abundant tau inclusions were detected by immunohistochemistry in both neuronal and glial cells of the neocortex, while less alpha-synuclein pathology was observed in more limited brain regions. Further, in sharp contrast to Alzheimer's disease (AD), levels of the lipid peroxidation product 8, 12-iso-iPF(2alpha)-VI isoprostane were not elevated in Guam PDC brains relative to controls. Thus, although the tau pathologies of Guam PDC share similarities with AD, the composite Guam PDC neuropathology profile of tau, alpha-synuclein and 8, 12-iso-iPF(2alpha)-VI isoprostane reported here more closely resembles that seen in other tauopathies including frontotemporal dementias (FTDs), which may imply that Guam PDC and FTD tauopathies share underlying mechanisms of neurodegeneration.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Dementia; Dinoprost; Female; Gene Expression Regulation; Guam; Humans; Lipid Peroxidation; Male; Middle Aged; Native Hawaiian or Other Pacific Islander; Neurons; Parkinson Disease; Periaqueductal Gray; tau Proteins

To quantify the isoprostane 8,12-iso-iPF2alpha-VI in brain tissues obtained from patients with AD, patients with frontotemporal dementia (FTD), and controls.. Enhanced brain oxidative stress with secondary damage to cellular macromolecules may play a role in the pathogenesis of AD and FTD. The isoprostane 8,12-iso-iPF2alpha-VI is a specific and sensitive marker of in vivo lipid peroxidation and is increased in AD.. Levels of this isoprostane were determined by gas chromatography/negative ion chemical ionization mass spectrometry.. Levels of 8,12-iso-iPF2alpha-VI were markedly elevated in both frontal and temporal cortex of AD brains compared to the corresponding areas of FTD and controls. No significant difference in brain 8,12-iso-iPF2alpha-VI levels for any regions considered was observed between FTD and controls.. Lipid peroxidation is a feature of AD, but not FTD. The generation of 8,12-iso-iPF(2alpha)-VI in the brain is not a general or final common pathway of neurodegeneration, but may be relatively specific for disease processes in AD and not FTD.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Biomarkers; Brain Chemistry; Dementia; Dinoprost; Female; Gas Chromatography-Mass Spectrometry; Humans; Lipid Peroxidation; Male; Middle Aged; Nerve Degeneration; Oxidative Stress; Parkinson Disease; Pick Disease of the Brain; Supranuclear Palsy, Progressive

Alzheimer's disease (AD) includes a group of dementing neurodegenerative disorders that have diverse etiologies but the same hallmark brain lesions. Since oxidative stress may play a role in the pathogenesis of AD and isoprostanes are chemically stable peroxidation products of arachidonic acid, we measured both iPF2alpha-III and iPF2alpha -VI using gas chromatography-mass spectrometry in AD and control brains. The levels of both isoprostanes, but not of 6-keto PGF1alpha, an index of prostaglandin production, were markedly elevated in both frontal and temporal poles of AD brains compared to the corresponding cerebella. Levels were also elevated compared to corresponding areas of brains from patients who had died with schizophrenia or Parkinson's disease or from nonneuropsychiatric disorders. iPF2alpha -IV, but not iPF2alpha-III, levels were higher in ventricular CSF of AD brains relative to the non-AD brains. These data suggest that specific isoprostane analysis may reflect increased oxidative stress in AD.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Brain Chemistry; Cerebellum; Cerebrospinal Fluid; Dinoprost; Female; Frontal Lobe; Humans; Lipid Peroxidation; Male; Neurofibrillary Tangles; Oxidative Stress; Parkinson Disease; Schizophrenia; Stereoisomerism; Temporal Lobe