E. Sofic

Transition metals, ferritin, glutathione, and ascorbic acid in parkinsonian brains

Abstract: The regional distributions of iron, copper, zinc, magnesium, and calcium in parkinsonian brains were compared with those of matched controls. In mild Parkinsons disease (PD), there were no significant differences in the content of total iron between the two groups, whereas there was a significant increase in total iron and iron (III) in substantia nigra of severely affected patients. Although marked regional distributions of iron, magnesium, and calcium were present, there were no changes in magnesium, calcium, and copper in various brain areas of PD. The most notable finding was a shift in the iron (II)/iron (III) ratio in favor of iron (III) in substantia nigra and a significant increase in the iron (III)‐binding protein, ferritin. A significantly lower glutathione content was present in pooled samples of putamen, globus pallidus, substantia nigra, nucleus basalis of Meynert, amygdaloid nucleus, and frontal cortex of PD brains with severe damage to substantia nigra, whereas no significant changes were observed in clinicopathologically mild forms of PD. In all these regions, except the amygdaloid nucleus, ascorbic acid was not decreased. Reduced glutathione and the shift of the iron (II)/iron (III) ratio in favor of iron (III) suggest that these changes might contribute to pathophysiological processes underlying PD.

Increased iron (III) and total iron content in post mortem substantia nigra of parkinsonian brain.

Significant differences in the content of iron (III) and total iron were found in post mortem substantia nigra of Parkinsons disease. There was an increase of 176% in the levels of total iron and 255% of iron (III) in the substantia nigra of the parkinsonian patients compared to age matched controls. In the cortex (Brodmann area 21), hippocampus, putamen, and globus pallidus there was no significant difference in the levels of iron (III) and total iron. Thus the changes in total iron, iron (III) and the iron (II)/iron (III) ratio in the parkinsonian substantia nigra are likely to be involved in the pathophysiology and treatment of this disorder.

Reduced and oxidized glutathione in the substantia nigra of patients with Parkinson's disease

Reduced and oxidized glutathione concentrations in post-mortem brain tissue from the substantia nigra of control subjects and patients with neuropathologically confirmed Parkinsons disease were measured by a coulometric method using high-pressure liquid chromatography and electrochemical detection. Reduced glutathione concentrations were decreased in the substantia nigra of parkinsonian patients compared with controls. Differences in the concentration of oxidized glutathione and in the percentage of oxidized glutathione of the total glutathione were not observed between parkinsonian and control subjects. The finding that oxidized glutathione is not decreased in Parkinsons disease suggests that the decrease in reduced glutathione is not exclusively the consequence of neuronal loss in the substantia nigra but may indicate a state of oxidative stress.

Selective Increase of Iron in Substantia Nigra Zona Compacta of Parkinsonian Brains

Abstract: Histochemical and biochemical determinations of total iron, iron (II), and iron (III) contents in brain regions from Parkinsons and Alzheimers diseases have demonstrated a selective increase of total iron content in parkinsonian substantia nigra zona compacta but not in the zona reticulata. The increase of iron content is mainly in iron (III). The ratio of iron (II):iron (III) in zona compacta changes from almost 2:1 to 1:2. This change is thought to be relevant and may contribute to the selective elevation of basal lipid peroxidation in substantia nigra reported previously. Iron may be available in a free state and thus can participate in autooxidation of dopamine with the resultant generation of H2O2 and oxygen free radicals.

The competitive NMDA antagonist CPP protects substantia nigra neurons from MPTP-induced degeneration in primates

SummaryDegeneration of nigrostriatal dopaminergic neurons is the primary histopathological feature of Parkinsons disease. The neurotoxin MPTP (1-methyl-4phenyl-1,2,3,6-tetrahydropyridine) induces a neurological syndrome in man and non-human primates very similar to idiopathic Parkinsons disease by selectively destroying dopaminergic nigrostriatal neurons. This gives rise to the hypothesis that Parkinsons disease may be caused by endogenous or environmental toxins. Endogenous excitatory amino acids (EAAs) such as l-glutamate could be involved in neurodegenerative disorders including Parkinsons disease. We report in this study that the competitive NMDA antagonist CPP (3-((±)-2-carboxypiperazin-4yl)-propyl-1-phosphonic acid) protects nigral tyrosine hydroxylase (TH) positive neurons from degeneration induced by systemic treatment with MPTP in common marmosets. This indicates that EAAs are involved in the pathophysiological cascade of MPTP-induced neuronal cell death and that EAA antagonists may offer a neuroprotective therapy for Parkinsons disease.

Depression in Parkinson's disease: biogenic amines in CSF of “de novo” patients

SummaryIntroduction. Etiology of depression in Parkinsons disease (PD) is associated with serotonergic dysfunction. Previous studies, supporting this hypothesis, were performed on patients treated with antiparkinsonian drugs. To eliminate the influence of parkinsonian drug therapy and to elucidate significance of different biochemical pathways in PD associated with depression we determined levels of biogenic amines in cerebrospinal fluid (CSF) of 26 untreated “de novo” Parkinsonian patients.Material and methods. Patients were scored with the Hamilton depression scale (HD) and subdivided into groups with HD score ≥ 18 and HD score <18. Diagnosis of depression was made according to DSM III R. Both groups were matched for age and motor disability.Results. In both groups no significant differences appeared between CSF levels of dopamine, noradrenaline, 3,4-dihydroxyphenylacetic acid, homovanillic acid, 3-methoxy-4-hydroxyphenylglycol and 5-hydroxyindole acetic acid, determined by high-performance liquid chromatography.Discussion. In contrast to previous studies on treated Parkinsonian patients no sign of altered serotonin metabolism especially in context with severity of depression in early stages of PD was found. Due to our results, we suggest, that biochemical markers of depression in CSF of PD may be influenced by antiparkinsonian therapy and that depression in PD may respond to serotonin reuptake inhibitors mainly in later stages of PD.

Variations of monoamines and their metabolites in the human brain putamen

The levels of the monoamines dopamine (DA), serotonin (5-HT) and norepinephrine (NE) and the monoaminergic metabolites 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) were measured with HPLC-ECD in 42 samples from human brain putamen. The influence of gender and of age was investigated and correlations between the monoamines were established. The DAergic system shows a significant difference between males and females, with females having lower DA and higher DOPAC levels and a higher DOPAC/DA ratio than males. No gender-related differences of 5-HT and its metabolites were observed, nor of NE. Three different age groups (group 1: 0-9.9 years: group 2: 10-59.9 years; group 3: 60 years and older) were defined according to previous studies on ontogenesis and senescence in human brain. An increase in 5-HT levels, decrease in 5-HIAA levels and a decrease in the 5-HIAA/5-HT ratio were observed after the first decade of life. Changes in the DAergic system were seen in senescence, with decreasing DA levels and an increase in the HVA/DA ratio. DOPAC, HVA and the DOPAC/DA ratio are unaffected. NE is similar in all age groups. The analysis of the relation of the levels of the three monoamines proved a strong correlation between the DAergic and 5-HTergic systems. The nature of this relationship might have an impact on neuro-psychiatric disorders and brain function.

Reduced concentrations and increased metabolism of biogenic amines in a single case of Rett-syndrome: apostmortem brain study

Preliminary data of a postmortem brain study in a single case with Rett-syndrome compared to a single control case show a severe reduction of dopamine (DA), noradrenaline (NA), and serotonin (5-HT) in most regions studied and in two regions of adrenaline (A). A marked increase in the 3,4-dihydroxyphenyl acetic acid (DOPAC)/DA, homovanillic acid (HVA)/ DA, and the 5-hydroxyindole acetic acid (5-HIAA)/5-HT ratios indicates increased metabolism of DA and 5-HT. Also a marked reduction of3H-spiroperidol-binding in putamen was found. This agrees with the assumption that a defect in maturation processes of central monoaminergic systems could be an underlying cause of Rett-syndrome.

Susceptibility of Brains from Patients with Alzheimer's Disease to Oxygen-Stimulated Lipid Peroxidation and Differential Scanning Calorimetry

The formation of thiobarbituric-acid-reactive substances (TBARS) indicative of oxygen-induced lipid peroxidation in vitro was assayed in the frontal cortex, hippocampus, putamen, basal nucleus of Meyn

Biogenic amines and metabolites in spinal cord of patients with Parkinson's disease and amyotrophic lateral sclerosis

SummaryIn four human controls, four cases of Parkinsons disease and three cases of amyotrophic lateral sclerosis analysis of dopamine, noradrenaline, serotonin and the metabolites 3,4-dihydroxyphenylacetic acid, homovanillic acid and 5-hydroxyindoleacetic acid was performed in various segments of postmortem spinal cord. In controls the concentrations of dopamine are about 1/3 to 1/4 that of noradrenaline; the significantly highest content of noradrenaline was found in the lumbar, and dopamine in thoracic, lumbar and sacral segments of the spinal cord. Intersegmental distribution of monoamines was only present in spinal cord of controls, while in the spinal cord of parkinsonian patients such a difference was not found.Otherwise, biogenic amine and metabolite concentrations in spinal cord segments of parkinsonian patients did not differ significantly from those in the control subjects. However, it cannot be excluded that these segments are sensitive to drugs including neuroleptics and combined L-DOPA treatment.In subjects with amyotrophic lateral sclerosis significantly lower concentrations of noradrenaline in the cervical and thoracic, and of dopamine and homovanillic acid in the thoracic and lumbar segments were found in comparison with controls. The concentrations of serotonin and 5-hydroxyindoleacetic acid in the thoracic segments of amyotrophic lateral sclerosis were significantly lower than that of controls. Differences in the inter-segmental distribution of noradrenaline in lumbar, lumbar-sacral, and serotonin in lumbar segments of spinal cord were found in this group.