Library

Notes: Abstract: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is thought to produce parkinsonism in humans and other primates through its inhibition of complex I. The recent discovery of mitochondrial complex I deficiency in the substantia nigra of patients with Parkinson's disease has provided a remarkable link between the idiopathic disease and the action of the neurotoxin MPTP. This article shows that complex I deficiency in Parkinson's disease is anatomically specific for the substantia nigra, and is not present in another neurodegenerative disorder involving the substantia nigra. Evidence is also provided to show that there is no correlation between l-3,4-dihydroxyphenylalanine therapy and complex I deficiency. These results suggest that complex I deficiency may be the underlying cause of dopaminergic cell death in Parkinson's disease.

Notes: Abstract: Polyunsaturated fatty acid (PUFA) levels (an index of the amount of substrate available for lipid peroxidation) were measured in several brain regions from patients who died with Parkinson's disease and age-matched control human postmortem brains. PUFA levels were reduced in parkinsonian substantia nigra compared to other brain regions and to control tissue. However, basal malondialdehyde (MDA; an intermediate in the lipid peroxidation process) levels were increased in parkinsonian nigra compared with other parkinsonian brain regions and control tissue. Expressing basal MDA levels in terms of PUFA content, the difference between parkinsonian and control substantia nigra was even more pronounced. Stimulating MDA production by incubating tissue with FeSO4 plus ascorbic acid, FeSO4 plus H2O2, or air alone produced lower MDA levels in the parkinsonian substantia nigra, probably reflecting the lower PUFA content. These results may indicate that an increased level of lipid peroxidation continues to occur in the parkinsonian nigra up to the time of death, perhaps because of continued exposure to excess free radicals derived from some endogenous or exogenous neurotoxic species.

Notes: Abstract: Muscarinic and nicotinic cholinergic receptors and choline acetyltransferase activity were studied in postmortem brain tissue from patients with histopathologically confirmed Parkinson's disease and matched control subjects. Using washed membrane homogenates from the frontal cortex, hippocampus, caudate nucleus, and putamen, saturation analysis of specific receptor binding was performed for the total number of muscarinic receptors with [3H]quinuclidinyl benzilate, for muscarinic M1 receptors with [3H]pirenzepine, for muscarinic M2 receptors with [3H]oxotremorine-M, and for nicotinic receptors with (–)-[3H]nicotine. In comparison with control tissues, choline acetyltransferase activity was reduced in the frontal cortex and hippocampus and unchanged in the caudate nucleus and putamen of parkinsonian patients. In Parkinson's disease the maximal binding site density for [3H]quinuclidinyl benzilate was increased in the frontal cortex and unaltered in the hippocampus, caudate nucleus, and putamen. Specific [3H]pirenzepine binding was increased in the frontal cortex, unaltered in the hippocampus, and decreased in the caudate nucleus and putamen. In parkinsonian patients Bmax values for specific [3H]oxotremorine-M binding were reduced in the cortex and unchanged in the hippocampus and striatum compared with controls. Maximal (–)-[3H]nicotine binding was reduced in both the cortex and hippocampus and unaltered in both the caudate nucleus and putamen. Alterations of the equilibrium dissociation constant were not observed for any ligand in any of the brain areas examined. The present results suggest that both the innominatocortical and the septohippocampal cholinergic systems degenerate in Parkinson's disease. The reduction of cortical [3H]oxotremorine-M and (–)-[3H]nicotine binding is compatible with the concept that significant numbers of the binding sites labelled by these ligands are located on presynaptic cholinergic nerve terminals, whereas the increased [3H]pirenzepine binding in the cortex may reflect postsynaptic denervation supersensitivity.

Notes: Abstract: The structure and function of mitochondrial respiratory-chain enzyme proteins were studied postmortem in the substantia nigra of nine patients with Parkinson's disease and nine matched controls. Total protein and mitochondrial mass were similar in the two groups. NADH-ubiquinone reductase (Complex I) and NADH cytochrome c reductase activities were significantly reduced, whereas succinate cytochrome c reductase activity was normal. These results indicated a specific defect of Complex I activity in the substantia nigra of patients with Parkinson's disease. This biochemical defect is the same as that produced in animal models of parkinsonism by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and adds further support to the proposition that Parkinson's disease may be due to an environmental toxin with action(s) similar to those of MPTP.

Notes: Abstract: Ferritin levels were measured in postmortem brain tissue from patients dying with Parkinson's disease [treated with L-3,4-dihydroxyphenylalanine (L-DOPA)] and from control patients. Ferritin levels were decreased in the substantia nigra, caudate-putamen, globus pallidus, cerebral cortex, and cerebellum when compared with age-matched control tissues. However, in CSF from L-DOPA-treated patients and in serum from L-DOPA-treated and untreated parkinsonian patients, ferritin levels were normal. Previous studies have suggested an increased total iron content in substantia nigra of parkinsonian brain. The failure of substantia nigra ferritin formation to be stimulated by increased iron levels suggests some defect in iron handling in this critical brain region in Parkinson's disease. The reason for decreased ferritin levels throughout the parkinsonian brain is not clear but does not seem to reflect a general system deficit in ferritin.

Notes: The total activity of superoxide dismutase (SOD) and cytosolic and particulate activity of SOD in human substantia nigra and cerebellum were measured by a spectrophotometric method based on the ability of SOD to inhibit the autoxidation of adrenaline. The cystosolic and particulate isoenzymes of SOD were differentiated by the inclusion of potassium cyanide which selectively inhibits cytosolic copper/zinc-dependent SOD activity. In autopsied human brains, there was no difference in total SOD) activity, or the activity of SOD in cytosol in substantia nigra jof patients dying with Parkinson's disease compared to age-matched controls. However, the activity of the particulate form of SOD was higher in the parkinsonian substantia nigra compared to control tissue. In the cerebellum there was no difference in the total, cytosolic, or particulate activity of SOD between parkinsonian patients and age-matched controls. Increased activity of SOD in particulate fraction may be a protective response to elevated levels of toxic free radicals in the parkinsonian substantia nigra. Alternatively, increased SOD activity may induce cell death through the accumulation of hydrogen peroxide.

Notes: Abstract: Levels of iron, copper, zinc, manganese, and lead were measured by inductively coupled plasma spectroscopy in parkinsonian and age-matched control brain tissue. There was 31-35% increase in the total iron content of the parkinsonian substantia nigra when compared to control tissue. In contrast, in the globus pallidus total iron levels were decreased by 29% in Parkinson's disease. There was no change in the total iron levels in any other region of the parkinsonian brain. Total copper levels were reduced by 34–45% in the substantia nigra in Parkinson's disease; no difference was found in the other brain areas examined. Zinc levels were increased in substantia nigra in Parkinson's disease by 50–54%, and the zinc content of the caudate nucleus and lateral putamen was also raised by 18–35%. Levels of manganese and lead were unchanged in all areas of the parkinsonian brain studied when compared to control brains, except for a small decrease (20%) in manganese content of the medial putamen. Increased levels of total iron in the substantia nigra may cause the excessive formation of toxic oxygen radicals, leading to dopamine cell death.

Notes: Abstract Treatment of common marmosets with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP; 1–4mg/kgfor up to 4 days) caused a profound parkinsonian state. Ten days from the start of MPTP treatment, all animals showed marked motor impairment, consisting of bradykinesia and akinesia, limb rigidity, postural abnormalities, loss of vocalisation and blink reflex, and, on occasions, postural tremor. Measurement of caudate-putamen monoamine content at this time showed a profound loss in 3,4-dihydroxyphenyl-ethylamine, homovanillic acid, and 3,4-dihydroxyphenylacetic acid concentrations. Measurement of neuropeptide concentrations in the caudate-putamen, internal and external segments of the globus pallidus, nucleus accumbens, substantia nigra, frontal cortex, and hippocampus showed met-enkephalin, leu-enkephalin, and cholecystokinin (CCK-8) concentrations to be unaffected by MPTP treatment. There was a small decrease in the substance P content of frontal cortex, but otherwise the content of this neuropeptide was unaltered. Parkinsonism in the marmoset, induced by MPTP treatment 10 days earlier, does not alter neuropeptide concentrations in the manner observed in Parkinson's disease.

Notes: Abstract: Oxidative damage has been implicated in the pathology of Parkinson's disease (PD), e.g., rises in the level of the DNA damage product, 8-hydroxy-2′-deoxyguanosine, have been reported. However, many other products result from oxidative DNA damage, and the pattern of products can be diagnostic of the oxidizing species. Gas chromatography/mass spectrometry was used to examine products of oxidation and deamination of all four DNA bases in control and PD brains. Products were detected in all brain regions examined, both normal and PD. Analysis showed that levels of 8-hydroxyguanine (8-OHG) tended to be elevated and levels of 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FAPy guanine) tended to be decreased in PD. The most striking difference was a rise in 8-OHG in PD substantia nigra (p = 0.0002); rises in other base oxidation/deamination products were not evident, showing that elevation in 8-OHG is unlikely to be due to peroxynitrite (ONOO−) or hydroxyl radicals (OH•), or to be a prooxidant effect of treatment with l-Dopa. However, some or all of the rise in 8-OHG could be due to a change in 8-OHG/FAPy guanine ratios rather than to an increase in total oxidative guanine damage.

Notes: Whereas the first success of petroleum exploration in France (the gas deposit in the St. Marcet anticline in the St. Gaudens region) was essentially based on geological surveys, the second (the Lacq field in the Pau region) was the fruit of reflection shooting. In fact, the Lacq anticline cannot be detected by surface geology because of the Quaternary and Tertiary cover. Besides, electric and telluric prospecting methods could not be used over this zone as an electrified railway line passes through it.As stated then, it was the reflection shooting method that revealed the Lacq structure in 1948, during a reconnaissance survey conducted by Compagnie Générate de Géophysique using a very simple technique (only one geophone per trace).By the seismic technique of 1948, quite good reflections were obtained from a level adjacent to the top Cretaceous, but only sporadic reflections were picked up from a deep level and then only on the flanks of the structure, except for the southern one where results were nil.Towards the end of 1949, the first well, La 1, using a heavy rig designed to reach deep layers, led to the unexpected discovery of the upper oil deposit at a depth of 600 m in the Upper Cretaceous (lower Senonian), while the third well, La 3, led to the discovery by blow-out of the lower gas accumulation at a depth of 3,500 m in beds later identified as lowermost Cretaceous and, more particularly, Upper Jurassic (Purbeckian).As no great geophysical effort was called for, the upper oil deposit was rapidly developed, its depth and dimensions being modest (6 km2).As far as the deeper gas deposit is concerned, the main objective up to 1954 was to gain a picture of the central part of the anticline. Despite the use of a more detailed seismic technique, it was difficult to plot the top of the structure at the level of the uppermost Jurassic. From 1952 to 1957 the wells La 101, La 102, La 103, La 104, La 105, La 106 and La 113 were drilled, which made it possible to evaluate the gas reserves.Then began the wide-scale and systematic exploration of the structure, by drilling on the one hand and by reflection shooting on the other. Profiles were shot perpendicular to the axis, but long enough (20 to 30 km) to cover the entire anticline (seismic surveys of 1956–57–58).The eastern pericline and the northern flank were quite easily plotted by seismic survey at the level of the top Jurassic, whereas the southern flank, which has a distinctly steeper slope than the northern one, could not be traced very far–so that the problem of the relationship between the uncomplicated structure of Lacq and the country to the south, with its complex, deep tectonics, still remains an open question.The western pericline, however, remained a subject of concern. Its relationship to the anticline of Ste. Suzanne (outcropping Jurassic) was a mystery.In 1956–57 the well SV 101 confirmed the hypothesis of an overthrust which, without affecting the anticline of Lacq, borders it to the south and west. The thrust is not very large in the south (Lagor wells) but assumes considerable proportions in the west: the Ste. Suzanne anticline actually forms part of a thrust from the south, about 5, 000 to 6, 000 m thick, as the exploration of the region by reflection shooting and drilling (SSE 101, OR 102) has shown. This exploration had been undertaken in search of a new structure under the thrust that might form an extension of the Lacq structure.In 1959 a detailed gravimetric survey (2 to 3 st./km2) was carried out in the Lacq region because the old survey map (1948–1 station/8 km2) had proved progressively inadequate for interpreting the seismic data. It was found that the structure of Lacq had only a small anomaly in comparison with its dimensions. This surprising phenomenon is still difficult to explain. Are the surfaces of equal specific gravity independent of the stratigraphic planes, or has the effect of the anticlinal roof of the Cretaceous and the Jurassic been balanced by that of a saliferous and intumescent Triassic right in the core of the structure?The small anomaly which it was possible to detect may be explained by a thick sequence of reef limestones in the centre of the anticline on the Lower Cretaceous, as indicated by drilling results. These severely fissured limestones are undoubtedly partly to blame for the bad seismic results obtained on the central part of the structure as far as the deep horizon, adjacent to the top Jurassic, is concerned. They are also responsible for the considerable anomalies in the velocity of seismic wave propagation.