In this study, a comparative analysis of metal-related neuronal vulnerability was performed in two brainstem nuclei, the locus coeruleus (LC) and substantia nigra (SN), known targets of the etiological noxae in Parkinson's disease and related disorders. LC and SN pars compacta neurons both degenerate in Parkinson's disease and other Parkinsonisms; however, LC neurons are comparatively less affected and with a variable degree of involvement. In this study, iron, copper, and their major molecular forms like ferritins, ceruloplasmin, neuromelanin (NM), manganese-superoxide dismutase (SOD), and copper͞zinc-SOD were measured in LC and SN of normal subjects at different ages. Iron content in LC was much lower than that in SN, and the ratio heavy-chain ferritin͞iron in LC was higher than in the SN. The NM concentration was similar in LC and SN, but the iron content in NM of LC was much lower than SN. In both regions, heavy-and light-chain ferritins were present only in glia and were not detectable in neurons. These data suggest that in LC neurons, the iron mobilization and toxicity is lower than that in SN and is efficiently buffered by NM. The bigger damage occurring in SN could be related to the higher content of iron. Ferritins accomplish the same function of buffering iron in glial cells. Ceruloplasmin levels were similar in LC and SN, but copper was higher in LC. However, the copper content in NM of LC was higher than that of SN, indicating a higher copper mobilization in LC neurons. Manganese-SOD and copper͞zinc-SOD had similar age trend in LC and SN. These results may explain at least one of the reasons underlying lower vulnerability of LC compared to SN in Parkinsonian syndromes. L ocus coeruleus (LC) is the main brain region containing norepinephrine neurons. The rostral projections from these neurons seem to be involved in the modulation of neuronal activity, metabolism, and memory (1, 2), whereas the spinal cord projections are known to modulate spinal motoneuron function (3, 4).Neuronal loss in LC occurs in conditions such as Parkinson's disease (PD) and Alzheimer's disease and Down's syndrome (5, 6) with different cellular loss in rostral and caudal parts of LC. In Alzheimer's disease and Down's syndrome, it is not clear whether neuronal loss in LC is a primary event or a consequence of retrograde degeneration of cortically projecting cells due to the loss of cortical synapses. In idiopathic PD, most studies have documented a higher degree of neuronal loss in substantia nigra (SN) compared to LC (5-8). However, a recent study reported extensive impairment of LC neurons in PD (9). SN and LC share anatomical and biochemical similarities, being both pigmented because of neuromelanin (NM), and both composed of catecholaminergic neurons. Yet, in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridineintoxicated subjects, LC neurons are spared, whereas a large neuronal depletion occurs in SN (10, 11). Also, in other types of Parkinsonian syndromes caused by exposure to toxins, the LC neurons seem less damaged than those of...

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The concentration of neuromelanin (NM) in substantia nigra pars compacta (SNPC) has been measured in male and female normal subjects at different ages in the range 1^97 years old and in SNPC of parkinsonian patients. A very similar age trend of NM concentration was found in both sexes. In the first year of life NM was not detectable, between 10 and 20 years the NM levels were 0.3^0.8 W Wg/mg of SNPC, between 20 and 50 years were 0.8^2.3 W Wg/mg SNPC and between 50 and 90 were 2.3^3.7 W Wg/mg of SNPC. In parkinsonian subjects, the NM levels were 1.2^1.5 W Wg/mg of SNPC, which is less than 50% with respect to the age-matched controls. These data demonstrate a continuous NM accumulation in SNPC neurons during aging, the presence of large amounts of NM in SNPC and severe depletion of NM in Parkinson's disease. ß 2002 Published by Elsevier Science B.V. on behalf of the Federation of European Biochemical Societies.

Scavenger receptor class B type I (SR-BI) mediates selective uptake of cholesterol from highdensity lipoprotein (HDL) particles by the liver and influences biliary cholesterol secretion. However, it is not clear, if this effect is direct or indirect. The aim of this study was to determine the impact of SR-BI on biliary cholesterol secretion, especially in a functional context with ATP-binding cassette transporter g5 (Abcg5)/Abcg8 and Abcb4. SR-BI was overexpressed by means of adenovirus (AdSR-BI) in livers of wild-type, liver X receptor-null (Lxr ؊/؊ ), Abcg5 ؊/؊ , and Abcb4 ؊/؊ mice. Consistent with previous reports, AdSR-BI decreased plasma HDL cholesterol levels in all models (P < 0.001). Hepatic cholesterol content increased (at least P < 0.05), whereas expression of sterol regulatory element binding protein 2 target genes was decreased (at least P < 0.05,) and established Lxr target genes were unaltered. Biliary cholesterol secretion was increased by AdSR-BI in wild-type as well as in Lxr ؊/؊ and Abcg5 ؊/؊ mice, and considerably less in Abcb4 ؊/؊ mice (each P < 0.001), independent of bile acid and phospholipid secretion. T he scavenger receptor class B type I (SR-BI) has been characterized as a receptor that mediates cholesterol transport across membranes. 1,2 In nonpolarized cells, namely macrophages and the hepatoma cell line Fu5AH, SR-BI expression either results in selective uptake of cholesterol, mainly from high-density lipoprotein (HDL), or in cholesterol efflux toward suitable acceptors. [3][4][5][6] In hepatocytes, which is a highly polarized cell type, SR-BI is the main receptor responsible for selective uptake of cholesterol from plasma HDL. 7 Consequently, hepatic overexpression of SR-BI results in decreased plasma HDL cholesterol levels, 8-10 whereas SR-BI knockout mice have increased plasma HDL cholesterol. 11,12 Interestingly, hepatocyte SR-BI appears to accelerate reverse cholesterol transport in vivo in the face of decreased plasma HDL cholesterol levels, 13 which is in line with studies demonstrating that hepatic SR-BI expression protects against atherosclerosis development in mouse models. 14,15 Hepatic SR-BI expression is also linked to biliary cholesterol

Neuromelanin (NM) is a peculiar biochemical component of several neurons in the Substantia Nigra (SN), the target area of the degenerative process in Parkinson Disease (PD). SN NM has peculiarities as to its composition and an impressive capacity of chelating metals, iron in particular, but not exclusively. Gaining insights into the structural and functional characteristics of NM should help understanding the reasons of selective vulnerability of nigral neurons in many parkinsonian conditions. From the present data a protective role of NM can be postulated until the buffering capability toward heavy metals are exhausted. The overloading of NM with iron and other metals in neurons may trigger inflammatory and degenerative processes aggravating the underlying pathological condition.

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vascular disease ( 1,2 ). This protective effect of HDL is largely ascribed to the role of this lipoprotein in reverse cholesterol transport (RCT), a process comprising the movement of excess cholesterol from the periphery back to the liver for subsequent secretion into the bile ( 3,4 ). Within the plasma compartment, substantial remodeling of HDL particles occurs. A factor exerting a major impact in this regard is endothelial lipase (EL).EL has recently been identifi ed as a member of the triacylglycerol lipase gene family. It is expressed in endothelial cells as well as in macrophages and hepatocytes ( 5, 6 ). Remarkably, EL possesses merely phospholipase activity ( 7 ). EL expression is upregulated in vitro by proinfl ammatory stimuli ( 8, 9 ), and EL plasma levels correlate with the levels of proinfl ammatory cytokines in human populations ( 10, 11 ). In experimental animals, both overexpression ( 5, 12 ) as well as loss-of-function models ( 13-15 ) have established EL to be a negative regulator of plasma HDL cholesterol levels by increasing HDL catabolism. Moreover, accumulating evidence points to a comparable role of EL in human HDL metabolism (15)(16)(17).Consistent with the role of HDL in RCT, HDL is thought to represent a preferred source of sterols that are subsequently secreted into the bile ( 3,4,18,19 ). Currently, no data are available regarding the effect of an acute decrease of plasma HDL cholesterol levels on biliary sterol excretion caused by a single physiologically relevant stimulus. This study aimed to test the hypothesis that an acute, substantial decrease of plasma HDL cholesterol levels by EL overexpression impacts liver cholesterol metabolism and biliary cholesterol secretion. Our data demonstrate that in wild-type mice, virtual elimination of HDL cholesterol by Abstract High density lipoprotein cholesterol is thought to represent a preferred source of sterols secreted into bile following hepatic uptake by scavenger receptor class B type I (SR-BI). The present study aimed to determine the metabolic effects of an endothelial lipase (EL)-mediated stimulation of HDL cholesterol uptake on liver lipid metabolism and biliary cholesterol secretion in wild-type, SR-BI knockout, and SR-BI overexpressing mice. In each model, injection of an EL expressing adenovirus decreased plasma HDL cholesterol ( P < 0.001) whereas hepatic cholesterol content increased ( P < 0.05), translating into decreased expression of sterol-regulatory element binding protein 2 (SREBP2) and its target genes HMG-CoA reductase and LDL receptor (each P < 0.01). Biliary cholesterol secretion was dependent on hepatic SR-BI expression, being decreased in SR-BI knockouts ( P < 0.001) and increased following hepatic SR-BI overexpression ( P < 0.001). However, in each model, biliary secretion of cholesterol, bile acids, and phospholipids as well as fecal bile acid and neutral sterol content, remained unchanged in response to EL overexpression. Importantly, hepatic ABCG5/G8 expression did not correlate with biliary cholesterol secret...

In the present work Principal Component Analysis applied to (1)H NMR spectra of balsamic and traditional balsamic vinegars is used to establish a simple and rapid aging determination protocol. Chemical composition of vinegar is dominated by carbohydrates even though several small components can be clearly observed in the proton NMR spectrum. Quantitative determination of some selected metabolites such as ethanol, acetic acid, malic acid, glucose, and HMF, considered as potential aging indicators, has been performed. (1)H NMR spectroscopy provides noninvasive characterization of such compounds, and our data demonstrate the validity of this approach, giving very promising results for assessing the quality of the final product.