Neuromelanin can protect against iron-mediated oxidative damage in system modeling iron overload of brain aging and Parkinson's disease

In Parkinson's disease (PD), dopamine neurons containing neuromelanin selectively degenerate. Neuromelanin binds iron and accumulates in aging. Iron accumulates in reactive form during aging, PD, and is involved in neurodegeneration. It is not clear how the interaction of neuromelanin and iron can be protective or toxic by modulating redox processes. Here, we investigated the interaction of neuromelanin from human substantia nigra with iron in the presence of ascorbic acid, dopamine, and hydrogen peroxide. We observed that neuromelanin blocks hydroxyl radical production by Fenton's reaction, in a dose-dependent manner. Neuromelanin also inhibited the iron-mediated oxidation of ascorbic acid, thus sparing this major antioxidant molecule in brain. The protective effect of neuromelanin on ascorbate oxidation occurs even in conditions of iron overload into neuromelanin. The blockade of iron into a stable iron–neuromelanin complex prevents dopamine oxidation, inhibiting the formation of neurotoxic dopamine quinones. The above processes occur intraneuronally in aging and PD, thus showing that neuromelanin is neuroprotective. The iron–neuromelanin complex is completely decomposed by hydrogen peroxide and its degradation rate increases with the amount of iron bound to neuromelanin. This occurs in PD when extraneuronal iron–neuromelanin is phagocytosed by microglia and iron–neuromelanin degradation releases reactive/toxic iron.     

Predictors of Weight Change in Middle‐aged and Old Men

Objective: Studies on weight change and mortality have yielded inconclusive results. This 10‐year prospective study was undertaken to improve understanding of factors affecting weight change. Research Methods and Procedures: The subjects were 1143 men, aged 36 to 88 years (mean, 53.3 years) at entry. A questionnaire was filled in at entry and at the end of the follow‐up with queries on weight, height, weight at the age of 20, physician‐diagnosed diseases, smoking, alcohol use, dietary habits, leisure physical activity, occupation, present occupational activity, living conditions (living alone or cohabiting), and former athletic status. Further information on morbidity was obtained from selected national registers. Factors predicting weight change during the study were identified by stepwise linear multiple regression analysis. Results: The mean 10‐year weight change was 0.8 (range, ?29 to +24) kg. Age at entry (β‐coefficient, ?0.17, SE 0.02), weight at entry (β, ?0.03, SE 0.01), diabetes at entry (β, ?3.55, SE 1.02), diabetes diagnosed after entry (β, ?3.94, SE 0.96), malignant cancer (β, ?1.60, SE 0.70), being a smoker (β, ?1.59, SE 0.48), and increased physical activity (β, ?1.27, SE 0.54) were significantly (p < 0.05) associated with weight loss in the final model. The model explained 13% of the variance of weight change. Discussion: The results emphasize the complexity of weight change. Some factors associated with weight change are apparently negatively, and some positively, associated with health. This could explain the equivocal findings on weight change and mortality in the literature.     

Biomarkers: in combination they may do better

The field of biomarkers is a growing one, particularly in osteoarthritis (OA). OA is the most common disabling condition in older persons and a major cause of morbidity. While the debate continues about which of the involved tissues - cartilage, bone or synovium - is the most important in OA aetiology, there is no doubt that the three develop abnormalities in concert; perhaps a truly useful biomarker will reflect just that. While efforts continue to identify reliable biomarkers useful for characterising the status, prognosis and measurement of treatment response in OA, combining existing biomarkers to improve their accuracy looks promising.     

Regulation of hepatic cholesterol biosynthesis by berberine during hyperhomocysteinemia

Hyperhomocysteinemia, an elevation of blood homocysteine levels, is a metabolic disorder associated with dysfunction of multiple organs. We previously demonstrated that hyperhomocysteinemia stimulated hepatic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase leading to hepatic lipid accumulation and liver injury. The liver plays an important role in cholesterol biosynthesis and overall homeostasis. HMG-CoA reductase catalyzes the rate-limiting step in cholesterol biosynthesis. Hepatic HMG-CoA reductase is a major target for lowering cholesterol levels in patients with hypercholesterolemia. The aim of the present study was to examine the effect of berberine, a plant-derived alkaloid, on hepatic cholesterol biosynthesis in hyperhomocysteinemic rats and to identify the underlying mechanism. Hyperhomocysteinemia was induced in Sprague-Dawley rats by feeding a high-methionine diet for 4 wk. HMG-CoA reductase activity was markedly elevated in the liver of hyperhomocysteinemic rats, which was accompanied by hepatic lipid accumulation. Activation of HMG-CoA reductase was caused by an increase in its gene expression and a reduction in its phosphorylation (an inactive form of the enzyme). Treatment of hyperhomocysteinemic rats with berberine for 5 days inhibited HMG-CoA reductase activity and reduced hepatic cholesterol content. Such an inhibitory effect was mediated by increased phosphorylation of HMG-CoA reductase. Berberine treatment also improved liver function. These results suggest that berberine regulates hepatic cholesterol biosynthesis via increased phosphorylation of HMG-CoA reductase. Berberine may be therapeutically useful for the management of cholesterol homeostasis.     

Pathophysiology of motility dysfunction in bowel obstruction: role of stretch-induced COX-2

In gastrointestinal conditions such as bowel obstruction, pseudo-obstruction, and idiopathic megacolon, the lumen of affected bowel segments is distended and its motility function impaired. Our hypothesis is that mechanical stretch of the distended segments alters gene expression of cyclooxygenase-2 (COX-2), which impairs motility function. Partial obstruction was induced with a silicon band in the distal colon of rats for up to 7 days, and wild-type and COX-2 gene-deficient mice for 4 days. Mechanical stretch was mimicked in vitro in colonic circular muscle strips and in primary culture of colonic circular smooth muscle cells (SMC) with a Flexercell system. The rat colonic circular muscle contractility was significantly decreased in the distended segment oral to obstruction, but not in the aboral segment. This change started as early as day 1 and persisted for at least 7 days after obstruction. The expression of COX-2 mRNA and protein increased dramatically also in the oral, but not aboral, segment. The upregulation of COX-2 expression started at 12 h and the effect persisted for 7 days. At 24 h after obstruction, the COX-2 mRNA level in the oral segment increased 26-fold compared with controls. This was not accompanied by any significant increase of myeloperoxidase or inflammatory cytokines. Immunohistochemical studies showed that COX-2 was selectively induced in the colonic SMC. In vitro stretch of colonic muscle strips or cultured SMC drastically induced COX-2 expression. Incubation of circular muscle strips from obstructed segment with COX-2 inhibitor NS-398 restored the contractility. The impairment of muscle contractility in obstructed colon was attenuated in the COX-2 gene-deficient mice. In conclusion, mechanical stretch in obstruction induces marked expression of COX-2 in the colonic SMC, and stretch-induced COX-2 plays a critical role in the suppression of smooth muscle contractility in bowel obstruction.     

3,4-Dihydroxyphenylethylamine and 5-Hydroxytryptamine Metabolism in the Rat: Acidic Metabolites in Cisternal Cerebrospinal Fluid Before and After Giving Probenecid

3,4-Dihydroxyphenylethylamine (DA, dopamine) and 5-hydroxytryptamine (5-HT) turnover values were determined in freely moving male rats by measuring the rates of accumulation of the acidic metabolites of the above transmitters, i.e., 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) in cisternal cerebrospinal fluid (CSF) samples after probenecid (200 mg/kg i.p.) administration. Determinations on samples before and after acid hydrolysis showed that the latter procedure was necessary for DA turnover determination. Thus whereas total (DOPAC + HVA) increased linearly with time after probenecid, free (DOPAC + HVA) did not. This was because the percentage of DOPAC + HVA in conjugated form increased with time. Determinations on a group of 28 rats during the dark (red light) period showed that cisternal amine metabolite concentrations before probenecid injection did not parallel turnover values. This was probably because individual differences in metabolite egress strongly affect the pre-probenecid values. The poor correlations between CSF tryptophan and 5-HT turnover suggested that differences of brain tryptophan concentration were not major determinants of differences of brain 5-HT metabolism within this group of normal rats. Considering that the rats were of similar weight and that the turnover values were all determined at approximately the same time of day, the three- to fourfold ranges of the turnover values are remarkable. The positive correlation between the DA and 5-HT turnovers of individual rats suggests the existence of common effects on DA and 5-HT turnover in normal rats.     

Monitoring the Effect of a Tryptophan Load on Brain Indole Metabolism in Freely Moving Rats by Simultaneous Cerebrospinal Fluid Sampling and Brain Dialysis

Rats were given L-tryptophan, 50 mg/kg i.p., and its concentration in the CNS was monitored in individual freely moving animals using repeated sampling of cisternal CSF and concurrent striatal dialysis. The 5-hydroxytryptamine metabolite 5-hydroxyindoleacetic acid (5-HIAA) was also measured. Results were compared with changes of central tryptophan and 5-HIAA concentrations in brains of rats killed at various times after administration of L-tryptophan, 50 mg/kg i.p. Tryptophan changes in CSF were proportionate to those in whole brain and followed essentially identical time courses. Results for the striatal dialysate and whole striatum also paralleled each other. Similarly, results for 5-HIAA showed proportionality between CSF and brain and between dialysate and striatum. The data obtained were used to determine pharmacokinetic data for individual rats, i.e., areas under curves for both tryptophan and 5-HIAA and half-lives for the decline of tryptophan. Kinetic parameters varied considerably from rat to rat. However, mean half-lives for tryptophan in CSF, brain, dialysate, and striatum were all comparable. Results in general show the value of repeated CSF sampling and intracerebral dialysis for concurrent monitoring of changes of indole metabolism in the whole brain and a specific brain region, respectively. The methods should be suitable for the continuous monitoring of changes of central transmitter metabolism in parallel with observation of behavior following environmental or dietary changes or drug administration. They also should be of use in the investigation of drug kinetics in the CNS.     

Vitamin E and selenium supplementation in geriatric patients

Sodium selenate (8 mg/d), organic selenium (50 μg/d) andd-alpha-tocopherol acetate (400 mg/d) were administered for 1 yr to 15 geriatric patients. Fifteen comparable controls received placebo. The mean age of both groups was 76 yr. The patients were assessed every 2 mo independently by two nurses using the Sandoz Clinical Assessment Geriatric-scale (SCAG). The propositae, showed significant improvement in the following SCAG parameters: depression, anxiety, self-care, mental alertness, emotional lability, motivation and initiative, hostility, interest in the environment, fatigue, anorexia, and general impression. A distinct improvement of the general condition was noticed after only 2 mo and the improvement continued up to the end of the 1-yr study period. The high selenium and vitamin E doses were well tolerated; there were no side effects whatsoever.