Biomedical subjects

Stephen C Bondy

Publications and source records attributed to Stephen C Bondy.

15 recordsLinked to original sources

PubMed2006

Effects of melatonin and age on gene expression in mouse CNS using microarray analysis.

The expression levels of a number of genes associated with inflammation and immune function change with advancing age. Melatonin modulates gene expression levels of several of these genes. Therefore the declining levels of melatonin associated with age may play a role in the physiological effects of aging. We used oligonucleotide microarrays to measure age-related changes in mRNA expression in the murine CNS, and to study the effect of prolonged administration of dietary melatonin upon these changes. CB6F1 male mice were fed 40 ppm melatonin for 2.1 months prior to sacrifice at age 26.5 months, and compared with both age-matched controls and young, 4.5-month-old untreated controls. Total RNA was extracted from whole brain (excluding cerebellum and brain stem) and individual samples were hybridized to Affymetrix Mouse 430-2.0 arrays. The expression of a substantial number of genes was modulated by melatonin treatment and changes in selected genes were validated by quantitative reverse transcription polymerase chain reaction (qRT-PCR). A subset of these genes did not change with age. Conversely, some genes modulated by age were also modulated by melatonin treatment. In general, melatonin treatment drove the expression levels of these genes closer to the expression levels detected in the younger animals. Notably, the abundance of lipocalin 2 (Lcn2) mRNA increased with age and was decreased in old animals treated with melatonin. Lcn2 is a member of the acute phase response family of proteins and its mRNA levels in the brain increase in response to inflammation. Many of the genes with expression reduced by melatonin are involved in inflammation and the immune system. This suggests that melatonin treatment may influence the inflammatory responses of old animals, driving them to resemble more closely those occurring in young animals.

Acute-Phase Proteins↗

PubMed2006

Aluminum and copper in drinking water enhance inflammatory or oxidative events specifically in the brain.

Inflammatory and oxidative events are up-regulated in the brain of AD patients. It has been reported that in animal models of AD, exposure to aluminum (Al) or copper (Cu) enhanced oxidative events and accumulation of amyloid beta (Abeta) peptides. The present study was designed to evaluate the effect of a 3-month exposure of mice to copper sulfate (8 microM), aluminum lactate (10 or 100 microM), or a combination of the salts. Results suggest that although Al or Cu may independently initiate inflammatory or oxidative events, they may function cooperatively to increase APP levels.

Aluminum↗

PubMed2006

Decreased expression of inflammation-related genes following inhalation exposure to manganese.

Excessive exposure to manganese (Mn) by inhalation can induce psychosis and Parkinsonism. The clinical manifestations of Mn neurotoxicity have been related to numerous physiological and cellular processes, most notably dopamine depletion. However, few studies have explored the molecular events that are triggered in response to exposure to Mn by inhalation. In this current study, the transcriptional patterns of genes related to oxidative stress or inflammation were examined in the brain rats of exposed to inhaled Mn during either gestation or early adulthood. The expression of genes encoding for proteins critical to an inflammatory response and/or possessing pro-oxidant properties, including TGFbeta and nNOS, were slightly depressed by prenatal exposure, whereas inhalation exposure to Mn during adulthood markedly down-regulated their transcription. However, when exposures to manganese occurred during gestation, the extent of altered gene expression induced by subsequent exposure to Mn in adulthood was reduced. This suggests that prior exposure to Mn may have attenuated the effects of inhalation exposure to Mn in adulthood, in which the expression of inflammation-related genes were suppressed.

Amyloid beta-Protein Precursor↗

PubMed2005

Parallel changes in gene expression in aged human and mouse cortex.

The intensity of expression of over 20,000 genes and expressed sequence tags within the cerebral cortex has previously been described for both the human and mouse genomes. In both these species, the degree of expression of a relatively limited number of cortical genes, around 300, is significantly altered during senescence. The extent of similarity between age-related alterations of levels of specific mRNAs in either species has been compared. There is a significant correlation between species in those genes whose expression changes markedly in either direction with aging. This parallel serves to validate the use of mouse strains to study general age-related genetic events associated with aging.

Age Factors↗

PubMed2005

Developmental neurotoxicology.

The developing brain has a distinctive set of characteristics that make it unusually sensitive to damage by toxic agents. Mechanistic understanding of the vulnerability of the immature nervous system to various chemicals is important from a preventive perspective but has also frequently given us new insights into maturation of neural circuitry. This review examines some of the developmental consequences of contact with various exogenous agents, including metals, solvents, pharmaceuticals, and natural products. This review emphasizes how subtle suboptimal brain function rather than acute toxicity can be a consequence of chemical exposures occurring during ontogenesis. The rate of brain aging may be influenced by events taking place in embryogenesis, following a prolonged asymptomatic period. The potential for appearance of adverse effects after prolonged latent periods is underscored.

Animals↗

PubMed2005

Potential occupational risks for neurodegenerative diseases.

BACKGROUND: Associations between occupations and neurodegenerative diseases (NDD) may be discernable in death certificate data. METHODS: Hypotheses generated from 1982 to 1991 study were tested in data from 22 states for the years 1992-1998. Specific occupations and exposures to pesticides, solvents, oxidative stressors, magnetic fields, and welding fumes were evaluated. RESULTS: About one third (26/87) of the occupations hypothesized with neurodegenerative associations had statistically significant elevated mortality odds ratios (MOR) for the same outcome. Occupations with the largest MORs were (a) for presenile dementia (PSD)-dentists, graders/sorters (non-agricultural), and clergy; (b) for Alzheimer's disease (AD)-bank tellers, clergy, aircraft mechanics, and hairdressers; (c) for Parkinson's disease (PD)-biological scientists, clergy, religious workers, and post-secondary teachers; and (d) for motor neuron disease (MND)-veterinarians, hairdressers, and graders and sorters (non-agricultural). Teachers had significantly elevated MORs for all four diseases, and hairdressers for three of the four. Non-horticultural farmers below age 65 had elevated PD (MOR = 2.23, 95% CI = 1.47-3.26), PSD (MOR = 2.22, 95% CI = 1.10-4.05), and AD (MOR = 1.76, 95% CI = 1.04-2.81). Sixty hertz magnetic fields exhibited significant exposure-response for AD and, below age 65, for PD (MOR = 1.87, 95% CI = 1.14-2.98) and MND (MOR = 1.63, 95% CI = 1.10-2.39). Welding had elevated PD mortality below age 65 (MOR = 1.77, 95% CI = 1.08-2.75). CONCLUSIONS: Support was observed for hypothesized excess neurodegenerative disease associated with a variety of occupations, 60 Hz magnetic fields and welding.

Adult↗

PubMed2004

Pro- or anti-oxidant manganese: a suggested mechanism for reconciliation.

The neurodegeneration induced by manganese has been attributed to its ability to undergo redox cycling, and catalysis of reactive oxygen species (ROS) formation, as with other transition metals. However, the characterization of manganese as a pro-oxidant is confounded by increasing evidence that the metal may scavenge superoxide anions and protect cells from oxidative damage. The current study was designed to address conflicting reports pertaining to the oxidative capacity of manganese. We found that the metal has distinctive redox dynamics in which the divalent reduced form, unlike iron, possessed no intrinsic oxidative capacity. The apparent ability of Mn(2+) to promote the formation of ROS within a cortical mitochondrial-synaptosomal fraction was quenched by the depletion of contaminating nanomolar concentrations of trivalent metals. The addition of manganic ions at trace concentrations dose-dependently restored the oxidative capacity attributed to divalent manganese, whereas the presence of the ferric ion retarded the rate of ROS generation. This result was paralleled by the spectrophotometric demonstration that the kinetics of iron oxidation is accelerated by trivalent but not divalent manganese. The markedly different capacities of the lower and higher valence states of manganese to promote free-radical formation in cortical fractions and to modulate the process of iron oxidation may account for earlier contradictory reports of anti- and pro-oxidant properties of manganese.

Animals↗

PubMed2004

Age-related changes in murine CNS mRNA gene expression are modulated by dietary melatonin.

Brain cellular functions decline with normal aging, accompanied by a changing profile of gene expression. Gene array analysis was used to quantitatively estimate messenger RNA (mRNA) expression levels in the cerebral cortex of both young (4-month) and old (27-month) B6C3F1 male mice. A stringent degree of significance was obtained by using multiple gene chips. Out of 12,423 mRNA levels, only 25 changed significantly with age. Nine of these genes coded for inflammatory proteins, all of which were elevated in aged, relative to younger mice. Melatonin (200 p.p.m.) included in the diet of aged animals for 8 wk elevated serum and cortical melatonin and reversed 13 of the 25 genes altered with age. In no case did melatonin potentiate age-related changes in gene expression. The restoration of a more youthful gene profile to brains of aged animals by melatonin, to a large extent, involves reversal of age-induced elevation of basal inflammatory parameters.

Aging↗

PubMed2004

Age-related changes in serum melatonin in mice: higher levels of combined melatonin and 6-hydroxymelatonin sulfate in the cerebral cortex than serum, heart, liver and kidney tissues.

Age-related changes in levels of melatonin and 6-hydroxymelatonin sulfate and effects of dietary melatonin on their levels in different tissues were determined in mice. Levels of melatonin were highest in the serum followed by liver, kidney, cerebral cortex and heart as measured by a quantitative and sensitive enzyme-labeled immunosorbent assay (ELISA). Serum melatonin levels decreased with age, and were reduced by 80% in 27-month old mice relative to 12-month old mice. Levels of 6-hydroxymelatonin sulfate were measured independently in various tissues. Levels of the melatonin metabolite, 6-hydroxymelatonin sulfate were significantly higher than free melatonin in all tissues tested. Levels of 6-hydroxymelatonin sulfate were highest in the cerebral cortex followed by the serum, heart, kidney, and liver. In 12-month old mice 6-hydroxymelatonin sulfate concentration was approximately 1000-fold greater than that of melatonin in the cerebral cortex, it was only 3-fold greater than melatonin levels in the serum. Thus only 0.1% of total melatonin in the brain was present in the free and unconjugated form but the corresponding value for serum was 27.4%. The cerebral cortex had the highest levels of combined melatonin and 6-hydroxymelatonin sulfate than other tissue tested in control mice. There was no significant change in 6-hydroxymelatonin sulfate levels between young and old mice. There was also no age-dependent change in levels of serotonin or cortisol in the serum samples. Dietary supplementation with melatonin resulted in a significant increase in levels of melatonin in the serum and all other tissue samples tested. Thus, any age-related decline of tissue melatonin can be reversed by supplementation with dietary melatonin.

Aging↗

PubMed2004

Dietary supplementation with melatonin reduces levels of amyloid beta-peptides in the murine cerebral cortex.

Melatonin levels decrease with aging in mice. Dietary supplementation with melatonin has recently been shown to result in a significant rise in levels of endogenous melatonin in the serum and all other tissue samples tested. Herein, the effects of dietary melatonin on brain levels of nitric oxide synthase, synaptic proteins and amyloid beta-peptides (Abeta) were determined in mice. Melatonin supplementation did not significantly change cerebral cortical levels of nitric oxide synthase or synaptic proteins such as synaptophysin and SNAP-25. Increased brain melatonin concentrations however, led to a significant reduction in levels of toxic cortical Abeta of both short and long forms which are involved in amyloid depositions and plaque formation in Alzheimer's diseases. Thus, melatonin supplementation may retard neurodegenerative changes associated with brain aging. Depletion of melatonin in the brain of aging mice may in part account for this adverse change.

Aging↗

PubMed2004

Oxidative basis of manganese neurotoxicity.

Exposure to excessive levels of manganese, an essential trace element, can evoke severe psychiatric and extrapyramidal motor dysfunction closely resembling Parkinson's disease. The clinical manifestations of manganese toxicity arise from focal injury to the basal ganglia. This region, characterized by intense consumption of oxygen and significant dopamine content, can incur mitochondrial dysfunction, depletion of levels of peroxidase and catalase, and catecholamine biochemical imbalances following manganese exposure. The site specificity of the pathology and the nature of the cellular damage caused by manganese have been attributed to its capacity to produce cytotoxic levels of free radicals. However, support for such a pro-oxidant role for manganese has been largely limited to inferences drawn from histopathological observations. More recently, research efforts into the molecular details of manganese toxicity have provided evidence of an etiological relationship between oxidative stress and manganese-related neurodegeneration. This review focuses on studies that evaluate the redox chemistry of manganese during the neurodegenerative process and its molecular consequences.

Animals↗

PubMed2003

Aluminum and copper interact in the promotion of oxidative but not inflammatory events: implications for Alzheimer's disease.

The etiology of Alzheimer's Disease (AD) is multifactorial. It has been suggested that transition metals such as copper (Cu) and iron (Fe) as well as aluminum (Al) may be involved in the pathogenesis of the disorder. While Cu and Fe are redox-active, Al only exists in the trivalent form and is redox-inert. We previously demonstrated that Al exposure causes an increase in inflammatory parameters in human glioblastoma T98G cells. In the present study we further demonstrate that co-exposure with Cu exacerbates the oxidative but not inflammatory effects of Al in this cell line. While Cu-induced reactive oxygen species (ROS) production was greatly enhanced in the presence of Al, TNF-alpha secretion induced by either metal was not further potentiated by simultaneous exposure to Al and Cu. Furthermore, exposure to both metals reduced the individual Al and Cu-induced activation of the immune-related transcription factor NF-kappaB. Therefore, while synergistic interaction between the two metals increases oxidative events, this does not lead to potentiation of Al-induced inflammation. Thus the ability of aluminum to promote inflammatory processes does not depend on an increase ROS production induced by interaction with transition metals.

Aluminum↗

PubMed2002

Pro-inflammatory effects of aluminum in human glioblastoma cells.

Inflammatory events have been associated with senile plaques, one of the pathological hallmarks of Alzheimer's disease (AD). It is believed that aggregated beta-amyloid (betaA) proteins, which form the core of these plaques, may be responsible for triggering the inflammatory reaction. In the present study, the ability of aluminum (Al) to initiate similar inflammatory events was investigated in a human glioblastoma cell line. A 6-day exposure to either lipopolysaccharide (LPS) or aluminum sulfate caused a significant increase in the rate of proliferation of the glioblastoma cells. Both treatments also caused activation of the immune-responsive transcription factor NF-kappaB although there were time-related differences. The levels of secreted cytokines, interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) were both increased by the LPS treatment although exposure to Al decreased the secretion of the former while elevating the levels of the latter. These events may be due to the activation of glial cells and subsequent stress response to either Al complexes or LPS. Although exposure to either stress factor caused a stimulation of inflammatory markers, there were time-dependent differences in the response. This may reflect the ability of the cells to discern different stress factors and thus orchestrate an innate immune response profile distinct to each immunogen.

Alum Compounds↗

PubMed2002

Dietary modulation of age-related changes in cerebral pro-oxidant status.

It has been proposed that senescence may be associated with changes associated with oxidative damage to macromolecules. Levels of cerebellar nitric oxide synthase (NOS) and rates of generation of cortical reactive oxygen species (ROS), have been determined in mice of various ages. Both of these parameters were significantly reduced in mice aged 9 months relative to 3-month-old mice. In order to determine whether dietary manipulation can modulate these changes, the effect of exposure of mice to differing diets incorporating various antioxidants, was examined. These diets were given to 3-month-old mice for a total period of 6 further months. The presence of melatonin (40 ppm) in the basal diet restored both NOS and ROS levels to the corresponding values found in the younger (3-month-old) group of mice while lipoic acid (1650 ppm) also restored levels of NOS to those found in 3-month-old animals. Addition of coenzyme Q (ubiquinone), 200 ppm or alpha-tocopherol (1000 ppm) to the basal diet had no effect on either NOS levels or ROS generation. These data suggest that dietary supplementation may aid in delaying onset of metabolic changes characteristic of the older brain. In behavioral testing, older (9-month-old) animals exhibited reduced motor activity and diminished recall ability on the second day of exposure to the test paradigm. While no diet altered motor activity or improved recall of older animals, lipoic acid or tocopherol treatment adversely affected place recall familiarity.

Aging↗

PubMedDate not supplied

Dietary melatonin selectively reverses age-related changes in cortical cytokine mRNA levels, and their responses to an inflammatory stimulus.

The basal levels of expression of mRNA of cytokines, interleukin-6 (IL-6) and tumor necrosis factor (TNF-alpha), in the cerebral cortex of 5 and 26 month-old male B6C3F1 mice have been compared. In addition, the responsivity of animals of differing age to an inflammatory stimulus (lipopolysaccharide, LPS) has been studied. Basal levels of both of these cytokine mRNAs were elevated in aged animals relative to the younger group. However LPS administration led to a robust increase in cytokine mRNA levels in the younger animals but in aged mice, there was either an unchanged (IL-6) or a depressed (TNF-alpha) response. Administration of dietary melatonin (200 ppm) to aged mice for 6 weeks prior to sacrifice, resulted in reduction of basal levels of cytokine mRNA to values found in the younger animals. Furthermore, following administration of LPS to melatonin fed animals, cerebral cytokine mRNA levels were significantly elevated rather than being unchanged or depressed. Taken together these findings reflect a trend in the cortices of melatonin-treated aged mice, to more closely approximate the status of younger mice. For comparative purposes, parallel studies were carried out using an immunologically active organ (spleen) and a non-neural organ with a low rate of cell turnover (heart muscle). In both these tissues, basal levels of cytokine mRNAs of animals of either age were very low, and there was a marked positive response to LPS. Dietary melatonin had no effect on the responses of TNF-alpha mRNA to LPS but attenuated the reaction of splenic IL-6 mRNA, thus bringing the response closer to that of the younger mice.

Aging↗