Biomedical subjects

S C Bondy

Publications and source records attributed to S C Bondy.

At least 37 records · Page 2Linked to original sources

PubMed1999

Decrease of glial fibrillary acidic protein in rat frontal cortex following aluminum treatment.

Aluminum lactate was injected either intraperitoneally or stereotactically into the lateral cerebral ventricles of rats. Rats were killed at various times after treatment, and frontal cortex, hippocampus, and striatum were dissected out. Microtiter plate-based sandwich ELISA and immunohistochemistry were used to measure the glial fibrillary acidic protein (GFAP) concentration. GFAP levels were significantly decreased in frontal cortex 7 days after a single lateral ventricular injection of aluminum lactate and 14 days following systemic treatment. In contrast, neither hippocampus nor striatum exhibited any significant changes in the content of this astrocytic intermediate filament protein after aluminum treatment. Levels of a predominantly astroglial enzyme, glutamine synthetase, were also selectively reduced in the frontal cortex following intraventricular injection of aluminum. This depression exhibited a regional and temporal specificity similar to that found for GFAP. These results suggest a selective and progressive diminution of astrocytic responsivity in frontal cortex following either systemic or intraventricular aluminum dosing. The depression of GFAP levels reported here, which was found in the rat cerebral cortex 7-14 days after aluminum treatment in a species that does not form neurofilamentous aggregates, may reflect extended impairment of astrocytic function and suggests that these cells may be the primary targets of aluminum neurotoxicity.

Aluminum Compounds↗

PubMed1998

Promotion of transition metal-induced reactive oxygen species formation by beta-amyloid.

beta-amyloid protein appears to be involved in the neural degeneration associated with Alzheimer's disease. However, its mechanism of action is poorly understood. The ability of the neurotoxic peptide fragment (25-35) derived from beta-amyloid, to promote the generation of reactive oxygen species (ROS) by a postmitochondrial fraction (P2) derived from rat cerebrocortex, has been examined. The peptide fragment, when incubated together with P2, did not cause excess ROS formation. However, 10 microM FeSO4 or 10 microM CuSO4 were able to enhance ROS production in the P2 fraction and this was increased further in the concurrent presence of the 25-35 fragment. The corresponding inverse sequence non-neurotoxic peptide (35-25) had no parallel ability to augment iron-stimulated ROS production suggesting a degree of specificity for the observed effect. There was no formation of excess ROS when the 25-35 peptide and 0.5 mM Al2(SO4)3 were incubated with the P2 fraction. However in the presence of both aluminum and iron salts together with the 25-35 peptide, ROS production was augmented to a level significantly higher than that in the absence of aluminum. Polyglutamate, a peptide reported to mitigate aluminum toxicity had no effect on iron-related ROS generation but completely prevented its further potentiation by aluminum. The results indicate that beta-amyloid is able to potentiate the free-radical promoting capacity of metal ions such as iron, copper and aluminum. Such potentiation may be a relevant mechanism underlying beta-amyloid-induced degeneration of nerve cells.

Alum Compounds↗

PubMed1998

Aluminum treatment induces nitric oxide synthase in the rat brain.

In an attempt to delineate the capacity of aluminum to promote pro-oxidant events in the central nervous system, levels of nitric oxide synthase (NOS) have been determined in the cerebellum of rats exposed to an aluminum salt, either alone or in combination with an iron compound. Relatively acute treatment with aluminum over a three-day period, increased cerebellar levels of NOS. Parallel results were obtained when animals were dosed over a more extended three-week period. Dosing with an iron compound resulted in no changes in levels of this enzyme. Concurrent treatment with aluminum and iron did not potentiate the NOS-inducing effects of aluminum. By use of selective inhibitors, the specific induction of iNOS by aluminum treatment was found. The results suggest that the presence of aluminum can induce cerebellar NOS and that these changes are independent of any interaction between aluminum and erogenous iron.

Aluminum↗

PubMed1998

Elevation of cerebral proteases after systemic administration of aluminum.

The levels of three proteases in the cerebral cortex of rats following a three week exposure to aluminum, were measured. The activity of apopain (CPP32), an interleukin 1beta converting enzyme (ICE)-like cysteine protease specifically associated with apoptosis, was increased following dosing with aluminum. The activity of calcium-activated neutral protease, calpain, was also increased. However, the enzyme activity of trypsin-like serine protease, known to be elevated by oxidative events, was unchanged. Since aluminum is suspected as a possible factor in the pathogenesis of Alzheimer's disease and other neurological diseases, it is speculated that changed levels in proteolytic enzymes may relate to the neurotoxicity of aluminum.

Alum Compounds↗

PubMed1998

Mechanisms underlying the aluminum-induced potentiation of the pro-oxidant properties of transition metals.

Aluminum is known to enhance the ability of iron to promote the generation of reactive oxygen species (ROS) but the mechanism subserving this is unknown. In an attempt to understand the means by which this potentiation occurs, several types of experiment have been conducted. It was found that iron must be in the ferrous form for aluminum-based stimulation of ROS to take place in a cerebral cortical synaptosomal-mitochondrial fraction. The ability of other transition metals of varying valences, copper and chromium, to catalyze formation of ROS was also increased in the presence of aluminum. Catalase but not superoxide dismutase blocked such stimulation suggesting hydrogen peroxide as an intermediate. The formation of aluminosilicates in the presence of brain tissue did not enhance iron-stimulated ROS formation. Furthermore, configurational changes of proteins which have been proposed to account for this phenomenon, do not appear to be a key element since iron-aluminum potentiation could be observed using protein-free liposomal micelles bearing an external negative charge.

Aluminum↗

PubMed1997

Lead-induced hypertension: interplay of nitric oxide and reactive oxygen species.

An elevation of mean blood pressure was found in rats treated with low lead (0.01% lead acetate) for 3 months, as contrasted to paired Sprague-Dawley control rats. In these rats, measurement of plasma and urine endothelins-1 and -3 revealed that plasma concentration and urinary excretion of endothelin-3 increased significantly after 3 months (plasma: lead group, 31.8+/-2.2, versus controls, 23.0+1.7 pg/mL, P<.001; urinary excretion: lead group, 46.6+11.7, versus controls, 35.6+6.7 pg/24 h, P<.05), whereas endothelin-1 was unaffected. Plasma and urinary nitric oxide (NO) and cyclic GMP concentrations were not significantly changed. However, assay of plasma and kidney cortex malondialdehyde by high-pressure liquid chromatography, as a measure of reactive oxygen species, was elevated in lead-treated rats compared with that in control rats (plasma: lead group, 4.74+1.27, versus controls, 2.14+.49 micromol/L, P<.001; kidney cortex: lead group, 28.75+3.46, versus controls, 16.38+2.37 nmol/g wet weight, P<.001). There was increased NO synthase activity in lead-treated rat brain cortex and cerebellum. In lead-treated rat kidney cortex, the endothelial constitutive NO synthase protein mass was unaffected, whereas the inducible NO synthase protein mass was increased. These data suggest a balance between increased NO synthesis and degradation (by reactive oxygen species) in lead-treated rats, which results in normal levels of NO. Thus, the hypertension may be related to an increase in the pressure substances, endothelin-3 and reactive oxygen species, rather than to an absolute decrease in nitric NO.

Animals↗

PubMed1997

Increased cerebral free radical production during thiamine deficiency.

Concentration of reactive oxygen species (ROS) and the antioxidant glutathione (GSH) was measured in thalamus and cortex after 13 and 14 days of pyrithiamine-induced thiamine deficiency (PTD) in the rat. The concentration of ROS was significantly elevated in thalamus and cortex on day 14 when righting reflexes were absent and spontaneous seizures occurred. No significant changes in GSH concentration were observed in thalamus or cortex on either day of treatment. These findings suggest that increased formation of free radicals occurs during the more acute symptomatic stage of thiamine deficiency and may contribute to the structural damage described in this model of Wernicke's encephalopathy.

Animals↗

PubMed1996

Effect of an NMDA receptor antagonist and a ganglioside GM1 derivative upon ethanol-induced modification of parameters of oxidative stress in several brain regions.

Dietary administration of ethanol to rats for 2 weeks was able to depress levels of glutathione (GSH) and Cu/Zn superoxide dismutase (SOD) in several brain regions. This was indicative of the generation of excess levels of reactive oxygen in treated animals. The potentially protective effect of both an NMDA receptor blocker (MK-801) and an internally esterified derivative of ganglioside GM1 (AGF2) upon ethanol-induced changes in these indices of oxidative stress, was studied. Both of these agents are reported to have neuroprotective properties, but neither was able to prevent ethanol-induced reduction of GSH and SOD levels in any brain area studied. In fact, both agents depressed SOD and GSH levels in midbrain independently of ethanol. MK-801 had a pronounced pro-oxidant potential, and when administered in combination with ethanol. GSH and SOD were reduced in midbrain and striatum to levels below those obtained with either agent alone. The pro-oxidant properties of ethanol may thus act independently of its actions upon the NMDA receptor. The protective properties of NMDA receptor inhibitors or gangliosides cannot be attributed to any antioxidant effect.

Animals↗

PubMed1996

The promotion of iron-induced generation of reactive oxygen species in nerve tissue by aluminum.

Aluminum is suspected to play a role in several neurological disorders. Reactive oxygen species (ROS) lead to oxidative stress, which is thought to be a possible mechanism for neurological damage. Interactions between aluminum and iron, a known promoter of prooxidant events, were studied in cerebral tissues using a fluorescent probe to measure rates of generation of ROS. Al2(SO4)3 alone failed to stimulate ROS production over a wide range of concentrations (50-1000 microM). The aluminum-deferrioxamine chelate in the absence of iron could also not potentiate ROS formation. However, Al2(SO4)3 potentiated FeSO4-induced ROS, with a maximal effect at 10 microM Fe and 500 microM Al. Kaolin, a hydrated aluminum silicate, did not potentiate iron-induced ROS formation. Ferritin had a minor stimulatory effect on ROS generation, but this was not potentiated by the concurrent presence of Al2(SO4)3. Transferrin had no effect on basal rates of ROS generation, but when Al2(SO4)3 was also present, ROS production was enhanced. It is concluded that: 1. There is a potentiation of iron-induced ROS by aluminum salts; 2. Free or complexed aluminum alone is not a key producer of ROS; and 3. High rates of ROS production are unlikely to be owing to the displacement by aluminum iron from its biologically sequestered locations.

Alum Compounds↗

PubMed1996

Lead potentiates iron-induced formation of reactive oxygen species.

There are reports that lead may promote free-radical initiated events in biological tissue. However, there are also reports on the inability of lead salts to stimulate the production of reactive oxygen species in isolated systems. Furthermore, there is no well understood rationale as to why lead should exhibit pronounced pro-oxidant properties. We are reporting that while lead acetate does not initiate any excess generation of reactive oxygen species in a cerebral synaptosomal suspension, it has a marked ability to enhance the pro-oxidant properties of ferrous iron in the same system. This property was maximal at a lead concentration of 0.5 mM when major precipitation of lead salts occurred. Therefore, it may reside in the ability of iron to form an active chelate on the surface of insoluble lead salts. Such an interaction may account for the discrepancies in the literature concerning the relation between lead toxicity and oxidative stress.

Analysis of Variance↗

PubMed1996

Prevention of ethanol-induced changes in reactive oxygen parameters by alpha-tocopherol.

Rats were given a 200 mg/kg body weight daily dose of alpha-tocopherol by i.p. injection for 15 days. This resulted in elevated levels of glutathione in both liver and brain, and in a reduced hepatic rate of generation of reactive oxygen species. The depression of hepatic and cerebral glutathione levels in ethanol-consuming rats was prevented by simultaneous treatment with alpha-tocopherol. Other putative indices of hepatic pro-oxidant events, namely levels of mixed function oxidase and proteolytic activity, were elevated by alpha-tocopherol both in the presence and absence of ethanol. In addition, levels of enzymes especially susceptible to oxidative degradation, glutamine synthetase and creatine kinase, were depressed in the liver following treatment with ethanol or alpha-tocopherol. Parameters rapidly responsive to oxidative changes revealed the antioxidant property of alpha-tocopherol, while protein-based indices reflecting more extended events suggested a pro-oxidant effect of this vitamin. Results suggest that high levels of alpha-tocopherol can simultaneously lead to a more reduced intracellular environment and yet to localized evidence of enhanced oxidative events.

Alcoholism↗

PubMed1995

Stimulation of synaptosomal free radical production by fatty acids: relation to esterification and to degree of unsaturation.

The ability of three fatty acids and their respective ethyl esters, to promote generation of reactive oxygen species (ROS), was compared in a preparation of rat brain synaptosomes. Arachidonic but not palmitic or linoleic acids promoted ROS generation. Ethyl esterification of each fatty acid significantly enhanced ROS production and also levels of lipid peroxidaton. Pro-oxidant activity was enhanced by fatty acids, proportionally to their degree of unsaturation. Since ethanol consumption is known to lead to esterification of membrane lipids, this transformation may in part account for the ROS-promoting potential of alcohol.

Analysis of Variance↗

PubMed1995

Regional selectivity in ethanol-induced pro-oxidant events within the brain.

Several biochemical parameters that reflect the presence of excess levels of reactive oxygen species were modulated in the brains of rats exposed acutely or subchronically to ethanol. These parameters included depression of cytosolic glutathione (GSH) concentration and of glutamine synthetase levels. However, using these indices, there was a significant difference in susceptibility to ethanol in different brain regions. After dietary exposure to ethanol for 12 days, these indices were selectively depressed in the striatum but not in the cerebral cortex or cerebellum. Eighteen hours after a single acute dose of ethanol (4.5 g/kg body wt), the striatum was also the only one of these areas in which proteolytic activity was elevated by ethanol treatment. Two injections of acetaldehyde (300 mg/kg), given 18 and 2 hr prior to tissue preparation, caused a specific reduction of glutamine synthetase in the striatum and a decrease of GSH levels in both striatum and cerebellum. Taken together, the results suggest a distinctive vulnerability of the striatum to ethanol-promoted oxidative events. Rather than ethanol exerting effects directly, the metabolite acetaldehyde may be the primary agent responsible for these changes.

Animals↗

PubMed1995

Excitotoxins, aging, and environmental neurotoxins: implications for understanding human neurodegenerative diseases.

We are an aging society and current demographic trends point to a likely increase in age-related neurodegenerative diseases. The aged population may have a number of unique risk factors that result in a predisposition to neuronal damage from environmental neurotoxins. This symposium addressed the involvement of excitatory amino acids as final common mediators of neuronal death associated with various types of neurotoxic insult. The roles of oxidative stress, mitochondrial energy metabolism, and disruption of calcium homeostasis were discussed in relation to excitoxicity and several experimental models of human neurodegenerative diseases. The neurotoxic actions of kainic acid, 3-nitropropionic acid, cyanide, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, and methamphetamine were examined for their relevance as models of human neurodegenerative disorders. The mechanisms of action of excitotoxins in experimental models of Huntingtons's disease and Parkinson's disease were explored in light of the enhanced susceptibility and potential vulnerability of the aged nervous system to neurotoxins that perturb cellular metabolism and homeostatic processes. Bioenergetic defects and oxidative stress were found to be critical links in a neurotoxic cascade of events that trigger the sustained release of excitotoxic amino acids. The interrelationships among the aging process, the pathophysiology of neurodegenerative diseases, and the mechanism of action of various neurotoxins were addressed from the unifying perspective of the excitotoxic hypothesis of neuronal death.

Aging↗

PubMed1995

Inhibition of plasma membrane and mitochondrial transmembrane potentials by ethanol.

The actions of ethanol and its primary oxidative metabolite, acetaldehyde, on plasma membrane and mitochondrial transmembrane potentials were examined in rat brain using fluorescence techniques. Subchronic treatment of adult rats with ethanol resulted in a significant depolarization of both the plasma and mitochondrial membranes when the mean blood ethanol level of the rats was 59 +/- 11 mM (mean +/- SEM, n = 6). Acute dosing of animals (4.5 g/kg, i.p.) failed to show any significant alterations. Various concentrations of ethanol, added in vitro to a crude synaptosomal preparation isolated from the rat cerebrocortex (P2) from untreated animals, depolarized both the plasma and mitochondrial transmembrane potentials in a dose-related manner. Addition of acetaldehyde in vitro did not reveal any significant effects on plasma or mitochondrial transmembrane potential.

Alcoholism↗

PubMed1995

Changes in markers of oxidative status in brain, liver and kidney of young and aged rats following exposure to aromatic white spirit.

Levels of glutathione and activity of glutamine synthetase were assayed in organs of rats following inhalation of a heterogeneous solvent mixture containing both aliphatic and aromatic hydrocarbons. This mixture was administered for 3 weeks (6 h daily) at two levels in the inhaled air (400 and 800 ppm) to young adult (5-month-old) and aged (14-month-old) rats. Depression of levels of glutamine synthetase in the P2 fraction of kidney was observed, which was more severe in aged than young adult rats. Glutamine synthetase is a cytosolic enzyme especially susceptible to oxidative damage. A parallel depression of this enzyme was also seen in the corresponding hepatic fractions. However, levels of glutamine synthetase in the hippocampus were elevated by this exposure. Glutathione levels were depressed in P2 fractions of livers of exposed rats, and also in the corresponding renal fraction. Glutathione concentration was unchanged in cerebral fractions. Overall results were interpreted to imply that pro-oxidant events were elevated in kidney and liver following prolonged inhalation of the solvent mixture. The changes found in brain tissue did not reveal evidence of oxidative stress but, however, suggested that glial activation was taking place.

Aging↗

PubMed1995

The relation of oxidative stress and hyperexcitation to neurological disease.

The expression of a considerable range of neurological diseases is thought to involve two pathological states, namely, the production of excessive amounts of reactive oxygen species and neuronal hyperactivity. These events may represent an outcome of general vulnerable features of nervous tissue. Since they are associated with many unrelated diseases, the phenomena may be considered the final common pathways of a range of metabolic defects. Superimposed on these general signs of cellular impairment are the more specific features of each disorder. This review describes some of the evidence for the presence of hyperactivity and oxidative stress in various neurological disorders. Mechanisms whereby the states may interact and modulate each other are discussed. The manner in which such understanding has implications for the development of novel therapeutic approaches is also described.

Alzheimer Disease↗

PubMed1995

Cerebral membranes isolated from rats consuming ethanol or gestationally exposed to ethanol have increased susceptibility to modulation by ethanol.

The actions of ethanol on membrane fluidity were examined. All assays were carried out using fluorescence techniques in the P2 fraction of crude synaptosomes isolated from rat brain. Subchronic treatment of rats with ethanol revealed a significant increase in order at the membrane interior. In vitro addition of ethanol to P2 fractions prepared from treated rats revealed a significant rise in fluidity at the membrane core that was not found in corresponding P2 fractions from untreated rats. The withdrawal of ethanol from subchronically treated rats revealed no significant alterations in membrane fluidity. However, in vitro addition of ethanol to P2 fractions prepared from these animals produced an increase in fluidity at the membrane centre. This effect was not observed in corresponding control rats. Rat pups that were gestationally exposed to ethanol also failed to show any significant differences in membrane fluidity compared with control rats. However, in vitro addition of a challenge dose of ethanol to P2 fractions resulted in a significant rise in fluidity not found in pups from untreated mothers. These findings suggest that the process of adaptation to chronic ethanol may be dissected into two separable events: one frequently reported effect that alters membrane fluidity and one that modulates membrane susceptibility to ethanol-induced perturbations.

Alcoholism↗