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Biomedical subjects

M J Forster

Publications and source records attributed to M J Forster.

At least 19 recordsLinked to original sources
PubMed2005

GABAergic modulation of the discriminative stimulus effects of methamphetamine.

To assess whether gamma-aminobutyric acid (GABA) modulation of dopamine is important in mediation of the discriminative stimulus effects of methamphetamine, the GABA compounds chlordiazepoxide (benzodiazepine site agonist), pentobarbital (barbiturate site agonist), bicuculline and pentylenetetrazol (GABA(A) receptor antagonists) were tested in Sprague-Dawley rats trained to discriminate methamphetamine (1 mg/kg, i.p.) from saline. Each of the compounds produced modest amounts of methamphetamine-appropriate responding (20-35%) when tested alone. When tested in combination with methamphetamine, the antagonists (bicuculline and pentylenetetrazol) failed to shift the methamphetamine dose-effect curve. In contrast, chlordiazepoxide (25 mg/kg, i.p.) reduced methamphetamine-appropriate responding at each dose of methamphetamine tested, and pentobarbital (10 mg/kg, i.p.) dose-dependently decreased the discriminative stimulus effects of 1 mg/kg methamphetamine. In conclusion, GABA(A) antagonists and positive modulators likely do not produce methamphetamine-like stimulus effects. However, activation of GABA(A) receptors can interfere with the discriminative stimulus effects of methamphetamine.

Animals↗
PubMed2001

Dopamine transporter binding without cocaine-like behavioral effects: synthesis and evaluation of benztropine analogs alone and in combination with cocaine in rodents.

RATIONALE: Previous SAR studies demonstrated that small halogen substitutions on the diphenylether system of benztropine (BZT), such as a para-Cl group, retained high affinity at the cocaine binding site on the dopamine transporter. Despite this high affinity, the compounds generally had behavioral effects different from those of cocaine. However, compounds with meta-Cl substitutions had effects more similar to those of cocaine. OBJECTIVES: A series of phenyl-ring analogs of benztropine (BZT) substituted with 3'-, 4'-, 3',4"- and 4',4"-position Cl-groups were synthesized and their pharmacology was evaluated in order to assess more fully the contributions to pharmacological activity of substituents in these positions. METHODS: Compounds were synthesized and their pharmacological activity was assessed by examining radioligand binding and behavioral techniques. RESULTS: All of the compounds displaced [3H]WIN 35,428 binding with affinities ranging from 20 to 32.5 nM. Affinities at norepinephrine ([3H]nisoxetine) and serotonin ([3H]citalopram) transporters, respectively, ranged from 259 to 5120 and 451 to 2980 nM. Each of the compounds also inhibited [3H]pirenzepine binding to muscarinic M1 receptors, with affinities ranging from 0.98 to 47.9 nM. Cocaine and the BZT analogs produced dose-related increases in locomotor activity in mice. However, maximal effects of the BZT analogs were uniformly less than those produced by cocaine, and were obtained 2-3 h after injection compared to the relatively rapid onset (within 30 min) of cocaine effects. In rats trained to discriminate i.p. saline from 29 mumol/kg cocaine (10 mg/kg), cocaine produced a dose-related increase in responding on the cocaine lever, reaching 100% at the training dose; however, none of the BZT analogs fully substituted for cocaine, with maximum cocaine responding from 20 to 69%. Despite their reduced efficacy compared to cocaine in cocaine discrimination, none of the analogs antagonized the effects of cocaine. As has been reported previously for 4'-Cl-BZT, the cocaine discriminative-stimulus effects were shifted left-ward by co-administration of the present BZT analogs. CONCLUSIONS: The present results indicate that although the BZT analogs bind with relatively high affinity and selectivity at the dopamine transporter, their behavioral profile is distinct from that of cocaine. The present results suggest that analogs of BZT may be useful as treatments for cocaine abuse in situations in which an agonist treatment is indicated. These compounds possess features such as reduced efficacy compared to cocaine and a long duration of action that may render them particularly useful leads for the development of therapeutics for cocaine abusers.

Animals↗
PubMed2000

Molecular modelling study of HIV p17gag (MA) protein shell utilising data from electron microscopy and X-ray crystallography.

The matrix protein p17gag (MA) is a product of proteolytic cleavage of the gag gene encoded polyprotein (pr55gag) and is formed when HIV particles undergo the process of maturation. The MA protein is associated with the inner surface of the viral membrane and determines the overall shape of the virion. Previous studies have shown the existence of trimers of MA in solution and in the crystalline state. Here, we used molecular modelling methods to identify feasible interactions between pairs of MA trimers and have related this to structural data from electron microscopy. A systematic search docking procedure was able to identify many energetically favourable conformations for a pair of trimers, including some which have been previously reported. These conformations were used to generate several networks of MA trimers, which were then evaluated against structural observations of the MA network. The model suggested here provides a good match with experimental data such as the spacing between gag protein rings, the number and disposition of glycoprotein (gp41-gp120) knobs and the number of copies of MA in a virus particle. It also rationalizes the observed distribution of sizes of virus particles and is consistent with the presence of icosahedral organisation in mature HIV. Energy minimisation performed with explicit water and counter ions, was used to identify residues participating in inter-trimer interactions. The nature of these interactions is discussed in relation to the conservation of these residues in reported variants of the HIV and SIV MA protein sequences.

Computer Simulation↗
PubMed2000

Effects of NMDA receptor blockers on cocaine-stimulated locomotor activity in mice.

Effects of MK-801 and ketamine, N-methyl-D-aspartate (NMDA) receptor blockers, on cocaine-stimulated locomotor activity were investigated in male Swiss-Webster mice. MK-801 (0.25, 0.5, 1.0 and 2.5 mg/kg), ketamine (10, 25 and 50 mg/kg) or saline was injected 20 min before cocaine (5, 10 and 20 mg/kg i.p.). Locomotor activity was measured for 30 min immediately following cocaine treatment. All doses of the drugs were also tested for ability to depress or stimulate locomotor activity in the naive (no cocaine-treated) mice. Cocaine produced a dose-dependent increase in locomotor activity that was blocked dose-dependently by MK-801 or ketamine. The blockade by MK-801 was more prominent than by ketamine. Our results may suggest that cocaine-induced locomotor stimulation in mice is modulated via NMDA receptor mediated mechanisms.

Animals↗
PubMed2000

Reversible effects of long-term caloric restriction on protein oxidative damage.

The age-associated increase in oxidative damage in ad libitum-fed mice is attenuated in mice fed calorically restricted (CR) diets. The objective of this study was to determine if this effect results from a slowing of age-related accumulation of oxidative damage, or from a reversible decrease of oxidative damage by caloric restriction. To address these possibilities, crossover studies were conducted in C57BL/6 mice aged 15 to 22 months that had been maintained, after 4 months of age, on ad libitum (AL) or a 60% of AL caloric regimen. One half of the mice in these groups were switched to the opposite regimen of caloric intake for periods up to 6 weeks, and protein oxidative damage (measured as carbonyl concentration and loss of sulfhydryl content) was measured in homogenates of brain and heart. In AL-fed mice, the protein carbonyl content increased with age, whereas the sulfhydryl content decreased. Old mice maintained continuously under CR had reduced levels of protein oxidative damage when compared with the old mice fed AL. The effects of chronic CR on the carbonyl content of the whole brain and the sulfhydryl content of the heart were fully reversible within 3-6 weeks following reinstatement of AL feeding. The effect of chronic CR on the sulfhydryl content of the brain cortex was only partially reversible. The introduction of CR for 6 weeks in the old mice resulted in a reduction of protein oxidative damage (as indicated by whole brain carbonyl content and cortex sulfhydryl), although this effect was not equivalent to that of CR from 4 months of age. The introduction of CR did not affect the sulfhydryl content of the heart. Overall, the current findings indicate that changes in the level of caloric intake may reversibly affect the concentration of oxidized proteins and sufhydryl content. In addition, chronic restriction of caloric intake also retards the age-associated accumulation of oxidative damage. The magnitude of the reversible and chronic effects appears to be dependent upon the tissue examined and the nature of the oxidative alteration.

Aging↗
PubMed2000

Conformation and dynamics of heparin and heparan sulfate.

The glycosaminoglycans heparin and heparan sulfate contain similar structural units in varying proportions providing considerable diversity in sequence and biological function. Both compounds are alternating copolymers of glucosamine with both iduronate- and glucuronate-containing sequences bearing N-sulfate, N-acetyl, and O-sulfate substitution. Protein recognition of these structurally-diverse compounds depends upon substitution pattern, overall molecular shape, and on internal mobility. In this review particular attention is paid to the dynamic aspects of heparin/heparan sulfate conformation. The iduronate residue possesses an unusually flexible pyranose ring conformation. This extra source of internal mobility creates special problems in rationalization of experimental data for these compounds. We present herein the solution-state NMR parameters, fiber diffraction data, crystallographic data, and molecular modeling methods employed in the investigation of heparin and heparan sulfate. Heparin is a useful model compound for the sulfated, protein-binding regions of heparan sulfate. The literature contains a number of solution and solid-state studies of heparin oligo- and polysaccharides for both isolated heparin species and those bound to protein receptors. These studies indicate a diversity of iduronate ring conformations, but a limited range of glycosidic linkage geometries in the repeating disaccharides. In this sense, heparin exhibits a well-defined overall shape within which iduronate ring forms can freely interconvert. Recent work suggests that computational modeling could potentially identify heparin binding sites on protein surfaces.

Animals↗
PubMed2000

Selection of putative immunogenic peptides by molecular modelling of the urease of Helicobacter pylori.

Computational methods such as molecular modelling are becoming an increasingly useful means of rationalising experimental data and creating a hypothesis that can suggest new experiments. In this report we discuss the application of molecular modelling methods to aid the selection of feasible peptide epitopes of the urease enzyme from Helicobacter pylori, an important vaccine candidate. Surface exposure was chosen as a criterion for the selection of three peptides which each had different levels of accessibility according to the 3D model. Antibodies raised against these peptides were analysed for their immunoreactivity with the holo enzyme. Only one anti-peptide antibody showed good reactivity with the urease. Our findings emphasise that surface exposure of peptide is not the only important criterion for the selection of immunogenic peptides.

Enzyme-Linked Immunosorbent Assay↗
PubMed1999

Effects of coenzyme Q10 and alpha-tocopherol administration on their tissue levels in the mouse: elevation of mitochondrial alpha-tocopherol by coenzyme Q10.

Coenzyme Q (CoQ) was previously demonstrated in vitro to indirectly act as an antioxidant in respiring mitochondria by regenerating alpha-tocopherol from its phenoxyl radical. The objective of this study was to determine whether CoQ has a similar sparing effect on alpha-tocopherol in vivo. Mice were administered CoQ10 (123 mg/kg/day) alone, or alpha-tocopherol (200 mg/kg/day) alone, or both, for 13 weeks, after which the amounts of CoQ10, CoQ9 and alpha-tocopherol were determined by HPLC in the serum as well as homogenates and mitochondria of liver, kidney, heart, upper hindlimb skeletal muscle and brain. Administration of CoQ10 and alpha-tocopherol, alone or together, increased the corresponding levels of CoQ10 and alpha-tocopherol in the serum. Supplementation with CoQ10 also elevated the amounts of the predominant homologue CoQ9 in the serum and the mitochondria. A notable effect of CoQ10 intake was the enhancement of alpha-tocopherol in mitochondria. alpha-Tocopherol administration resulted in an elevation of alpha-tocopherol content in the homogenates of nearly all tissues and their mitochondria. Results of this study thus indicate that relatively long-term administration of CoQ10 or alpha-tocopherol can result in an elevation of their concentrations in the tissues of the mouse. More importantly, CoQ10 intake has a sparing effect on alpha-tocopherol in mitochondria in vivo.

Animals↗
PubMed1999

Effect of age and caloric restriction on bleomycin-chelatable and nonheme iron in different tissues of C57BL/6 mice.

The objective of this study was to test the hypothesis that the widely observed age-associated increase in the amounts of macromolecular oxidative damage is due to an elevation in the availability of redox-active iron, that is believed to catalyze the scission of H2O2 to generate the highly reactive hydroxyl radical. Concentrations of bleomycin-chelatable iron and nonheme iron were measured in various tissues and different regions of the brain of mice fed on ad libitum (AL) or a calorically restricted (to 60% of AL) diet at different ages. The concentrations of these two pools of iron varied markedly as a function of tissue, age, and caloric intake. There was no consistent ratio between the amounts of nonheme and the bleomycin-chelatable iron pools across these conditions. Nonheme iron concentration increased with age in the liver, kidney, heart, striatum, hippocampus, midbrain and cerebellum of AL animals, whereas bleomycin-chelatable iron increased significantly with age only in the liver. Amounts of both nonheme and bleomycin-chelatable iron remained unaltered during aging in the cerebral cortex and hindbrain of AL mice. Caloric restriction had no effect on iron concentration in the brain or heart, but caused a marked increase in the concentration of both bleomycin-chelatable and nonheme iron in the liver and the kidney. The results do not support the hypothesis that accumulation of oxidative damage with age, or its attenuation by CR, are associated with corresponding variations in redox-active iron.

Aging↗
PubMed1998

Differential responsiveness to cocaine in C57BL/6J and DBA/2J mice.

The present study compared cocaine-induced hyperlocomotion and cocaine i.v. self-administration in DBA/2J and C57BL/6J mice. In the locomotor activity experiment, these strains were tested for hyperlocomotion after i.p. cocaine injection (0-60.0 mg/kg), using a Digiscan Animal Activity Monitoring System. In the cocaine i.v. self-administration experiment, they were compared for their ability to acquire and maintain cocaine self-administration in operant chambers with levers as the manipulanda. Animals were first trained to respond for food as a reinforcer (condensed milk solution); they were then submitted to surgical i.v. insertion of an in-dwelling catheter, and required to respond for i.v. cocaine (0.25-4.0 mg/kg per injection) as a reinforcer. DBA/2J mice showed significantly higher maximal cocaine-induced hyperlocomotion, more rapid acquisition of cocaine self-administration, and significantly lower rates of cocaine self-administration. Cocaine concentration in the brains of DBA/2J and C57BL/6J mice failed to differ following i.p. injection, suggesting that distribution factors were not involved in the differential responses to cocaine. Although not conclusive, this pattern of effects may suggest that cocaine has greater reinforcing efficacy in DBA/2J mice, confirming genetic make-up as a determinant factor in cocaine taking behavior.

Animals↗
PubMed1998

Caloric restriction prevents age-associated accrual of oxidative damage to mouse skeletal muscle mitochondria.

The purpose of this study was to understand the nature of the causes underlying the senescence-related decline in skeletal muscle mass and performance. Protein and lipid oxidative damage to upper hindlimb skeletal muscle mitochondria was compared between mice fed ad libitum and those restricted to 40% fewer calories--a regimen that increases life span by approximately 30-40% and attenuates the senescence-associated decrement in skeletal muscle mass and function. Oxidative damage to mitochondrial proteins, measured as amounts of protein carbonyls and loss of protein sulfhydryl content, and to mitochondrial lipids, determined as concentration of thiobarbituric acid reactive substances, significantly increased with age in the ad libitum-fed (AL) C57BL/6 mice. The rate of superoxide anion radical generation by submitochondrial particles increased whereas the activities of antioxidative enzymes superoxide dismutase, catalase, and glutathione peroxidase in muscle homogenates remained unaltered with age in the AL group. In calorically-restricted (CR) mice there was no age-associated increase in mitochondrial protein or lipid oxidative damage, or in superoxide anion radical generation. Crossover studies, involving the transfer of 18- to 22-month-old mice fed on the AL regimen to the CR regimen, and vice versa, indicated that the mitochondrial oxidative damage could not be reversed by CR or induced by AL feeding within a time frame of 6 weeks. Results of this study indicate that mitochondria in skeletal muscles accumulate significant amounts of oxidative damage during aging. Although such damage is largely irreversible, it can be prevented by restriction of caloric intake.

Age Factors↗
PubMed1996

Effect of age and caloric intake on protein oxidation in different brain regions and on behavioral functions of the mouse.

The objective of this study was to determine if oxidative stress/damage is a possible causal factor in the senescence-related loss of brain functions in the mouse. If such a relationship indeed existed, it was expected that oxidative protein damage would increase with age within regions of the brain associated with senescence-related functional loss, and that calorie restriction, an intervention which retards certain aspects of age-associated functional loss, would reverse such increases. Dietary restriction was found to retard age-associated decline of sensorimotor coordination and improve performance of aged mice on an avoidance learning problem. Protein carbonyl concentration, one measure of protein oxidation, increased from 8 to 27 months of age in most regions of the mouse brain, with the most notable increases occurring in the striatum and hippocampus, regions of the brain strongly implicated in age-associated functional loss. Age-associated loss of protein sulfhydryls was more uniform across brain regions and did not involve the hippocampus. Dietary restriction resulted in reversal of the age-associated regional trends in carbonyl and sulfhydryl concentration, with the largest changes occurring within the striatum. Cross over studies in aged calorie restricted and ad libitum fed mice indicated that lowering of carbonyl content by calorie restriction could be induced or reversed within a time frame of 3 to 6 weeks. These findings suggest that the beneficial effects of dietary restriction upon brain function and life span may depend upon its ability to acutely reduce steady-state levels of oxidative stress.

Aging↗
PubMed1996

Age-related losses of cognitive function and motor skills in mice are associated with oxidative protein damage in the brain.

The hypothesis that age-associated impairment of cognitive and motor functions is due to oxidative molecular damage was tested in the mouse. In a blind study, senescent mice (aged 22 months) were subjected to a battery of behavioral tests for motor and cognitive functions and subsequently assayed for oxidative molecular damage as assessed by protein carbonyl concentration in different regions of the brain. The degree of age-related impairment in each mouse was determined by comparison to a reference group of young mice (aged 4 months) tested concurrently on the behavioral battery. The age-related loss of ability to perform a spatial swim maze task was found to be positively correlated with oxidative molecular damage in the cerebral cortex, whereas age-related loss of motor coordination was correlated with oxidative molecular damage within the cerebellum. These results support the view that oxidative stress is a causal factor in brain senescence. Furthermore, the findings suggest that age-related declines of cognitive and motor performance progress independently, and involve oxidative molecular damage within different regions of the brain.

Aging↗
PubMed1995

Effect of the spin-trapping compound N-tert-butyl-alpha-phenylnitrone on protein oxidation and life span.

N-tert-Butyl-alpha-phenylnitrone (PBN), a lipophilic spin-trapping compound, has been reported to decrease the concentration of protein carbonyls, the products of protein oxidation, in the brain of old gerbils to virtually the level found in the young gerbils (Carney, J. M., et al. (1991) Proc. Natl. Acad. Sci. USA 88, 3633-3636). The validity of this finding as well as that of the commonly used 2,4-dinitrophenylhydrazine procedure for the measurement of protein carbonyls was recently called into question by Cao and Cutler ((1995) Arch. Biochem. Biophys. 320, 106-114). The objective of the present study was to examine some of the relevant issues such as (a) whether the original findings on the effects of PBN can be confirmed, (b) whether similar effects of PBN occur in other species and tissues, and (c) whether PBN affects the life span of animals. Results of this study provide confirmation of the original finding that PBN indeed causes a decrease in protein carbonyl content in the gerbil brain cortex. However, a similar effect is not observed in the gerbil heart or the mouse brain cortex. Effects of PBN on protein carbonyls are thus variable depending upon tissue and species. PBN administration did not extend the life span of houseflies and at relatively high concentrations it was found to be toxic.

Aging↗
PubMed1994

Effect of age and caloric restriction on DNA oxidative damage in different tissues of C57BL/6 mice.

The objective of this study was to explore the role of molecular oxidative damage and caloric intake in the aging process. The concentration of 8-hydroxydeoxyguanosine (8-OHdG), a product of DNA oxidation, was compared in five different tissues of mice (skeletal muscle, brain, heart, liver and kidney) as a function of age and in response to dietary restriction. A comparison of 8- and 27-month-old mice indicated that the age-related increase in 8-OHdG concentration was greater in skeletal muscle, brain and heart, which are primarily composed of long-lived, post-mitotic cells, than in liver and kidney, which consist of slow-dividing cells. Dietary restricted (DR) mice kept on 60% caloric intake as compared to the ad libitum-fed (AL) mice showed a lower concentration in 8-OHdG content in all the tissues compared to AL mice. The DR-related amelioration of DNA oxidative damage was greater in the post-mitotic tissues compared to those undergoing slow mitoses. Results support the hypothesis that oxidative damage to long-lived post-mitotic cells may be a key factor in the aging process.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1994

The effect of variation of substitution on the solution conformation of heparin: a spectroscopic and molecular modelling study.

The effect of variations in substitution on the conformation of iduronate-containing sequences in heparin and heparan sulphate has been studied using a series of chemically-modified heparins in which substitution with O- and N-sulphate and N-acetyl substituents has been systematically altered. Monosaccharides corresponding to residues in these modified heparins have also been investigated. The conformations of the glycosidic linkages in O- and N-desulphated re-N-acetylated heparin, O-desulphated re-N-sulphated heparin, and 6-O-desulphated re-N-sulphated heparin have been compared with those of N-desulphated re-N-acetylated heparin and of heparin itself, which have been compared with those of N-desulphated re-N-acetylated heparin and of heparin itself, which have previously been reported [B. Mulloy, M.J. Forster, C. Jones, and D.B. Davies, Biochem. J., 293 (1993) 849-858]. The overall conformation of all the polysaccharides is shown to be similar, regardless of substitution pattern. The conformational equilibrium of the pyranose ring of iduronic acid residues in the polysaccharides has been monitored by the use of 13C NMR chemical shift temperature coefficients, and shown to be similar for all the modified heparins with the exception of N-desulphated re-N-acetylated heparin. Circular dichroism spectra of all the polysaccharides are reported, and their variations attributed to differences in the proportions of pyranose ring forms in the iduronate conformational equilibrium.

Carbohydrate Conformation↗
PubMed1994

Oxidative damage, mitochondrial oxidant generation and antioxidant defenses during aging and in response to food restriction in the mouse.

This study was conducted in order to test the concept that oxidative damage is associated with aging and may be a factor in the modulation of life span in response to variations in caloric intake. Mice fed a diet that was 40% lower in calories (DR) than the ad libitum fed (AL) animals exhibited a 43% extension in average life span and a 61% prolongation in mortality rate doubling time. A comparison of AL and DR mice at 9, 17 and 23 months of age indicated that the protein carbonyl content in the brain, heart and kidney increased with age and was significantly greater in the AL than DR group in each organ at each of the three ages. Mitochondrial state 4 or resting respiratory rate increased with age in the AL, but not the DR group, and was also relatively higher in the former. The rates of mitochondrial superoxide and hydrogen peroxide generation increased with age and were higher in the AL than DR mice in all the three organs at each age. In contrast, there was no clear-cut overall pattern of age-related or dietary-related changes in antioxidant defenses provided by superoxide dismutase, catalase and glutathione peroxidase. Results suggest that mechanisms of aging and life span shortening by enhanced caloric intake are associated with oxidative damage arising from corresponding changes in mitochondrial oxidant production. Protein carbonyl content, and mitochondrial O2.- and H2O2 generation may act as indices of aging.

Aging↗