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Biomedical subjects

M Bogdanov

Publications and source records attributed to M Bogdanov.

At least 19 recordsLinked to original sources
PubMed2006

Creatine in Huntington disease is safe, tolerable, bioavailable in brain and reduces serum 8OH2'dG.

In a randomized, double-blind, placebo-controlled study in 64 subjects with Huntington disease (HD), 8 g/day of creatine administered for 16 weeks was well tolerated and safe. Serum and brain creatine concentrations increased in the creatine-treated group and returned to baseline after washout. Serum 8-hydroxy-2'-deoxyguanosine (8OH2'dG) levels, an indicator of oxidative injury to DNA, were markedly elevated in HD and reduced by creatine treatment.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed2000

Increased oxidative damage to DNA in ALS patients.

Although the cause of amyotrophic lateral sclerosis (ALS) is unknown, substantial evidence indicates that oxidative toxicity is associated with neuronal death in this disease. We examined levels of a well-established marker of oxidative damage to DNA, 8-hydroxy-2'-deoxyguanosine (8OH2'dG) in plasma, urine, and cerebrospinal fluid (CSF) at a single time point from subjects with ALS, other neurological diseases, or no known disorders. We also measured the rate of change of 8OH2'dG levels in plasma and urine from ALS and in urine from control subjects over 9 months and examined the relationship to disease severity. In each fluid, 8OH2'dG levels were significantly elevated in the ALS group as compared to control subjects. In all subjects, the plasma and CSF 8OH2'dG levels increased with age, providing further evidence for a role of oxidative damage in normal aging. Plasma and urine 8OH2'dG levels increased significantly with time in the ALS group only. The rate of increase in urine 8OH2'dG levels with time was significantly correlated with disease severity. These findings are consistent with the hypothesis that oxidative pathology accompanies the neurodegenerative process in ALS and suggest that 8OH2'dG may provide a useful tool for monitoring therapeutic interventions in this disease.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed2000

Mice deficient in cellular glutathione peroxidase show increased vulnerability to malonate, 3-nitropropionic acid, and 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine.

Glutathione peroxidase (GSHPx) is a critical intracellular enzyme involved in detoxification of hydrogen peroxide (H(2)O(2)) to water. In the present study we examined the susceptibility of mice with a disruption of the glutathione peroxidase gene to the neurotoxic effects of malonate, 3-nitropropionic acid (3-NP), and 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP). Glutathione peroxidase knock-out mice showed no evidence of neuropathological or behavioral abnormalities at 2-3 months of age. Intrastriatal injections of malonate resulted in a significant twofold increase in lesion volume in homozygote GSHPx knock-out mice as compared to both heterozygote GSHPx knock-out and wild-type control mice. Malonate-induced increases in conversion of salicylate to 2,3- and 2, 5-dihydroxybenzoic acid, an index of hydroxyl radical generation, were greater in homozygote GSHPx knock-out mice as compared with both heterozygote GSHPx knock-out and wild-type control mice. Administration of MPTP resulted in significantly greater depletions of dopamine, 3,4-dihydroxybenzoic acid, and homovanillic acid in GSHPx knock-out mice than those seen in wild-type control mice. Striatal 3-nitrotyrosine (3-NT) concentrations after MPTP were significantly increased in GSHPx knock-out mice as compared with wild-type control mice. Systemic 3-NP administration resulted in significantly greater striatal damage and increases in 3-NT in GSHPx knock-out mice as compared to wild-type control mice. The present results indicate that a knock-out of GSHPx may be adequately compensated under nonstressed conditions, but that after administration of mitochondrial toxins GSHPx plays an important role in detoxifying increases in oxygen radicals.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1999

Detection of dopaminergic cell loss and neural transplantation using pharmacological MRI, PET and behavioral assessment.

We demonstrate the use of magnetic resonance imaging (MRI) for detection of neurotransmitter stimulation using the dopamine transporter ligands amphetamine and CFT (2beta-carbomethoxy-3beta-(4-fluorophenyl)tropane) as pharmacological challenges. We demonstrate that the unilateral loss of a hemodynamic response to either amphetamine or CFT challenge by unilateral 6-hydroxydopamine lesioning is restored by transplantation of fetal dopamine neurons in the striatum. The time course for the hemodynamic changes parallels the time courses for dopamine release, measured by prior microdialysis studies, and also for the rotational behavior in the unilaterally lesioned animals. Transplantation of the fetal cells results in hemodynamic time courses after CFT or amphetamine challenges at the graft site that are identical to those induced both before transplantation and on the intact contralateral side. The transplantation also results in complete behavioral recovery. The spatial extent of the dopaminergic recovery in the lesioned striatum is the same when measured using either PET of tracer levels of [11C]CFT binding or MRI. These results show great promise for the application of pharmacological MRI for application to studies of dopamine cell loss and potential recovery in Parkinson's disease.

Amphetamine↗
PubMed1999

Phospholipid-assisted refolding of an integral membrane protein. Minimum structural features for phosphatidylethanolamine to act as a molecular chaperone.

Escherichia coli-derived phosphatidylethanolamine (PE) or PE with fully saturated fatty acids was able to correct in vitro a defect in folding in the lipid-dependent epitope 4B1 of lactose permease (LacY) resulting from in vivo assembly in the absence of PE. PE plasmalogen, PE with two unsaturated fatty acids, and lyso-PE, which all do not favor bilayer organization, did not support proper refolding. Proper refolding occurred when these latter lipids were mixed with a bilayer-forming lipid (phosphatidylglycerol), which alone could not support refolding. L-Phosphatidylserine (PS; natural diastereomer) did support proper refolding. PE derivatives of increasing degrees of methylation were progressively less effective in supporting refolding, with phosphatidylcholine being completely ineffective. Therefore, the properties of nonmethylated aminophospholipids capable of organization into a bilayer configuration are essential for the recovery of the native state of epitope 4B1 after misassembly in vivo in the absence of PE. Neither D-PS (sn-glycero-1-phosphate backbone) nor P-D-S (D-serine in the head group) is competent in supporting proper refolding unless used in binary mixtures with phosphatidylglycerol. The detailed characterization of phospholipid-assisted refolding reported here further supports a specific rather than nonspecific role for PE in structural maturation of lactose permease in vivo (Bogdanov, M., and Dowhan, W. (1998) EMBO J. 17, 5255-5264).

Amines↗
PubMed1999

Reduction of post-traumatic brain injury and free radical production by inhibition of the caspase-1 cascade.

Necrotic and apoptotic cell death both play a role mediating tissue injury following brain trauma. Caspase-1 (interleukin-1beta converting enzyme) is activated and oligonucleosomal DNA fragmentation is detected in traumatized brain tissue. Reduction of tissue injury and free radical production following brain trauma was achieved in a transgenic mouse expressing a dominant negative inhibitor of caspase-1 in the brain. Neuroprotection was also conferred by pharmacological inhibition of caspase-1 by intracerebroventricular administration of the selective inhibitor of caspase-1, acetyl-Tyr-Val-Ala-Asp-chloromethyl-ketone or the non-selective caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone. These results indicate that inhibition of caspase-1-like caspases reduces trauma-mediated brain tissue injury. In addition, we demonstrate an in vivo functional interaction between interleukin-1beta converting enyzme-like caspases and free radical production pathways, implicating free radical production as a downstream mediator of the caspase cell death cascade.

Amino Acid Chloromethyl Ketones↗
PubMed1998

Phospholipid-assisted protein folding: phosphatidylethanolamine is required at a late step of the conformational maturation of the polytopic membrane protein lactose permease.

Previously we presented evidence that phosphatidylethanolamine (PE) acts as a molecular chaperone in the folding of the polytopic membrane protein lactose permease (LacY) of Escherichia coli. Here we provide more definitive evidence supporting the chaperone properties of PE. Membrane insertion of LacY prevents its irreversible aggregation, and PE participates in a late step of conformational maturation. The temporal requirement for PE was demonstrated in vitro using a coupled translation-membrane insertion assay that allowed the separation of membrane insertion from phospholipid-assisted folding. LacY was folded properly, as assessed by recognition with conformation-specific monoclonal antibodies, when synthesized in the presence of PE-containing inside-out membrane vesicles (IOVs) or in the presence of IOVs initially lacking PE but supplemented with PE synthesized in vitro either co- or post-translationally. The presence of IOVs lacking PE and containing anionic phospholipids or no addition of IOVs resulted in misfolded or aggregated LacY, respectively. Therefore, critical folding steps occur after membrane insertion dependent on the interaction of LacY with PE to prevent illicit interactions which lead to misfolding of LacY.

Antibodies, Monoclonal↗
PubMed1997

Excitability of neural elements within the rat corpus striatum.

The excitability of cholinergic, glutamatergic and dopaminergic elements within the rat neostriatum was studied in both in vivo and in vitro preparations. In vivo, the microdialysis technique was used to measure the release of striatal acetylcholine and dopamine under basal and electrically evoked conditions. For comparison, acetylcholine, dopamine and glutamate release was assayed in media obtained from superfused rat striatal slices. Electrical stimulation was used to derive the strength-duration functions and their chronaxies of stimulated elements containing the three neurotransmitter types. The chonaxies for experiments in vitro and in vivo were similar: the chronaxy values for elements containing acetylcholine were the shortest, the values for glutamate were intermediate, and the values for those containing dopamine were the longest. Based on the chronaxy estimates, it is proposed that the elements containing acetylcholine are the large cholinergic interneurons of striatum, and the elements containing glutamate and dopamine are the terminals of corticostriatal and nigrostriatal neurons, respectively. These results indicate that electrical stimulation of neural elements surrounding a microdialysis probe can be an additional tool to examine the factors that regulate neurotransmitter release. Likewise, investigators can activate specific striatal elements by using pulse durations that coincide with their chronaxies.

Acetylcholine↗
PubMed1997

Detection of dopaminergic neurotransmitter activity using pharmacologic MRI: correlation with PET, microdialysis, and behavioral data.

The metabolic activation resulting from direct dopaminergic stimulation can be detected using auto-radiography, positron emission tomography (PET) or, potentially, fMRI techniques. To establish the validity of the latter possibility, we have performed a number of experiments. We measured the regional selectivity of two different dopaminergic ligands: the dopamine release compound D-amphetamine and the dopamine transporter antagonist 2 beta-carbomethoxy-3 beta-(4-fluoropheny) tropane (CFT). Both compounds led to increased signal intensity in gradient echo images in regions of the brain with high dopamine receptor density (frontal cortex, striatum, cingulate cortex > > parietal cortex). Lesioning the animals with unilaterally administered 6-hydroxydopamine (6-OHDA) led to ablation of the phMRI response on the ipsilateral side; control measurements of rCBV and rCBF using bolus injections of Gd-DTPA showed that the baseline rCBV and rCBF values were intact on the lesioned side. The time course of the BOLD signal changes paralleled the changes observed by microdialysis measurements of dopamine release in the striatum for both amphetamine and CFT; peaking at 20-40 min after injection and returning to baseline at about 70-90 min. Signal changes were not correlated with either heart rate, blood pressure or pCO2. Measurement of PET binding in the same animals showed an excellent correlation with the phMRI data when compared by either measurements of the number of pixels activated or percent signal change in a given region. The time course for the behavioral measurements of rotation in the 6-OHDA lesioned animals correlated with the phMRI. These experiments demonstrate that phMRI will become a valuable, noninvasive tool for investigation of neurotransmitter activity in vivo.

Adrenergic Agents↗
PubMed1996

A phospholipid acts as a chaperone in assembly of a membrane transport protein.

A mutant of Escherichia coli lacking phosphatidylethanolamine (PE) and a monoclonal antibody (mAb 4B1) directed against a conformationally sensitive epitope (4B1) of lactose permease were used to establish a novel role for a phospholipid in the assembly of a membrane protein. Epitope 4B1 is readily detectable in spheroplasts and right-side-out membrane vesicles from PE-containing but not from PE-deficient cells expressing lactose permease. Lactose permease from PE-containing membranes, but not from PE-deficient membranes, subjected to sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis and Western blot analysis is also recognized by mAb 4B1. If total E. coli phospholipids or PE (but not phosphatidylcholine, phosphatidylglycerol, or cardiolipin) are blotted on nitrocellulose sheets (Eastern blot) prior to transfer of proteins from SDS-polyacrylamide gels, the permease from PE-deficient cells regains its recognition by mAb 4B1. Therefore, PE is required during assembly to form epitope 4B1, but, once formed, sufficient "conformational memory" is retained in the permease to either retain or reform this epitope in the absence of PE. Lactose permease lacking epitope 4B1 can be induced to form the epitope if partially denatured and then renatured in the presence of PE specifically. These results establish for the first time a role for PE as a molecular chaperone in the assembly of the lactose permease.

Antibodies, Monoclonal↗
PubMed1995

Phosphatidylethanolamine is required for in vivo function of the membrane-associated lactose permease of Escherichia coli.

Experiments with mutant Escherichia coli cells lacking phosphatidylethanolamine (PE) as a membrane component (DeChavigny, A., Heacock, P. N., and Dowhan, W. (1991) J. Biol. Chem. 266, 5323-5332) were carried out to establish whether or not PE is necessary for full function of the lac permease in vivo. The Vmax for active transport of both lactose (in cells lacking beta-galactosidase, lacZ) and the unhydrolyzable lactose analog, methyl-beta-D-galactopyranoside (TMG), by mutant cells lacking PE was reduced 5-10-fold relative to cells containing PE, while the Km for the uptake of both substrates was the same in both types of cells. The low rate of TMG and lactose uptake by PE-deficient cells was unaffected by the presence of a protonophore (uncoupler) and for TMG uptake was on the order of the greatly reduced rate of uptake in uncoupler-treated cells containing PE. The rate of entry of lactose into lacZ+ derivatives of both types of cells, as a measure of facilitated diffusion, was nearly the same. The Km for lactose (lacZ cells) and TMG transport in PE-deficient cells was unaffected by the presence of an uncoupler which had a small effect on Vmax. In PE-containing cells these kinetic parameters for TMG transport were reduced by an uncoupler to the level found with PE-deficient cells while an uncoupler reduced lactose uptake by PE-containing (lacZ) cells to below measureable levels. Inverted membrane vesicles made from both types of cells could be loaded with TMG, but energizing TMG-loaded vesicles by ATP only induced rapid, uphill, permease-dependent efflux of TMG from PE-containing vesicles. The decrease in apparent active transport activity of cells with no PE was not due to a change in membrane permeability, to a reduced delta microH+ (proton electrochemical gradient) across the cell membrane, or to a reduced level of membrane-associated lac permease protein. These results suggest that in the absence of PE the lac permease cannot couple substrate uptake to delta microH+ in order to effect accumulation of substrate and as a result only carries out facilitated diffusion.

Biological Transport, Active↗
PubMed1993

Effects of systemic nicotine on serotonin release in rat brain.

We used in vivo microdialysis to examine the acute effects of systemically administered nicotine (0.8-8.0 mg/kg, s.c.) on extracellular levels of serotonin (5-HT) in the frontal cortex of awake rats and animals anesthetized with chloralose/urethane. In anesthetized animals, 5-HT efflux was elevated during the initial 15 min after nicotine administration (2-8 mg/kg), but then returned to baseline values. All of the effective nicotine doses also lowered and then raised blood pressure in these animals. However, other drugs which raised (methoxamine, 0.07 mg/kg, i.v.) or lowered (mecamylamine, 5 mg/kg, i.p.) blood pressure without directly activating nicotinic receptors failed to alter 5-HT release. Moreover, pretreatment with a centrally active dose of mecamylamine, a known nicotinic antagonist, blocked the effects of nicotine (4 mg/kg) on 5-HT release. For studies on awake rats the perfusion fluid also contained fluoxetine, since basal 5-HT levels were barely detectable without this uptake blocker. In such animals, 1.6 mg/kg of nicotine significantly increased 5-HT release, an effect apparent in the initial 20 min after treatment and persisting for at least 2 h. These observations demonstrate that systemically administered nicotine increases frontocortical 5-HT release, that this effect is independent of the cardiovascular responses to the drug, and that it probably results from the activation of previously described nicotinic receptors on raphe neurons. The present findings are consistent with the hypothesis that the appetitive and mood disturbances associated with nicotine withdrawal may be mediated by diminished serotoninergic transmission.

Anesthetics↗
PubMed1993

The pss and psd genes are required for motility and chemotaxis in Escherichia coli.

Mutants of Escherichia coli defective in phosphatidylserine synthase (encoded by pss) and phosphatidylserine decarboxylase (encoded by psd) make cell membranes deficient in phosphatidylethanolamine. In this report we show that wild-type pss and psd genes are required for motility and chemotaxis. Null mutants or strains with temperature-sensitive pss or psd mutations grown at high temperature (35 degrees C) were nonmotile. They lacked flagella and showed reduced rates of transcription of the flhD master operon (encoding FlhD and FlhC), the fliA operon (encoding sigma F), and the fliC operon (encoding flagellin). At low temperature (25 degrees C), the temperature-sensitive mutant cells showed motility and chemotaxis but at reduced levels. The extent of the motility and chemotaxis defects in the mutants was correlated with the amount of phosphatidylethanolamine in the membranes, suggesting a link between membrane phospholipid composition and expression of the flagellum chemotaxis regulon.

Bacterial Proteins↗
PubMed1979

[Induction of synchronized labor on commercial swine farm complexes with the synthetic prostaglandin F2 alpha analog, cloprostenol].

Experiments were carried out under conditions existing in industrial swine complexes with two groups of experimental sows: I group -- consisting of 17 sows injected on the 108th and 109th day of pregnancy with 175 g cloprostenol, and II group -- consisting of 145 sows injected on the 110th, 111th, 112nd and 113th day of pregnancy. On 125 sows of 110--111 day of pregnancy a reduced single dose application of 150 g cloprostenol was tested. Studies were performed on the period to farrowing following cloprostenol injection, the duration of farrowing, the changes in physiological behaviour, the number of viable and unviable new born piglets, the results following weaning of offspring at the age of 28 days and on the economic evaluation of the technology of forced synchronized and programmated farrowing in industrial swine complexes. It was established that the synthetic analogue of prostaglandine F2L (cloprostenol) applied once by intramuscular injection at a rate of 175 g per sow on the 110--113th day of pregnancy has a luteinizing effect and leads to forced synchronized farrowing of 75--80% of the sows, 27 +/- 5 h post treatment. Similar results were obtained by a reduced rate of 150 g cloprostenol. Synchronized farrowing provides an opportunity for simultaneous weaning of equated piglet groups and contributes for better labour organization and veterinary service. Shortening the pregnancy period below the 110th day is not feasible physiologically and economically.

Animals↗