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F Fonnum

Publications and source records attributed to F Fonnum.

At least 73 records · Page 4Linked to original sources
PubMed1993

Effect of pyridostigmine pretreatment, HI-6 and Toxogonin treatment on rat tracheal smooth muscle response to cholinergic stimulation after organophosphorus inhalation exposure.

The ex vivo contraction response of the rat tracheal smooth muscle was examined after 10 min in vivo inhalation of soman and/or pretreatment with pyridostigmine and/or post-exposure treatment with HI-6 ([[[(4-aminocarbonyl)pyridinio]methoxy]methyl]-2[(hydroxy imino) methyl]pyridinium dichloride) or Toxogonin (1,1'-[oxybis-(methylene)]bis[4-[(hydroxyimino)methyl]-py rid inium] dichloride). In vivo pretreatment with pyridostigmine was achieved by subcutaneous (s.c.) implantation of an osmotic pump that delivered pyridostigmine continuously (0.01 mg/h) in the neck region of the rat 18 h before soman exposure. The ex vivo cholinergic tracheal smooth muscle response increased during the first 60 min after soman exposure in animals pretreated with pyridostigmine. The amplitude of the contraction response in pyridostigmine pretreated animals was about 60% of control, compared to 15% of control without pyridostigmine pretreatment. Pyridostigmine pretreatment also produced significant recovery of the total cholinesterase (ChE) activity in plasma, but not in trachea and lung. Intraperitoneal (i.p.) injection of HI-6 or Toxogonin (50 mg/kg), immediately after 10 min inhalation exposure to soman, also significantly improved the ex vivo cholinergic contraction response of the trachea (decapitation 15 min after oxime administration). The recovery of the physiological response with Toxogonin was, however, not stable. HI-6 was superior to Toxogonin with respect to the initial airway contraction response, and the response increased up to a stable level not significantly different from control. There was no significant reactivation of the ChE activity after treatment with the oximes. Combination of pyridostigmine pretreatment and oxime treatment enhanced the recovery of the tracheal contraction response and the ChE activity in the trachea compared to treatment with oximes alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗
PubMed1993

Effect of toxin of Prymnesium patelliferum on neurotransmitter transport mechanisms: development of a sensitive test method.

A crude extract of the ichthyotoxic phytoflagellate Prymnesium patelliferum strongly inhibited the uptake of neurotransmitters into isolated nerve endings (synaptosomes) and synaptic vesicles. These systems were about 100 and 10 times more sensitive toward the algal toxin, respectively, than a standard hemolysis assay often used for testing the toxicity of Prymnesium spp. and other ichthyotoxic algae. Prymnesium patelliferum grown in phsophorus-deficient (-P) medium was about five times more active than when grown in phosphorus sufficient (+P) medium. The inhibition ratio between the high-affinity synaptosomal uptake of L-glutamate and gamma-aminobyturic acid (GABA) was 1/2.7 for the -P culture and 1/1.9 for the +P culture. The inhibition ratios for the low-affinity vesicular uptake of L-glutamate, GABA, and dopamine (DA) were 1/5.8/0.3 and 1/1.7/0.2, respectively. The synaptosomal transport of L-glutamate is a rapid, simple, and sensitive test method for toxicity determination of Prymnesium spp. and will be a useful tool in the further isolation and purification of the toxic principles of this and other related algae. It is suggested that the toxin interferes with ion channels or acts as an ionopore.

Animals↗
PubMed1993

NMR spectroscopic studies of 13C acetate and 13C glucose metabolism in neocortical astrocytes: evidence for mitochondrial heterogeneity.

Neocortical astrocytes were incubated with 13C-labeled substrates to determine metabolic pathways. 13C NMR spectroscopy was used to analyze 13C incorporation into glutamine and citrate from the different precursors--[1-13C]glucose or [2-13C]acetate. When glucose was the labeling substrate, incorporation due to pyruvate carboxylation should be observed in the C-2 position in glutamine and the C-4 position in citrate. A large incorporation due to pyruvate carboxylation was observed in glutamine in the C-2 and C-3 positions, but not in citrate. When acetate was the precursor, the labeling ratios in the C-2/C-4 positions in glutamine and in the equivalent positions in citrate were 0.27 and 0.11, respectively. Moreover, acetate labeled lactate in the C-2 position much less than did glucose. Altogether, these observations led to the conclusion that glutamine precursors and citrate are either produced in different types of astrocytes or in different tricarboxylic acid cycles, situated in functionally different mitochondria in the same cell, and that in all likelihood pyruvate carboxylase is expressed differently in these mitochondria.

Acetates↗
PubMed1992

Heterogeneity of carboxylesterases in rat liver cells.

Rat liver cells were separated into parenchymal cells (PC), Kupffer cells (KC) and endothelial cells (EC). The distribution of carboxylesterases (EC 3.1.1.1) between these cell types was investigated by PAGE and chromatogenic substrate staining, and compared with the results for total liver preparation and individual isoenzymes isolated by chromatofocusing. All of the liver carboxylesterase isoenzymes could be detected in the PC, whereas in both KC and EC only those with isoelectric point (pI) 6.4/6.2 could be detected. Use of carboxylesterase inhibitors like bis-(4-nitrophenyl)phosphate and paraoxon, and organophosphorus compound hydrolase inhibitors like 4-hydroxymercuribenzoate and EDTA confirmed that these esterases were of the carboxylesterase type.

Animals↗
PubMed1992

Changes in neurotransmitter parameters in the brain induced by L-cysteine injections in the young rat.

A single subcutaneous injection of L-cysteine (1.2 mg/g body wt.) to 4-day-old rats leads to atrophy of the brains examined 27-31 days later. The brains could be separated into two groups (type 1 and 2) on account of the degree of atrophy. Type-1 lesion, with a brain weight reduction of 20%, was dominated by a severe reduction in high-affinity uptake of L-glutamate in CNS regions receiving corticofugal fibers such as thalamus and striatum. Glutamate decarboxylase was only reduced in cortical structures. In type-2 lesion, with a severe brain atrophy of about 50%, high-affinity glutamate uptake was further reduced and there was a more pronounced reduction in glutamate decarboxylase activity in several brain regions. Cholinergic neurons were less affected by the lesion and the levels of choline acetyltransferase showed a relative increase in brain regions which partly compensated for their reduction in size.

Acetylcholine↗
PubMed1992

Selective inhibition of glial cell metabolism in vivo by fluorocitrate.

The effect of fluorocitrate on glial and neuronal amino acid metabolism was studied. One nmol of fluorocitrate administered intrastriatally in the rat caused a 95% reduction of glutamine formation from [14C]acetate, a substrate which enters the glial cells selectively. The metabolism of [14C]glucose which enters neurons, was unaffected by fluorocitrate treatment except for the glutamine formation. This is evidence that fluorocitrate is a selective inhibitor of the glial Krebs' cycle. [14C]Citrate and 2-oxoglutarate labelled amino acids in a manner similar to [14C]acetate, which shows that these substrates are taken up and metabolized by glial cells. Differences in the labelling of gamma-aminobutyric acid (GABA) from [14C]acetate and citrate suggest that astrocytes associated with GABAergic and glutamatergic nerve terminals may differ in their preference for amino acid precursors.

Acetates↗
PubMed1992

Inhibition of L-glutamate uptake into synaptic vesicles.

The effects of different agents similar in structure to glutamate were tested for inhibition of the vesicular uptake of L-glutamate. Kainate and L-homocysteate turned out to be non-competitive inhibitors of the L-glutamate uptake. Kainate was not taken up by the vesicle fraction. The vesicular uptake of gamma-aminobutyric acid (GABA) was also inhibited by kainate and L-homocysteate. Kynurenate, on the other hand, strongly inhibited the uptake of L-glutamate, whereas the uptake of GABA was hardly affected. L-alpha-Aminoadipate and D-glutamate inhibited the uptake of L-glutamate, whereas L- and D-aspartate and L-cysteate only weakly inhibited the uptake of L-glutamate. GABA, glycine, L-serine and taurine did not inhibit the uptake of L-glutamate.

Amino Acids↗
PubMed1992

The ontogeny of the uptake systems for glutamate, GABA, and glycine in synaptic vesicles isolated from rat brain.

The ontogeny of the uptake of glutamate, GABA and glycine into synaptic vesicles isolated from rat brain has been investigated. The vesicular uptake of the three amino acids increased with developmental age in parallel with synaptogenesis, indicating a functional role of uptake of the amino acids by synaptic vesicles in the nerve terminals. Uptake of the amino acids by plasma membrane particles (synaptosomes) in brain homogenate showed a somewhat different developmental profile. The uptake of glutamate increased markedly with developmental time, while the uptake of GABA showed only a slight increase. Uptake of glycine by plasma membrane particles was very low and therefore not registered. The observed developmental increase in uptake of glycine by synaptic vesicles isolated from brain, supports previous reports indicating that glycine can be taken up by vesicles from non-glycine terminals.

Adenosine Triphosphate↗
PubMed1992

Differential rearing conditions in rats: effects on neurochemistry in neocortical areas and cognitive behaviors.

Previous studies have shown that environmental factors can influence several aspects of the central nervous system that are associated with behavioral changes. In the present study, an attempt was made to investigate how cholinergic and glutamergic transmission systems in neocortical areas might respond to differential rearing conditions and how potential neurochemical changes might be accompanied by alterations in behavior. The results show that only glutamergic levels in the lateral entorhinal cortex (LEC) responded to differential environmental stimulation. The levels of glutamergic activity in LEC correlated significantly with learning and retention of a visual discrimination task and total time exploring objects in a novelty test. A comparatively complex pattern of neurochemical relations was seen in terms of differences across brain structures and hemispheres for both glutamergic and cholinergic activity. The results are interpreted as supporting the glutamergic hypothesis of Alzheimer's disease.

Acetylcholine↗
PubMed1991

The ontogeny of the uptake systems for glycine, GABA and glutamate in synaptic vesicles isolated from rat spinal cord-medulla.

Synaptic vesicles have been isolated from rat spinal cord-medulla at different postnatal ages, and the ontogeny of the uptake of glycine, gamma-aminobutyric acid (GABA) and glutamate has been investigated. The accumulation of the 3 amino acids increased with increasing time after birth reaching adult level at about postnatal day 30. This developmental increase probably parallels the synaptogenesis and suggests a functional role of the uptake of the amino acids into synaptic vesicles in the nerve terminals. The developmental time course for these vesicular uptake systems was totally different from those of the corresponding plasma membrane uptakes.

Aging↗
PubMed1991

Carboxylesterases in guinea pig. A comparison of the different isoenzymes with regard to inhibition by organophosphorus compounds in vivo and in vitro.

The different isoenzymes of carboxylesterase (CarbE) from guinea pig liver, lung and plasma were separated by gel filtration and chromatofocusing. The isoenzymes were characterized by inhibition with several different organophosphorus compounds. The bimolecular rate constants showed the same tendency of decreased inhibition for all of the isoenzymes in the order; paraoxon greater than soman greater than diisopropylphosphofluoridate (DFP) greater than bis(p-nitrophenyl)phosphate. With two exceptions the inhibition constants for the different isoenzymes differed little. Subcutaneous and intraperitoneal administration of DFP and paraoxon rapidly inhibited the CarbE activity in guinea pig plasma. Much higher doses were necessary to obtain a marked inhibition in lung and liver. About 25% of CarbE activity in lung was resistant to paraoxon and DFP inhibition. Gel filtration of lung homogenate after treatment with the organophosphorus compounds showed that the CarbE activity of the medium molecular mass fractions was inhibited only weakly. This could be due to reduced accessibility to some of the lung CarbE isoenzymes.

Animals↗
PubMed1991

Uptake of glycine, GABA and glutamate by synaptic vesicles isolated from different regions of rat CNS.

Synaptic vesicle fractions have been isolated from cerebral cortex, subcortical telencephalon, whole brain and spinal cord by density gradient centrifugation. The Mg2+ ATP-dependent vesicular uptake and the Na(+)-dependent synaptosomal uptake of glycine, GABA and L-glutamate has been compared in the different regions. All these regions contain GABA as inhibitory neurotransmitter, whereas glycine only plays a dominant role as such in the spinal cord. The ratio between GABA and glycine uptake in the different vesicle fractions was similar, and the ratios differed greatly from the ratios in the synaptosomal uptake. In contrast, the ratio between glutamate and GABA uptake in vesicles from different regions differed, and these ratios corresponded to the ratios in the synaptosomal uptake. These results indicate that glycine is taken up into synaptic vesicles from non-glycine terminals, and we suggest that GABA and glycine can be taken up into the same vesicle population.

Adenosine Triphosphate↗
PubMed1991

Effect of AH5183 (vesamicol) on cholinergic transmission in intact airway smooth muscle.

The effect of the vesicular acetylcholine (ACh) transport blocker trans-2-(4- phenyl-piperidino)-cyclohexanol (AH5183) was studied in bronchial smooth muscle during activation of the vagus nerve. AH5183 inhibited in a dose-dependent manner the Ca(2+)-sensitive electrically induced smooth muscle contractions in vitro with a half-inhibitory concentration (IC50) of 1.6 +/- 0.4 microM. The inhibition was complete within 68 +/- 1 min (n = 8) at approximately 20 microM AH5183 and was partly reversible after washing of the preparations. AH5183 (20 microM) reduced the level of endogenous ACh by 47.4 +/- 7.6% (n = 4) during this time period. The effect of AH5183 is most likely prejunctional, since the contractions induced post-junctionally by carbachol were not altered by AH5183. The irreversible anticholinesterase, soman, increased the tonus of airway smooth muscle as a result of accumulation of spontaneously released ACh from prejunctional leakage. AH5183 had no effect on this increase of muscle contraction. The present results show that the nerve-evoked release of ACh comes from an AH5183-sensitive pool, probably a vesicular pool, whereas leakage of ACh presumably comes from the cytoplasmic pool in airway smooth muscle.

Acetylcholine↗
PubMed1991

Transport of gamma-aminobutyrate and L-glutamate into synaptic vesicles. Effect of different inhibitors on the vesicular uptake of neurotransmitters and on the Mg2(+)-ATPase.

The uptakes of gamma-aminobutyrate (GABA) and L-glutamate into synaptic vesicles isolated from rat brain were compared with respect to the effects of 4-acetamido-4'-isothiocyanostilbene-2,2'- disulphonic acid (SITS), 4,4'-di-isothiocyanostilbene-2,2'-disulphonic acid (DIDS) and 5-nitro-2-(3-phenylpropylamino)benzoic acid (N144), agents known to block anion channels. The uptake of glutamate was inhibited by low micromolar concentrations of SITS, DIDS and N144. GABA uptake was much less sensitive to these agents than was glutamate uptake. SITS and N144 inhibited the vacuolar H(+)-ATPase of synaptic vesicles to a smaller extent than the glutamate uptake. The uptake of GABA was not affected by the permeant anions Cl- and Br-, whereas the uptake of glutamate was highly stimulated by low concentrations of these ions. The uptakes of both glutamate and GABA were inhibited by similar, but not identical, concentrations of the lipophilic anion SCN-.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1991

Inhibition of gamma-aminobutyrate and glycine uptake into synaptic vesicles.

The substrate specificity of vesicular GABA and glycine uptake was studied in vesicle fractions from brain and spinal cord, respectively. Glycine, beta-alanine and gamma-vinyl-GABA were competitive inhibitors of the GABA uptake were competitive inhibitors of the GABA uptake by synaptic vesicles in brain. Likewise GABA and beta-alanine turned out to be competitive inhibitors of vesicular uptake of glycine in spinal cord. The apparent K1 values were in the same range as the respective Km values for the transport systems. Accumulation of different amino acids were examined, and the structurally related amino acids GABA, beta-alanine and glycine were all taken up by both vesicle fractions. In the present study, we suggest that there are similarities in the vesicular transporters for GABA and glycine, and the two amino acids are probably taken up into the same vesicle population. The key factor in differentiating between GABA and glycine as transmitters in the terminals could be the synthesis and the high-affinity synaptosomal uptake.

Alanine↗
PubMed1991

Purification and characterization of carboxylesterases from rat lung.

Carboxylesterase (EC 3.1.1.1) has played an important part in our understanding of the toxicokinetic behaviour of the organophosphorus cholinesterase inhibitors. Carboxylesterases are a heterogeneous group of enzymes that can be separated on the basis of their isoelectric points and by their substrate-specificity. We have purified the isoenzyme (pI 5.8) present in greatest activity in rat lung to near homogeneity. The enzyme was purified by (NH4)2SO4 precipitation, gel filtration, chromatofocusing, separation on anion- and cation-exchangers and hydrophobic-interaction chromatography. The purified enzyme has a molecular mass of approx. 180 kDa with subunits of 60 kDa. The substrate and inhibitor specificities of the enzyme have been characterized. Edman degradation revealed the first 19 amino acid residues of the enzyme. The N-terminus was found to be tyrosine. Inhibition of the enzyme by organophosphorus compounds differed greatly from that of cholinesterases, despite the partial analogy at the N-terminal region.

Acetylcholinesterase↗