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Biomedical subjects

B Ault

Publications and source records attributed to B Ault.

At least 37 records · Page 2Linked to original sources
PubMed1990

The role of altered sodium currents in action potential abnormalities of cultured dorsal root ganglion neurons from trisomy 21 (Down syndrome) human fetuses.

Trisomy 21 (Down syndrome) results in abnormalities in electrical membrane properties of cultured human fetal dorsal root ganglion (DRG) neurons. Action potentials have faster rates of depolarization and repolarization, with decreased spike duration, compared to diploid neurons. In order to analyze the faster depolarization rate observed in trisomic neurons, we examined sodium currents of cultured human fetal DRG neurons from trisomy 21 and control subjects, using the whole-cell patch-clamp technique. The neurons were replated in culture to reduce dendritic spines. Two components of the sodium current were identified: (1) a fast, tetrodotoxin (TTX)-sensitive current; and (2) a slow, TTX-resistant component. The inactivation curves of both current types in trisomic neurons showed a shift of approximately 10 mV towards more depolarized potentials compared to control neurons. Thus, whereas essentially all of the fast sodium channels were inactivated at normal resting potentials in control neurons, approximately 10% of these channels were available for activation in trisomy 21 cells. Furthermore, the fast current showed accelerated activation kinetics in trisomic neurons. The slow sodium current of trisomic neurons showed slower deactivation kinetics than control cells. No differences were observed between trisomic and control neurons in the maximal conductance or current densities of either fast or slow current components. These data indicate that the greater rate of depolarization in trisomy 21 neurons at resting potentials is primarily due to activation of residual fast sodium channels that also have a faster time course of activation.

Action Potentials↗
PubMed1990

Replating improves whole cell voltage clamp recording of human fetal dorsal root ganglion neurons.

The whole cell patch clamp technique allows recording of membrane currents in an entire cell under voltage clamp conditions. However, technical difficulties arise in large cells bearing extensive processes, such as human fetal dorsal root ganglion (DRG) neurons in culture. In order to improve space clamp conditions, human fetal DRG neurons cultured for 1-2 weeks were enzymatically detached and replaced in new dishes, yielding round or oval cells with absent or short processes at 24 h in culture. Current clamp recordings demonstrated no difference in action potential parameters of the replated cells compared to control non-replated cells. Analysis of passive properties showed a reduction of 40% in mean specific membrane capacitance and a 57% increase in mean specific membrane resistance in the replated cells, consistent with the decrease of cell membrane surface area. Whole cell voltage clamp studies demonstrated great improvement of the space clamp, indicating that more efficient voltage clamp conditions can be achieved in neurons in culture by eliminating neurites through replating.

Down Syndrome↗
PubMed1989

Electrophysiological analysis of cultured fetal mouse dorsal root ganglion neurons transgenic for human superoxide dismutase-1, a gene in the Down syndrome region of chromosome 21.

Our recent whole cell patch-pipette studies have shown that human trisomy 21 (Down syndrome) cultured fetal dorsal root ganglion (DRG) neurons have accelerated rates of action potential depolarization and repolarization, with reduced spike duration, compared to control neurons. Similar observations were made using DRG neurons from the trisomy 16 mouse, an animal model of trisomy 21. In this study we have used transgenic mice in order to investigate the relationship between excess gene dosage and neurophysiological abnormalities. DRG neurons which possessed additional copies of the gene for human superoxide dismutase-1 (SOD), a gene from the Down syndrome region of chromosome 21, were compared to normal neurons. No electrophysiological differences were found between the two groups of neurons, indicating that increased dosage of the SOD gene alone is not causal to action potential dysfunction found in trisomy 21 and trisomy 16 neurons.

Animals↗
PubMed1989

Neurophysiological abnormalities in cultured dorsal root ganglion neurons from the trisomy-16 mouse fetus, a model for Down syndrome.

The trisomy-16 mouse is considered to be a model of human trisomy-21 (Down syndrome). We have examined the electrical membrane properties of cultured dorsal root ganglion (DRG) neurons from normal and trisomy-16 fetuses. Trisomy-16 neurons had significantly accelerated rates of action potential depolarization and repolarization compared to diploid neurons, resulting in decreased spike duration. These changes match those reported in human trisomy-21 DRG neurons. Such abnormalities may contribute to the mental retardation characteristic of Down syndrome.

Action Potentials↗
PubMed1987

Pro-convulsant actions of theophylline and caffeine in the hippocampus: implications for the management of temporal lobe epilepsy.

The pro-convulsant actions of theophylline and caffeine have been investigated using the hippocampal slice preparation and rats administered kainic acid or Metrazol. Both theophylline and caffeine induced the generation of epileptiform activity in the CA3 region of the hippocampal slice with convulsive dose50 (CD50) values of 3 microM respectively. Kainic acid-induced bursting in hippocampal slices was enhanced by theophylline (0.3-30 microM) and caffeine (1-100 microM). Theophylline induced burst firing in response to electrical stimulation in hippocampal area CA3 but not area CA1. Theophylline (50 mg/kg) strongly potentiated the effect of the limbic convulsant kainic acid in vivo whilst a dose of 200 mg/kg was necessary to significantly lower the threshold dose of Metrazol required to induce generalized convulsions. We conclude that alkylxanthines, probably by antagonizing the effect of endogenous adenosine, exert a pro-convulsant action in the hippocampus which preferentially promotes limbic seizures.

Animals↗
PubMed1987

L-proline depolarizes rat spinal motoneurones by an excitatory amino acid antagonist-sensitive mechanism.

1 Isolated spinal cords prepared from neonatal rats were used to examine the effects of L-proline (L-Pro). 2 L-Pro (1-8 mM) depolarized ventral and dorsal roots in a dose-dependent manner with one sixth of the potency of L-glutamate (L-Glu). L-Pro was four times more potent than D-Pro. Prolonged application of L-Pro produced a plateau depolarization of motoneurones with no apparent fade. 3 Omission of calcium ions from the medium potentiated the depolarizing actions of L-Pro, L-Glu and quisqualate. 4 L-Pro was antagonized by concentrations of 2-amino-5-phosphonovalerate (25 microM), gamma-D-glutamylglycine (100 microM) and Mg2+ ions (1 mM) that depressed responses to N-methyl-D-aspartate (NMDA). The NMDA receptor-mediated component of the response to L-Pro was estimated to be 60-70%. 5 These data suggest that L-Pro should be considered as a possible excitatory neurotransmitter and that, because L-Pro is a neutral compound, excitatory amino receptors may not require an agonist to possess two anionic groups and one cationic group.

Amino Acids↗
PubMed1986

Baclofen suppresses bursting activity induced in hippocampal slices by differing convulsant treatments.

Epileptiform activity was induced in area CA3 of hippocampal slices by superfusion of medium containing 50 microM bicuculline and 3.5 mM K, 50 microM bicuculline and 5 mM K, 50 nM kainic acid and 3.5 mM K, or 7 mM K. Burst potentials were recorded at rates between 5 and 44/min, depending on the convulsant treatment. Baclofen reduced the frequency of burst firing in all slices tested in a dose-dependent manner, with little change in the morphology of individual bursts. Thus baclofen primarily affected the initiation of epileptiform discharges. IC50 values varied between 27 and 500 nM and were positively correlated with the rate of bursting. These experiments indicate that baclofen, at concentrations present in the CSF of patients treated for spasticity, has an anticonvulsant-like effect in the hippocampal formation and suggest that its mode of action is to reduce the excitability of pyramidal cells.

Action Potentials↗
PubMed1986

Comparison of seizures and brain lesions produced by intracerebroventricular kainic acid and bicuculline methiodide.

Intracerebroventricular kainic acid produces in rats brain lesions similar to Ammon's horn sclerosis in humans. To test the hypothesis that these lesions result indirectly from prolonged seizure activity and not from a direct action of kainic acid on the neurons that are destroyed, the effects of intracerebroventricular kainic acid and bicuculline methiodide were compared. Although bicuculline methiodide seizures differed dramatically from kainic acid seizures, both electrographically and behaviorally, the resulting brain lesions were similar for a given total limbic seizure duration. These results, in combination with other data, support the view that lesions made by intracerebroventricular administration of convulsants are indeed caused by prolonged limbic seizures. The total duration of seizure activity appears to be one important variable.

Animals↗
PubMed1986

Adenosine inhibits epileptiform activity arising in hippocampal area CA3.

The ability of adenosine and structurally-related compounds to inhibit epileptiform activity induced by bicuculline in the CA3 region of the hippocampal slice of the rat was examined. Bath application of all purinoceptor agonists tested reduced the frequency of generation of burst potentials. Analysis of dose-response curves yielded the following IC50 values: adenosine, 1.5 microM; 2-chloroadenosine, 0.144 microM; 5'-(N-ethyl)carboxamidoadenosine, 30.2 nM; L-phenylisopropyladenosine, 12.1 nM; cyclohexyladenosine, 7.9 nM. Theophylline (30 microM) increased the rate of bursting and antagonized the effect of exogenous adenosine. Dipyridamole (0.03-1 microM) reduced the occurrence of burst firing. In slices untreated with bicuculline, theophylline (30 microM) and adenosine deaminase (10 micrograms ml-1) induced bursting activity. These results demonstrate that purinoceptor agonists can suppress epileptiform activity in the hippocampus and suggest that adenosine may act as an endogenous anticonvulsant.

Adenosine↗
PubMed1986

Baclofen suppresses hippocampal epileptiform activity at low concentrations without suppressing synaptic transmission.

Baclofen is used clinically to treat spasticity, but has received little attention as a potential antiepileptic agent. To explore the antiepileptic potential of baclofen further, we tested its effect on stimulus train-induced bursting, an in vitro model of hippocampal epileptiform activity. In hippocampal slices prepared from male rats, extracellular field potentials were recorded in stratum pyramidale of CA3, and electrical stimuli were delivered to s. radiatum of CA3. After stable responses to single stimuli were established, stimulus trains were delivered every 5 min until stable triggered and spontaneous population bursting were elicited. (+/-)-Baclofen was bath-applied to the slices at varying concentrations to study its ability to suppress synaptic transmission and epileptiform activity. EC50 values for suppression of orthodromic population spike amplitude, of triggered burst duration and of spontaneous burst frequency were 2300, 355 and 26.9 nM, respectively; all statistically significantly different. These findings suggest that baclofen suppresses epileptiform electrical activity in the hippocampus at concentrations well below those which suppress normal synaptic transmission, and support renewed consideration of baclofen as an antiepileptic agent.

Animals↗
PubMed1986

Efficacy of baclofen and phenobarbital against the kainic acid limbic seizure-brain damage syndrome.

Baclofen and phenobarbital were tested for anticonvulsant efficacy against limbic seizures produced by i.c.v. infusion of kainic acid (KA) in unanesthetized rats. All rats treated with KA alone developed a prolonged status epilepticus associated with extensive neuronal degeneration. When administered immediately after the KA infusion, baclofen (5 mg/kg i.p.) protected five of six animals against the development of status epilepticus and did not alter the behavioral expression of the residual discrete electrographic seizures. Phenobarbital (40 mg/kg i.p.) given 15 min before KA also prevented the development of status epilepticus in five of six rats, but blocked the behavioral expression of the residual electrographic seizures. In two of five additional rats, baclofen prevented or reversed status epilepticus when administered 50 to 60 min after the end of the KA infusion. The ability of these drugs to prevent KA-induced neuronal degeneration correlated with their anticonvulsant action.

Animals↗
PubMed1983

Anticonvulsant-like actions of baclofen in the rat hippocampal slice.

1 The effects of baclofen were tested on epileptiform discharge in the rat hippocampal slice. Slices were superfused with bicuculline methiodide (100 microM) and maximal periods of afterdischarge were evoked by stimulating the Schaffer collateral-commissural pathway in area CA1, mossy fibres in area CA3 or perforant path fibres in the fascia dentata or by antidromic stimulation of CA1 pyramidal cells. 2 (-)-Baclofen attenuated the afterdischarge evoked by stimulating all three sets of fibres in areas CA1 and CA3. In each case, a threshold effect was observed at a concentration of 0.25 or 0.5 microM, and complete suppression was usually attained with a concentration of 5 microM. EC50 values ranged between 1 and 2 microM. (-)-Baclofen attenuated hippocampal afterdischarge with 120 times the potency of (+)-baclofen. It did not, however, affect the repetitive firing of dentate granule cells in response to stimulation of perforant path fibres. 3 (-)-Baclofen also reduced the amplitude of the initial population spike evoked by stimulation of Schaffer collateral-commissural fibres, but did not affect the antidromic population spike nor the initial population spike evoked by stimulation of the mossy fibres. 4 Recurrent inhibition in area CA1 was abolished by 1 microM (-)-baclofen. Thus baclofen, unlike many anticonvulsants, does not suppress afterdischarge by potentiating GABAergic inhibition. 5 These results suggest that baclofen attenuates hippocampal afterdischarge by a combination of pre- and postsynaptic mechanisms.

Animals↗
PubMed1983

Effects of baclofen on synaptically-induced cell firing in the rat hippocampal slice.

The effects of baclofen on the synaptically-induced firing of pyramidal and granule cell populations were tested in the rat hippocampal slice. Population spikes were evoked by stimulating excitatory pathways in the presence and absence of bath-applied drug. (+/-)-Baclofen (20 microM) completely blocked the firing of CA1 or CA3 hippocampal pyramidal cells subsequent to stimulation of projections that originate in area CA3. In contrast, the firing of dentate granule cells evoked by stimulation of the perforant path fibres was depressed by only 46% and baclofen did not affect the monosynaptic firing of CA3 pyramidal cells evoked by mossy fibre stimulation. These results are consistent with the effects of baclofen on the corresponding extracellularly-recorded excitatory postsynaptic potentials (e.p.s.ps). The Schaffer collateral-commissural population spike in area CA1 was depressed by (-)-baclofen (EC50 = 2.8 microM), GABA (EC50 = 2.2 mM) and 3-aminopropanesulphonic acid (3-APS) (EC50 = 0.34 mM). (-)-Baclofen was 180 times as potent as (+)-baclofen. Bicuculline methiodide (100 microM) did not reverse the depressant action of (-)-baclofen. GABA-induced depressions were antagonized to only a small degree, whilst the effect of 3-APS was readily reversed. Raising the concentration of bicuculline from 100 microM to 500 microM did not further reverse the action of GABA. The effects of (-)-baclofen and 3-APS on the relationship between extracellular e.p.s.p. and population spike were tested by stimulation of the Schaffer collateral-commissural fibres in area CA1. (-)-Baclofen shifted the 'input/output' curve to the right at a concentration of 1 microM, but less or not at all at 3 microM. In contrast, increasing the concentration of 3-APS shifted this curve farther to the right.

Animals↗
PubMed1982

Baclofen selectively inhibits transmission at synapses made by axons of CA3 pyramidal cells in the hippocampal slice.

The effects of baclofen, an antispastic drug, on excitatory transmission were tested by bath application to the hippocampal slice preparation. (+/-)-Baclofen (20 microM) strongly depressed extracellularly recorded synaptic responses to stimulation of projections that originate from CA3 hippocampal pyramidal cells. Responses to stimulation of four other excitatory pathways were little affected and the amplitudes of presynaptic fiber potentials and antidromic responses were unaltered. When tested on the Schaffer collateral-commissural-CA1 pyramidal cell synapse. (-)-baclofen depressed the amplitude of the extracellular excitatory postsynaptic potential with an IC50 of 3.7 microM and was 180 times more potent than (+)-baclofen. gamma-Aminobutyric acid, 3-aminopropanesulfonic acid and imidazole-4-acetic acid also inhibited transmission at this site. Baclofen could suppress the response completely, and its action was unaffected by bicuculline. In contrast, imidazole-4-acetic acid could suppress the response by a maximum of only 75%, and its action was highly sensitive to bicuculline. gamma-Aminobutyric acid and 3-aminopropanesulfonic acid could suppress the response completely, and their actions were relatively weakly antagonized by bicuculline. These results are consistent with the hypothesis that baclofen inhibits excitatory transmission by interacting with a bicuculline-insensitive gamma-aminobutyric acid receptor. These receptors may be located on one type of glutamatergic/aspartergic synaptic terminal, exemplified by axon terminals of CA3 hippocampal pyramidal cells. Synapses made by these axons may therefore serve as models for studying the mechanism of action of baclofen.

Action Potentials↗
PubMed1981

The depressant action of baclofen on the isolated spinal cord of the neonatal rat.

Neurotransmission in isolated hemisected spinal cord preparations from immature rats was depressed by micromolar levels of baclofen (threshold 0.5 microM). The depressant action of baclofen was not antagonised by bicuculline and baclofen, unlike GABA, did not depolarize primary afferent fibres. Neurotransmission in isolated vas deferens, anococcygeus muscle and superior cervical ganglion of the rat was unaffected by baclofen (0.1-1 mM). Depolarization of motoneurones, as recorded in ventral roots of tetrodotoxin-blocked spinal cord preparations, induced by excitant amino acids, substance P, noradrenaline or carbachol was unaffected by baclofen (250 microM or higher). The depressant action of baclofen on spinal cord preparations was similar to that produced by the excitant amino acid antagonist alpha,epsilon-diaminopimelic acid. A structure-activity study showed that the (--)-isomer of baclofen was over 20 times more potent than the (+)-isomer as a spinal depressant. Also the position and nature of the halogen substitutent in the ring is critical with baclofen giving optimal activity. It is concluded that the depressant action of baclofen from depression of the presynaptic release of excitant amino acid transmitter(s).

Amino Acids↗
PubMed1981

Skin testing in farmers' lung disease.

Intradermal skin tests with a culture filtrate antigen of Micropolyspora faeni grown on a synthetic medium were performed on patients with farmers' lung disease (FLD) and well farmers with and without antibodies to a panel of FLD antigens. Seventy-five percent of the FLD patients, 79% of the well farmers with M. faeni antibody, and 5% of well farmers without M. faeni antibody had a 2+ or greater intradermal immediate skin-test reaction. Prausnitz-Küstner (P-K) reactions were positive using serum of M. faeni immediate skin test-positive FLD patients. IgG-rich fractions from a staphylococcal protein A-Sepharose column of such serum contained the sensitizing factor whereas IgG-depleted fractions did not. M. faeni-specific IgE could not be detected in serum by a polystyrene radioimmunoassay. Positive late-onset (6-hr) skin tests occurred only in FLD patients and farmers with precipitating antibody. Biopsy specimens of the 6-hr reactions revealed a generalized dermal and perivascular polymorphonuclear infiltrate with deposits of immunoglobulin and complement about blood vessels. The skin-sensitizing factor noted in FLD patients and well farmers with antibody is not disease specific. This factor appears to be associated with the IgG-rich fraction of serum, and its role in the pathogenesis of FLD is unclear.

Enzyme-Linked Immunosorbent Assay↗
PubMed1981

Bronchial hyperreactivity to methacholine in farmers' lung disease.

Methacholine inhalation challenges were performed in five groups: 14 patients with history of farmers' lung disease (FLD), nine well farmers with precipitating antibodies to Micropolyspora faeni antigen, II normal subjects, 12 asthmatic patients, and 10 patients with interstitial lung disease (ILD) other than hypersensitivity pneumonitis. After calculating the mean areas under the dose-response curves, FLD patients had a significantly greater degree of methacholine sensitivity than did well farmers with M. faeni antibody and normals. However, the methacholine sensitivity of FLD patients was indistinguishable from a group of patients with ILD and significantly less than the asthmatic group. Fifty percent of patients with FLD had positive methacholine challenges (greater than or equal to 20% decrease in their 1-sec forced vital capacity [FEV1] from the control FEV1). Hyperirritable airways was a common finding in FLD.

Antibodies, Fungal↗