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Biomedical subjects

C M Regan

Publications and source records attributed to C M Regan.

At least 55 records · Page 3Linked to original sources
PubMed1993

Cholinergic and dopaminergic agents which inhibit a passive avoidance response attenuate the paradigm-specific increases in NCAM sialylation state.

The influence of cholinergic and dopaminergic agents on the acquisition of a passive avoidance response in the rat is demonstrated. Trifluoperazine (0.12 mg/kg), a dopamine antagonist, inhibited task acquisition when present during training or later, during consolidation, at the 10-12 h post-training period and at no other intervening time point. Induction of amnesia was dose-dependent and was not apparent when the dose exceeded 0.12 mg/kg. This effect appears to be due to an increase in dopamine release through presynaptic receptor antagonism as similar results could be obtained by the administration of apomorphine (0.5 mg/kg), a dopamine agonist, and this effect could be antagonized by the D1 receptor selective antagonist SCH-23390. Scopolamine (0.15 mg/kg), a muscarinic antagonist, impaired acquisition of the passive avoidance response when administered during training and, separately, at the 6 h post-training period. This could not be attributed to presynaptic antagonism as oxotremorine (0.2 mg/kg), a muscarinic agonist, had no amnesic action. Administration of apomorphine or scopolamine during training and at the appropriate post-training period prevented subsequent paradigm-specific increases of neural cell adhesion molecule sialylation state in hippocampal immunoprecipitates obtained at 24 h after task acquisition and 4 h following intraventricular infusion of the labelled sialic acid precursor - N-acetyl-D-mannosamine. Oxotremorine alone did not influence neural cell adhesion molecule sialylation state. These observations provide further evidence of a regulatory role for neural cell adhesion molecule sialylation state in information storage processes.

Amnesia↗
PubMed1993

Nefiracetam (DM-9384) preserves hippocampal neural cell adhesion molecule-mediated memory consolidation processes during scopolamine disruption of passive avoidance training in the rat.

Scopolamine (0.15 mg/kg), a muscarinic antagonist, when administered during training or at a discrete 6-h posttraining time point, is demonstrated to inhibit the recall of a step-down passive avoidance response when tested at 24 and 48 h after task acquisition. Nefiracetam (3 mg/kg), a piracetam-related nootropic, when given with scopolamine during training tended to improve task recall, and this effect was more pronounced when given at the 6-h posttraining time. Co-administration of nefiracetam with scopolamine was not necessary to achieve the antiamnesic action, as nefiracetam given during training significantly improved the memory deficits produced by scopolamine at the 6-h posttraining time. The paradigm-specific increase in hippocampal neural cell adhesion molecule sialylation, which is observed during consolidation of a passive avoidance response, was attenuated by the presence of scopolamine during training and at the 6-h posttraining time, and this effect was reversed by co-administration of nefiracetam, albeit in a paradigm-independent manner. These results suggest nefiracetam exerts a neurotrophic action that protects memory consolidation from drug interventive insults.

Animals↗
PubMed1992

Clorazepate synchronizes cultured rat C6 glioma in the early G1 phase of the cell cycle.

A water soluble benzodiazepine, clorazepate, has been used to establish the point of benzodiazepine proliferative arrest in the rat C6 glioma. Clorazepate inhibited C6 proliferation in a dose-dependent manner with an IC50 value of 280 microM, as judged by a nuclei counting procedure. Release of cells from a 48 h exposure to 350 microM clorazepate, at which over 70% of the cells were arrested, resulted in a synchronous entry into S phase 8-9 h later, as evidenced by a sharp increase in the incorporation of [3H]thymidine. This restriction point was demonstrated to be 2-3 h into the G1 phase by measuring the length of G1 in synchronized populations of C6 cells obtained by selection of mitotic figures from an asynchronous culture. Synchronous arrest of C6 by clorazepate required an exposure period of 24-36 h, approximately twice the doubling time of the cell line. A morphological study confirmed an early G1 point of proliferative arrest. Clorazepate synchronized cells exhibited a uniform morphology with the majority of cells assuming a configuration representative of anchorage-dependent cells in an early phase of attachment. The majority of cells were somewhat rounded and attached to the substratum by cytoplasmic 'skirts' with punctate structures which may represent focal adhesion points.

Animals↗
PubMed1992

Hippocampal NCAM180 transiently increases sialylation during the acquisition and consolidation of a passive avoidance response in the adult rat.

Synaptic connectivity change is a consistent anatomical feature of memory formation and the possibility that this is mediated by a replay of neurodevelopmental events has been investigated by measuring change in neural cell adhesion molecule sialylation state during the acquisition and consolidation of a passive avoidance response in the adult rat. The avoidance response was always generated after two to three trials and the animals remained on the platform for the criterion time of 5 min. In all cases training was complete within 5-8 min. Change in sialylation state was monitored following intraventricular infusion of the 3H-ManNAc precursor at 4 hr prior to the reference point. No task-specific change in general glycoconjugate sialylation was apparent in hippocampal P2 pellets at increasing times following training. Increased sialylation state was observed only in neural cell adhesion molecule (NCAM) immunoprecipitates of hippocampal membrane fractions at 12 and 24 hr after training. Change in hippocampal sialylation state could not be attributed to an increased accumulation of NCAM as detected by an immunoabsorbent assay. Immunoblotting of antibody precipitated NCAM demonstrated the 3H-ManNAc to be incorporated into the synapse-specific, 180 kDa isoform of NCAM and a novel 210 kDa isoform. Immunoprecipitation and immunoblotting procedures with an antibody specific for a2-8-polysialic acid showed the 180 and 210 kDa isoforms to be polysialylated. The role of NCAM180 sialylation as a mechanism for synapse selection in information storage is discussed.

Animals↗
PubMed1992

Studies on valproate-induced perturbations of neurulation in the explanted chick embryo.

The effect of the anticonvulsant sodium valproate on in vitro neurulation of the chick embryo, explanted after a 25-h in ovo incubation period, is described. Sodium valproate, at concentrations of 0.5-1.5 mM did not appear to have any profound effect on embryo growth when assessed by light microscopy. However scanning electron microscopy revealed a dose-dependent increase in the incidence of open anterior and posterior neuropores after 20 h of in vitro development (Stage 11). Concentrations of sodium valproate which were greater than 1.5 mM markedly increased the number of gross malformations, which were manifested as a complete disruption of the neural tube along its entire length. Failure of neuropore closure could not be attributed to a drug-induced neurodevelopmental delay as these defects were still apparent following 27 h of in vitro culture, a time coincident with the onset of embryo torsion.

Animals↗
PubMed1992

Intraventricular infusions of anti-neural cell adhesion molecules in a discrete posttraining period impair consolidation of a passive avoidance response in the rat.

Intraventricular infusions of anti-neural cell adhesion molecule (anti-NCAM) are demonstrated to inhibit consolidation of a passive avoidance response when administered in the 6-8 h posttraining period. Anti-NCAM was ineffective when administered during training or at any other time up to 10 h thereafter, and no amnesic effects were observed with absorbed anti-NCAM or anti-neurofilament protein. Amnesia was observed only at the 48-h recall time, and this could not be attributed to poor antibody penetration or a prolonged residence time, as studies with 125I-labelled anti-NCAM in trained animals demonstrated a rapid accumulation into all brain regions, and this was marked in the olfactory bulb and hippocampus, areas showing an inherent and paradigm-specific increase in NCAM sialylation state, respectively. The lack of an amnesic action at the 24-h recall time is attributed to anti-NCAM-impaired synapse structuring becoming apparent following the paradigm-specific increases in NCAM sialylation state.

Amnesia↗
PubMed1991

The anticonvulsant valproate teratogen restricts the glial cell cycle at a defined point in the mid-G1 phase.

Direct cell counting and extent of [3H]thymidine incorporation demonstrated valproate to inhibit C6 glioma proliferation rate in a dose-dependent manner with a 1 mM concentration achieving 50% inhibition. The antiproliferative effect was reversible and could not be attributed to cytotoxicity at the valproate concentrations employed. The site of valproate action within the cell cycle was determined to be in the G1 phase, at a point 6-6.5 h prior to S phase, by estimating the time to increased [3H]thymidine incorporation following release from a 70% proliferative arrest. Synchronised cells obtained by a mitotic selection procedure required 11-12 h to enter S phase and demonstrated the valproate restriction point to be 5 h into the G1 phase of the C6 cell cycle. Exposure of valproate to the part of the G1 period which follows the restriction point was without effect on cell entry into S phase.

Animals↗
PubMed1991

Transient heat shock in mid-G1-phase of the C6 glioma cell cycle impairs entry into S-phase.

Synchronous populations of rat C6 glioma cells have been obtained by a mitotic selection procedure and used to establish the effect of transient temperature elevation on their progression through the cell cycle. A transient 3-h exposure to a 42 degree C heat shock within defined area in the mid-G1-phase of the cell cycle has been demonstrated to impair progression to S-phase. This anti-proliferative heat shock effect was not apparent in asynchronous cell populations. A small, but significant, decrease in 3H-thymidine incorporation was observed (approximately 5%) following an 8-h exposure to heat shock.

Animals↗
PubMed1991

In vitro screening for anticonvulsant-induced teratogenesis: drug alteration of cell adhesivity.

Anticonvulsant-induced alteration in C6 glioma cell adhesivity has been evaluated in two independent in vitro assay systems. A centrifugal shear assay was employed to determine drug-induced change in cell-substratum adhesivity. Valproate and clonazepam were found to significantly increase cell-substratum adhesivity when cells were cultured at concentrations which were within twice their therapeutic plasma level. A second assay evaluated change in affinity for concanavalin A lectin coated surfaces to determine change in cell surface glycoconjugate expression. Valproate and clonazepam and, to a lesser extent, diazepam significantly decreased drug-exposed C6 glioma cell affinity for concanavalin A lectin coated surfaces. Valproate and clonazepam had approximate IC50 values of 0.75 mM and 75 microM, respectively. These findings are compared and discussed in relation to those obtained with an anti-proliferative assay which has been suggested to predict teratogen potential.

Animals↗
PubMed1990

Intraventricular infusions of antibodies to amyloid-beta-protein precursor impair the acquisition of a passive avoidance response in the rat.

Intraventricular infusions of an antiserum raised against a 14 amino acid residue in the extracellular domain of amyloid-beta-protein precursor significantly decreased stepdown latency, at both 24 h and 48 h recall times, in rats trained to avoid an electroshock by remaining on a platform. The antiserum was effective when infused up to 2.5 h following training and no retention deficit was noted when it was administered at 4h or 6h after training. An antiserum generated against a 17 amino acid residue of the A4 amyloid peptide had no effect on learning. Thus the amyloid precursor protein, which is aberrantly processed in Alzheimer's disease, appears to be directly involved in memory formation.

Adult↗
PubMed1990

A monoclonal anti-imipramine antibody with antidepressant binding properties similar to the muscarinic receptor.

A murine monoclonal antibody raised using imipramine conjugated to bovine serum albumin bound free imipramine with high affinity (KD = 24 nM). The antibody had a binding affinity profile for tricyclic and other uptake-inhibitor type antidepressants which correlated highly with the affinities of the same compounds for the brain acetylcholine muscarinic receptor, but not for plasma-membrane 5-hydroxytryptamine carriers. This antibody was not similar in binding properties to polyclonal antisera produced using the same antigen but was highly similar in binding properties to a monoclonal anti-nortriptyline antibody, ANT3, raised by Marulo et al. (Marulo S, Hoebeke J, Guillet JG, Andre C and Strosberg AD, J Immunol 138: 524-526, 1987) using a different antigen.

Animals↗
PubMed1990

Learning-induced change in neural activity during acquisition and consolidation of a passive avoidance response in the rat.

Time-dependent alterations in neural activity have been established during the acquisition and consolidation of a stepdown passive avoidance paradigm. Change in neural activity was established by administering a glucose analogue, [3H]2-deoxyglucose, 50min prior to sacrifice and estimating perchloric acid soluble counts in nine hand dissected brain regions. Change in [3H]2-deoxyglucose uptake was closely paralleled in both trained and yoked animals for up to 40min following task acquisition however the striatum was the only area to exhibit a task-specific increase in [3H]2-deoxyglucose uptake at 20-30min after training. Longterm changes in neural activity were also apparent as the amygdala and brainstem showed increased [3H]2-deoxyglucose uptake at the 24 h time point. No further paradigm-specific changes were apparent at 48 h. These findings are concluded to suggest that the striatum is involved in the early events of acquiring a passive avoidance response and the amygdala and brainstem during the later events.

Amygdala↗
PubMed1990

In vitro screening for anticonvulsant-induced teratogenesis in neural primary cultures and cell lines.

To establish inherent potential for the induction of neural tube defects the ability of selected anticonvulsant agents to interfere with cell division has been established in vitro using an antiproliferative assay in clonal cell lines and a cytotoxicity assay using primary cultures of cerebral cortex neurons at different stages of development. In order to evaluate the relative toxicities of these agents their in vitro effects were determined at 2-3 times the plasma therapeutic level. By these procedures valproate and the benzodiazepines, diazepam and clonazepam, exerted a potent antiproliferative action which could not be attributed to increased cytotoxicity. In contrast phenytoin was markedly cytotoxic but was without an antiproliferative action. This cytotoxicity was most pronounced during the periods of extensive fibre outgrowth. When compared to epidemiological and animal study data, agents which inhibited cell proliferation within twice therapeutic concentration were consistently associated with major neural tube malformations. However phenytoin, found to be positive in the cell cytotoxicity assay, is not associated with neural tube malformations but rather is primarily associated with mental retardation. Thus assessment of antiproliferative activity of anticonvulsant drugs may be one criterion for identification of teratogenic potential during neurulation.

Animals↗
PubMed1990

Expression of a neural cell adhesion molecule serum fragment is depressed in autism.

The level of a neural cell adhesion molecule (NCAM) serum fragment in autism was determined by using an antiserum prepared with immunoaffinity purified mouse NCAM. Autistic patients (N = 16) had statistically significantly decreased serum NCAM levels compared with age-matched controls (p less than 0.0005). This observation could not be attributed to a medication-induced effect. Depressed serum NCAM levels in autism are distinct from schizophrenia, in which serum NCAM levels are elevated.

Adolescent↗
PubMed1989

Analysis of secular trends in surgery for glue ear in the North Western Region (1975-1984).

Hospital Activity Analysis (HAA) data relating to operations for glue ear and tonsillectomy performed on residents of the North Western Region, aged 0-9 years during the period 1975-1984 were studied. The rate of surgery for glue ear has risen from 45/10,000 to 107/10,000 representing an increase of 137 per cent. The tonsillectomy rate by comparison has undergone a more modest increase of 19 per cent. The study casts doubt on a 'vacuum effect', as has been argued by Black. Marked variation in rates of surgery between Districts in the Region were noted, and the possible explanations discussed. A review of the literature revealed considerable controversy concerning the management of glue ear and the need for a definitive trial is highlighted.

Child↗