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C K Atterwill

Publications and source records attributed to C K Atterwill.

At least 19 recordsLinked to original sources
PubMed1999

The neurotoxic effects of methylenedioxymethamphetamine (MDMA) and its metabolites on rat brain spheroids in culture.

Rat whole-brain spheroids were used to assess the intrinsic neurotoxicity of methylenedioxy-methamphetamine (MDMA, Ecstasy) and two of its metabolites, dihydroxymethamphetamine (DHMA) and 6-hydroxy-MDMA (6-OH MDMA). Exposure of brain spheroids to MDMA or the metabolite 6-OH MDMA (up to 500 micromol/L) for 5 days in culture did not alter intracellular levels of glutathione (GSH), glial fibrillary acidic protein (GFAP) or serotonin (5-HT). In contrast, exposure to the metabolite DHMA, which can deplete intracellular thiols, significantly increased GSH levels (up to 170% of control) following exposure to 50 and 100 micromol/L DHMA. There was also a significant reduction in the levels of glial fibrillary acidic protein (GFAP) and GSH by DHMA at the highest concentration tested (500 micromol/L) but there was no effect on 5HT. This may constitute a sublethal neurotoxic compensatory response to DHMA in an attempt to replenish depleted intraneural GSH levels following metabolite exposure. Rat whole-brain spheroids may thus be a useful in vitro model to delineate mechanisms and effects of this class of neurotoxin.

3,4-Methylenedioxyamphetamine↗
PubMed1998

NMDA-induced increases in rat brain glutamine synthetase but not glial fibrillary acidic protein are mediated by free radicals.

Both excitotoxicity and oxidative stress are implicated in the pathophysiology of central nervous system (CNS) ischaemia-reperfusion injury whereby astrocytes offer neural protection through the production of endogenous antioxidants and removal of glutamate from the extracellular milieu. This study investigated whether exogenous alpha-tocopherol, an antioxidant, could prevent N-methyl-D-aspartate (NMDA)-produced increases of the glial specific proteins, glutamine synthetase (GS) and glial fibrillary acidic protein (GFAP) in rat brain spheroids in vitro. NMDA (320 microM; 3 days in vitro (DIV)) was unable to induce lipid peroxidation in rat brain spheroids implying that excitotoxicity in this system did not involve substantial free radical formation. However at non-cytotoxic concentrations, increases in astroglial GS were prevented by alpha-tocopherol treatment, suggesting a role for ROS in the excitotoxic process. In contrast, NMDA-induced increases in GFAP remained unchanged by alpha-tocopherol indicating that oxidative stress may not be involved in reactive gliosis at non-cytotoxic NMDA concentrations.

Animals↗
PubMed1996

Characterisation of a functional polyamine site on rat mast cells: association with a NMDA receptor macrocomplex.

Polyamines can modulate activation of N-methyl-D-aspartate (NMDA) receptors by binding to a specific polyamine site associated with a NMDA receptor macrocomplex. Polyamines induce histamine release from mast cells, although the mechanism had not been defined. We have examined whether spermine, a natural polyamine, and compound 48/80, regarded as a synthetic polyamine, activate mast cells by a polyamine site associated with a NMDA receptor macrocomplex. Spermine induced secretion of histamine from rat peritoneal mast cells and rat brain mast cells in a concentration-dependent manner. Rat peritoneal mast cells were used as a model system to explore the effects of NMDA antagonists on polyamine-induced histamine release. Ifenprodil, MK801 and arcaine inhibited histamine secretion from mast cells exposed to polyamines; the percentage inhibition was greater against spermine than compound 48/80. These data support the proposal that spermine (and possibly compound 48/80) induce histamine release from mast cells by interacting with a specific polyamine site on a NMDA receptor complex.

Animals↗
PubMed1995

Mast cells in neuroimmune function: neurotoxicological and neuropharmacological perspectives.

Mast cells are located in close proximity to neurons in the peripheral and central nervous systems, suggesting a functional role in normal and aberrant neurodegenerative states. They also possess many of the features of neurons, in terms of monoaminergic systems, responsiveness to neurotrophins and neuropeptides and the ability to synthesise and release bioactive neurotrophic factors. Mast cells are able to secrete an array of potent mediators which may orchestrate neuroinflammation and affect the integrity of the blood-brain barrier. The 'cross-talk' between mast cells, lymphocytes, neurons and glia constitutes a neuroimmune axis which is implicated in a range of neurodegenerative diseases with an inflammatory and/or autoimmune component, such as multiple sclerosis and Alzheimer's disease. Mast cells appear to make an important contribution to developing, mature and degenerating nervous systems and this should now be recognised when assessing the neurotoxic potential of xenobiotics.

Animals↗
PubMed1994

Human placental mast cells as an in vitro model system in aspects of neuro-immunotoxicity testing.

1. In both the developing and adult nervous systems, nerve growth factor (NGF) influences neuronal survival, differentiation and recovery following insult. 2. The effect of NGF upon human placental mast cells (HPMC) was investigated, since it is known that rodent mast cells express a functional receptor for NGF and secrete histamine upon challenge with this neurotrophic factor. Furthermore, human placental tissue contains a significant amount of NGF and expresses a NGF receptor. 3. HPMC were shown to secrete histamine in a concentration dependent manner in response to NGF (0.001-10.0 micrograms ml-1) in the presence of the lipid cofactor phosphatidylserine (10.0 micrograms ml-1). 4. NGF induced histamine release from isolated HPMC with an EC50 of 0.1 microgram ml-1 NGF and maximal secretion of total cellular histamine of 22.3 +/- 3.4% at 3.0 micrograms ml-1. 5. The response was shown to be a secretory process, dependent upon the presence of exogenous calcium ions and to be pH- and temperature-sensitive. 6. HPMC are suggested to be a suitable primary cell model for use in aspects of in vitro toxicity testing, in terms of assessing the neuro-immunotoxic potential of neurotrophic therapeutics. In addition, mechanistic studies concerning those xenobiotics which may exert their neurotoxic effect via interaction with neurotrophic factors and, or their receptors, may be studied in this human cell model.

Calcium↗
PubMed1992

Nerve growth factor (NGF) receptors on mast cells: effects of the cholinergic neurotoxin ethylcholine mustard aziridinium ion (ECMA).

The effects of nerve growth factor (NGF) on rat peritoneal mast cells were studied as a model for delineating the potential actions of the cholinergic neurotoxin ethyl choline mustard aziridinium (ECMA) on cholinergic neuronal NGF receptors. Both NGF and compound 48/80 (a polycationic secretagogue) were used to induce histamine release from a mixed population of rat peritoneal cells in vitro. NGF induced a dose-dependent release of up to 80% of the total cellular content (160% of endogenous release) in the presence of L-alpha-phosphatidyl serine (10 micrograms/ml) at concentrations of 0.1-10 micrograms/ml. Compound 40/80 also elicited comparable release of histamine over a concentration range of 1-10 micrograms/ml. ECMA had no effect on endogenous histamine release and was also shown to partially block the NGF induced histamine release at a concentration of 6 microM and 12.5 microM, and significantly at 50 microM (50 microM blocking up to 60% of the release). ECMA did not affect the 48/80 induced release. However, preincubation of the cells with ECMA (2 hr 37 degrees C) followed by replacement with fresh medium did not affect NGF induced histamine release. This suggests that although ECMA can alkylate NGF it probably does not inactivate the receptor in this peripheral model. Ouabain (1-10 mM) decreased histamine release by 25% supporting the proposed links between NGF receptor mediated events in neurones and the sodium pump.

Animals↗
PubMed1992

Models for the in vitro assessment of neurotoxicity in the nervous system in relation to xenobiotic and neurotrophic factor-mediated events.

We have been investigating the use of three culture types for both screening and mechanistic neurotoxicology in vitro. These are the neuroblastoma cell lines (IMR32 - human; C-1300 - mouse), primary mixed monolayer cultures of the rat and chick embryonic midbrain ('micromass' systems) and organotypic whole rat brain reaggregate cultures. The performance of these models for neurotoxicity resting has been investigated with ethylcholine mustard aziridinium (ECMA), vincristine, aluminium, glutamate receptor antagonists, MPTP, and 'hypothyroidism'. From a 'screening' viewpoint, in vitro exposure through a tiered testing system (ranging from simple cytotoxicological parameters in the neural cell lines to neurotransmitter measurements in the organotypic cultures) may permit detection of CNS neurotoxicity and delineation of possible mechanisms. The type of developmental neurotoxicological information gained is highlighted in the cases of aluminum and the glutamate receptor antagonists. High concentrations of aluminum caused significant neural cell death in differentiated neuroblastoma cell lines after approximately two weeks exposure in vitro. In contrast, cell death was detected in the developing midbrain cultures as early as 24 - 48 hr. Studies in whole brain reaggregates suggest that cholinotoxicity may occur in a similar time-frame and is consistent with some of aluminium's effects in vivo. Preliminary experiments have shown that exposure of immature developing midbrain rat primary cultured neurones to the glutamate receptor antagonists, AP3 and MK-801 induces neural cell death which may relate to control of NGF by glutamate cells. Developing neural culture systems may prove useful for testing agents which cause neurotoxicity through disturbances of neurotrophic function.

Aluminum↗
PubMed1991

Comparative studies on the effect of noxythiolin and other thioureas on the thyroid using in vitro and in vivo models of thyroid function.

Noxythiolin (Noxyflex-S) inhibited iodide organification (thyroid hormone synthesis) by cultured porcine thyrocytes in vitro after 5 hr (IC50 approx. 9.0 microM). The positive control, the anti-thyroid thiourea methimazole, was about 15 times more potent an inhibitor of iodide organification (IC50 approx. 0.6 microM) under the same incubation conditions. In an in vivo assessment of follicular organification capacity using the perchlorate discharge test, 14 days of ip treatment of male Charles River rats with noxythiolin (50 mg/kg body weight) produced no inhibition of iodide organification when tested 24 hr after the last administration of noxythiolin whereas the positive control, propylthiouracil, was a highly potent inhibitor.

Animals↗
PubMed1990

Comparative toxicology of temelastine. A novel H1 antagonist in dog, rat, and monkey.

The toxicity of temelastine 2-[4-(5-bromo-3-methylpyrid-2-yl)butylamino]-5-[(6-methylpyrid+ ++-3-yl) methyl]-4-pyrimidone a potent, selective, competitive histamine H1-receptor antagonist was examined in dogs and rats. The major toxicological response seen in the dog was marked, but intermittent and reversible, increases in the plasma activity of a number of liver-associated enzymes, viz alanine aminotransferase (ALT), glutamate dehydrogenase (GLDH), and alkaline phosphatase (ALP). The increases first seen in two male dogs treated for 30 consecutive days at a dose of 300 mg/kg became apparent at lower doses, i.e., 100 and 33.3 mg/kg/day, in 6- and 12-month studies. Although the increases were suggestive of hepatotoxicity, the only histological changes were increases in hepatocellular lipofuscin pigment and foci of macrophages seen in dogs treated at 300 mg/kg for 12 months. Rats treated for up to 12 months at doses as high as 300 mg/kg/day showed no treatment-related increases in plasma enzymes although increases in liver weights and hepatocellular lipofuscin pigment together with centrilobular hypertrophy were seen in the 300 mg/kg/day treatment group. To investigate differences in hepatic responsiveness between species dogs, rats, and monkeys were exposed to high concentrations of temelastine by continuous 24-hr intravenous infusion. The results of the study showed the dog to be most sensitive to the hepatic effects of temelastine. The major toxicological effect of temelastine in the rat was a histopathological lesion of the thyroid gland characterized by agglomeration and depletion of colloid, follicular epithelial hypertrophy and reduced follicular size. The no-effect dose for this lesion was between 10 and 33.3 mg/kg/day. These histopathological changes, characteristic of a "TSH-driven" thyroid gland, were not seen in the thyroid glands of dogs.

Alanine Transaminase↗
PubMed1989

Effect of nerve growth factor and thyrotropin releasing hormone on cholinergic neurones in developing rat brain reaggregate cultures lesioned with ethylcholine mustard aziridinium.

Foetal rat whole brain reaggregate cultures were prepared in a serum-supplemented (S+) or serum-free medium (S-). Ethylcholine mustard aziridinium (ECMA) was added to the cultures at 9 days in vitro (DIV) at concentrations of 12.5, 25 or 50 microM. Choline acetyltransferase (ChAT) activity was measured at +2, +48 and +96 hr following treatment. In certain experiments the neurotrophic factors, thyrotropin releasing hormone (TRH: 50 micrograms/ml, daily from 9 DIV) or nerve growth factor (NGF: 7S subunit, 5 ng/ml, 0 and +48 hr following ECMA) were added during ECMA treatment. In both types of reaggregate cultured in S+ and S- media there was a 40-80% loss of ChAT activity following ECMA exposure (final concentration = 12.5 microM), presumed to reflect cholinergic cell loss. In both S+ and S- brain reaggregates NGF produced increased ChAT activity with more marked effects in S+ (45-55% increase, +48-96 hr) than in S- medium (20-25% increase, 2-96 hr). No effect on cholinergic muscarinic receptors (specific 3H-QNB binding) was evident after treatment with NGF. TRH had no effect on ChAT activity in the S+ cultures but produced small increases in the S- culture condition (approx 20%, +2-48 hr). Despite a residual "ECMA-resistant" pool of ChAT in the cultures, neither neurotrophic agent was found to cause a reversal of the lesion. In conclusion, the cholinotoxin ECMA appears to produce a cholinergic deficit in both developing S+ and S- reaggregates. This was not reversible by NGF or TRH at the concentrations and under the conditions tested. NGF had marked effects on ChAT activity without affecting muscarinic receptors in untreated developing brain reaggregates cultured in an S+ medium.

Animals↗
PubMed1989

Relation between dopaminergic control of pituitary lactotroph function and deceleration of age-related changes in serum prolactin of diet-restricted rats.

Pituitary lactotroph function has been examined in diet-restricted (6 hr/day) male and female rats and compared with that in animals fed ad lib. After 12 months the age-related increase in serum prolactin concentration was significantly attenuated in diet-restricted female rats. Similar effects were not observed in male rats. Isolated superfused anterior pituitary glands removed from rats on both feeding regimens at 12 or 18 months and challenged with dopamine in vitro (5 microM) did not show differential prolactin secretion. No significant differences were observed in serum prolactin secretion in vivo after administration of bromocriptine (3 mg/kg body weight, sc) or haloperidol (1.75 mg/kg body weight, ip). These results do not support an altered dopamine receptor function in the anterior pituitary lactotrophs. In contrast, central dopamine receptor function in rats 12 months of age was altered by dietary restriction, since the frequency of cataleptic responses to haloperidol injection (2 mg/kg body weight, ip) was significantly depressed in the test animals.

Aging↗
PubMed1989

Mechanistic investigation of species-specific thyroid lesions induced by treatment with the histamine H1 antagonist temelastine (SK&F 93944) in rats.

Temelastine (SK&F 93944), an H1 histamine receptor antagonist, induces thyroid histopathological lesions in the rat, indicative of thyroid follicular cell stimulation, at oral doses of 10-33 mg/kg body weight/day. These changes do not occur in the dog or mouse. Endocrinological short-term studies support an increased thyroid follicular activity (increased radioiodide accumulation) with decreased circulating thyroxine (T4) at oral doses at or above 300 mg/kg body weight/day and increased circulating thyroid stimulating hormone (TSH). This is thought to be responsible for the thyroid follicular stimulation following Temelastine treatment. No direct inhibition of thyroid function occurs. Temelastine produces these species-specific changes by enhancing thyroxine clearance from the circulation in the rat, but not in the dog or mouse. In vitro studies with cultured rat hepatocytes suggest that the mechanism behind these changes is a drug-induced increase of hepatocellular T4 binding and uptake which leads to an enhanced metabolic clearance of the hormone.

Animals↗
PubMed1989

The effects of desipramine (DMI) and electroconvulsive shock (ECS) on the function of the hypothalamo-pituitary-thyroid axis in the rat.

Monoaminergic systems influence the hypothalamo-pituitary-thyroid (HPT) axis. Since two different antidepressant treatments, desipramine (DMI) and electroconvulsive shock (ECS), are known to alter monoaminergic function in the rat central nervous system (CNS), the effects of DMI and ECS on the function of the HPT axis in the rat were examined. Animals were treated with either DMI (5 mg/kg) twice daily for 14 days (DMI x 14) or once only (DMI x 1) or ECS five times in 10 days (ECS x 5) or once only (ECS x 1). Three and 24 hours after the final treatment, blood samples were taken for measurement of plasma total thyroxine (TT4), total tri-iodothyronine (TT3), free thyroxine (FT4), free tri-iodothyronine (FT3) and thyroid stimulating hormone (TSH). Plasma TSH concentrations were decreased by the DMI x 14 and increased by the ECS x 5 regimen. Small decreases in thyroid hormones (T3 and T4) occurred after DMI x 14. No other consistent changes were observed in the animals treated with ECS. The effect of DMI or ECS treatment on the responsiveness of pituitary thyrotrophs was assessed in vitro. Isolated superfused pituitary glands from rats treated in vivo with either DMI x 14 or ECS x 5 were exposed to a pulse of thyrotropin releasing hormone (TRH; 1 ng/ml). No significant change in TSH secretion was observed in response to TRH in either case. Therefore, the changes observed in circulating plasma TSH levels are unlikely to have resulted from either direct or indirect effects on pituitary thyrotroph TRH receptor sensitivity.

Animals↗
PubMed1989

SK&F 93574, a histamine H2-receptor antagonist, releases histamine in the dog.

This study was designed to establish whether SK&F 93574 releases histamine in dogs. Three female beagle dogs each received single infusions (on separate days) of each of SK&F 93574 (2.5 mg kg-1), polyvinylpyrrolidone (PVP, 20 mg kg-1) and sterile saline. The treatments were given at 14 day intervals by rapid intravenous infusion at 0.5 mL kg-1 min-1 for 2 minutes. Dogs showed clinical signs of histamine release such as vasodilation, licking lips, head drooping and increased gut movement after treatment with the known histamine releaser PVP or the test compound SK&F 93574. These signs were of similar severity and duration for the two compounds. No such changes were observed when the dogs received vehicle alone. Treatment with PVP or SK&F 93574 also resulted in markedly elevated plasma histamine concentrations (greater than 10-fold increase over control). It is concluded that intravenous administration of SK&F 93574 to dogs is associated with histamine release.

Animals↗