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Biomedical subjects

A J Cross

Publications and source records attributed to A J Cross.

At least 37 records · Page 2Linked to original sources
PubMed1995

Review of the pharmacology and clinical pharmacology of 3,4-methylenedioxymethamphetamine (MDMA or "Ecstasy").

3,4-Methylenedioxymethamphetamine (MDMA or "Ecstasy") was first synthesised 80 years ago, but has recently received prominence as an illegally synthesised recreational drug of abuse. There is a widely held belief among misusers that it is safe. In the last 2-3 years there have been a number of reports of the drug producing severe acute toxicity and death and there are concerns that it may cause long term toxic damage to 5-hydroxytryptamine (5-HT) nerve terminals. There is a considerable literature on the acute pharmacological effects of MDMA in experimental animals, and this is reviewed. The drug produces both hyperthermia and the "serotonin syndrome", a series of behavioural changes which result from increased 5-HT function. Acute clinical toxicity problems following MDMA ingestion also include hyperthermia and the appearance of the serotonin syndrome. The hyperthermia appears to precipitate other severe clinical problems and the outcome can be fatal. In agreement with others, we suggest that the recent increase in the number of reports of MDMA toxicity probably results from the widespread use of the drug at all night dance parties or "raves". The phenomenon of amphetamine aggregation toxicity in mice was reported 40 years ago. If applicable to MDMA-induced toxicity in humans, all the conditions necessary to induce or enhance toxicity are present at raves: crowded conditions (aggregation), high ambient temperature, loud noise and dehydrated subjects. Administration of MDMA to rodents and non-human primates results in a long term neurotoxic decrease in 5-HT content in several brain regions and there is clear biochemical and histological evidence that this reflects neurodegeneration of 5-HT terminals. Unequivocal data demonstrating that similar changes occur in human brain do not exist, but limited and indirect clinical evidence gives grounds for concern. There are also data suggesting that long term psychiatric changes can occur, although there are problems of interpretation and these are reviewed. Suggestions for the rational treatment of the acute toxicity are made on the basis of both pharmacological studies in animals and current clinical practice. Cases presenting clinically are usually emergencies and unlikely to allow carefully controlled studies. Proposals include decreasing body temperature (possibly with ice), the use of dantrolene and anticonvulsant and sedative medication, particularly benzodiazepines. The use of neuroleptics requires care because of the theoretical risk of producing the neuroleptic malignant syndrome and the possibility of precipitating seizures. In rats, chlormethiazole antagonises the hyperthermia produced by MDMA and has been shown clinically to block MDMA-induced convulsive activity.

Animals↗
PubMed1995

The neuroprotective effect of chlormethiazole on ischaemic neuronal damage following permanent middle cerebral artery ischaemia in the rat.

The ability of chlormethiazole to protect against ischaemic cell damage in a rat model of permanent focal ischaemia has been examined. Chlormethiazole (1 mmol/kg) was administered intraperitoneally either 1 or 3 h after occlusion of the middle cerebral artery with an intraluminal filament. Twenty four hours after the start of occlusion there was histological evidence for ischaemic damage in both cortex and striatum. The volume of ischaemic damage in control (saline injected) animals was 310 +/- 25 mm3 (mean +/- SEM; n = 6). Chlormethiazole administered 1 h after occlusion reduced this damage by 58% (128 +/- 40 mm3; n = 6; P < 0.01), protection being observed in both brain regions. The drug was ineffective when given 3 h after occlusion (304 +/- 25 mm3; n = 5). Chlormethiazole had no effect on body temperature, mean arterial blood pressure, blood pH, pO2 or pCO2, but did induce mild bradycardia. Chlormethiazole therefore appears to be an effective neuroprotective agent in this model of permanent ischaemia, complementing previous data on the efficacy of this drug in other focal and global models of cerebral ischaemia.

Analysis of Variance↗
PubMed1995

Animal models of acute ischaemic stroke: can they predict clinically successful neuroprotective drugs?

Substantial efforts are being made to develop drugs which will protect the brain from the neurodegeneration that follows an acute ischaemic stroke. However, while there are already a significant number of animal models of stroke, there is currently no information as to whether activity of a compound in any of them will predict clinical efficacy. In this article, Jackie Hunter, Richard Green and Alan Cross review the major models of acute cerebral ischaemia and propose rational protocols for examining novel neuroprotective agents.

Animals↗
PubMed1995

The protective action of chlormethiazole against ischaemia-induced neurodegeneration in gerbils when infused at doses having little sedative or anticonvulsant activity.

1. The effect of chlormethiazole administration on delayed neuronal death in gerbil hippocampus following transient global ischaemia has been examined. Chlormethiazole was administered either intraperitoneally or by intravenous infusion with either the dose or the time of infusion varied. 2. Chlormethiazole (600 mumol kg-1, i.p.) given 60 min after ischaemia produced substantial (> 60%) neuroprotection when damage was assessed 5, 14 or 21 days later, indicating the drug does not merely delay cell death. 3. Infusion protocols were developed which would result in sustained and defined plasma concentrations. Chlormethiazole (930 mumol kg-1) was then infused intravenously for 30 min, 76.5 min or 110 min in ways resulting in sustained plasma concentrations of 200, 100 and 50 nmol ml-1 respectively. When treatment was initiated 30 min after the ischaemic episode all protocols provided effective neuroprotection. There was a dose-dependent decline in protection when plasma chlormethiazole concentrations of 50, 30 and 10 nmol ml-1 were sustained for 110 min with no protection observed at 10 nmol ml-1. 4. In contrast, when a plasma concentration of 10 nmol ml-1 was sustained by infusion for 24 h, almost total neuroprotection against the ischaemic damage was achieved. This plasma concentration produced no sedative or anticonvulsant activity. 5. These data suggest that neuroprotection depends on both dose and duration of chlormethiazole administration and that excellent neuroprotection is possible in the absence of the sedative and anticonvulsant effects of the drug.

Animals↗
PubMed1995

The effect of chlormethiazole on neuronal damage in a model of transient focal ischaemia.

1. The effect of chlormethiazole has been studied in a transient middle cerebral artery (MCA) occlusion model of cerebral ischaemia in the rat. The MCA was occluded for 1 h by use of an intraluminal suture technique, with reperfusion for 24 h following removal of the occluding filament. Neuronal damage was determined by measurement of the area of necrosis following Cresyl Violet staining of sections taken through the ischaemic region. 2. In the initial experiment, occlusion of the MCA produced a large volume of ischaemic damage in both cortex and striatum, characterized by necrosis and pyknosis (total volume of damage, 287 +/- 13 mm3, n = 9). Rats injected with chlormethiazole (1000 mumol kg-1, i.p.) 60 min before occlusion had a reduced volume of damage in both regions (104 +/- 11 mm3; n = 9; P < 0.001). 3. In a subsequent study systemic physiological parameters (heart rate, blood pressure, blood pH, blood gases and rectal temperature) were measured throughout the ischaemic period. 4. Chlormethiazole (1000 mumol kg-1) pretreatment produced little change in systemic physiology and the neuroprotective effect of the drug when given 60 min prior to the MCA occlusion was confirmed. Chlormethiazole was also neuroprotective when given 10 min following the start of reperfusion (control group: 244 +/- 52 mm3, n = 10; chlormethiazole pretreatment group: 102 +/- 23 mm3, n = 10; P < 0.001; chlormethiazole post-ischaemia group: 122 +/- 16 mm3; P < 0.001, n = 10). 5. It is concluded that chlormethiazole is an effective neuroprotective agent in this model of transient focal ischaemia. The observation that chlormethiazole is protective when given after reperfusion indicates that the effect of the drug is unlikely to be due to an alteration of intra-ischaemic cerebral blood flow, but is more probably a direct effect on the development of ischaemic damage.

Animals↗
PubMed1994

Attenuation by chlormethiazole of oedema following focal ischaemia in the cerebral cortex of the rat.

When a photochemically-induced infarct was produced in the right cortex of rats, tissue water content was increased markedly 4 and 24 h later (control: 79.00 +/- 0.08% ischaemia, 24 h: 82.96 +/- 0.15%). The left cortex was unaffected. Chlormethiazole (200 mg/kg i.p.) injection 5 min after onset of ischaemia decreased the oedema (ischaemia/chlormethiazole, 24 h: 82.16 +/- 0.21%, P < 0.01). At 24 h, ischaemic tissue Na+ content was increased (61%) and the K+ content decreased (9%). The Na+/K+ ratio therefore increased significantly (P < 0.001), a change that was diminished by chlormethiazole administration (P < 0.02). Chlormethiazole (1 mM), unlike furosemide (5 mM), did not reduce swelling of C6 glioma cells in hypotonic medium. The data suggest that chlormethiazole decreases oedema in this stroke model because of its neuroprotective properties and not because of an effect on anion transport.

Animals↗
PubMed1994

Attenuation by chlormethiazole administration of the rise in extracellular amino acids following focal ischaemia in the cerebral cortex of the rat.

1. In vivo microdialysis has been used to investigate the concentration of various amino acids and lactate in the extracellular fluid of the rat cortex following focal ischaemia, the probe being placed in the core of the infarct area. 2. An ischaemic infarct was produced in the cortex by use of a photochemical dye (Rose Bengal) and light irradiation. There was a marked increase in lactate concentration (300%) over the next 4 h. Substantial increases were also seen in the concentration of the excitatory (glutamate and aspartate), inhibitory (GABA and taurine) and other amino acids (serine, alanine, asparagine). 3. Administration of chlormethiazole (200 mg kg-1, i.p.) 5 min after the onset of ischaemia reduced the ischaemia-induced neurodegeneration by approximately 30%, measured histologically 24 h later. 4. Chlormethiazole (200 mg kg-1, i.p.) administration also reduced the rise in the concentration of lactate and all the amino acids by between 30-60% during the first 4 h after the onset of ischaemia. 5. Analysis of the time course of the amino acid changes suggested that chlormethiazole is not neuroprotective because of the inhibition of excitatory amino acid release but rather that the attenuated rise in the concentration of all the amino acids is reflective of neuroprotection and therefore decreased cell death. 6. This conclusion was supported by the observation that the enhanced efflux of glutamate from slices of cerebral cortex which had been induced by incubation of the slices in an hypoxic medium was unaltered by the presence of a high concentration of chlormethiazole (1 mM) in the medium. 7. Overall the data strengthen the evidence for the neuroprotective effect of chlormethiazole in this model of focal ischaemia.

Amino Acids↗
PubMed1994

The differential effects of felodipine and nitrendipine on cerebral dihydropyridine binding ex vivo and the ethanol withdrawal syndrome in mice.

1. The ability of two dihydropyridine calcium channel antagonists, felodipine and nitrendipine both to displace [3H]-isradipine binding in CNS tissue measured ex vivo and to protect against the ethanol withdrawal syndrome has been investigated. 2. Mice were injected with various doses of felodipine or nitrendipine and [3H]-isradipine binding measured in brain homogenates prepared 0.5, 3 or 5 h later. Inhibition versus dose curves were sigmoid and the dose required to produce 50% inhibition increased linearly with time after administration. Felodipine was approximately 10 times more potent than nitrendipine. 3. Nitrendipine (50 mg kg-1, i.p.) and felodipine (10 mg kg-1, i.p.) produced around a 75% inhibition of [3H]-isradipine binding 3 h later. Binding of [3H]-nitrendipine to cerebral tissues measured after in vivo injection of the ligand was decreased by nitrendipine (50 mg kg-1) and felodipine (10 mg kg-1) to a similar extent. 4. Nitrendipine (50 mg kg-1) prevented the behavioural signs of ethanol withdrawal as measured by handling induced convulsions, but felodipine (10 mg kg-1 or 2 mg kg-1) did not provide any protection against this effect of ethanol withdrawal. Felodipine (10 mg kg-1, twice daily) during the course of ethanol treatment also failed to attenuate the withdrawal syndrome. 5. The convulsive response to a mild audiogenic stimulus during ethanol withdrawal was increased following one dose of felodipine (5 mg kg-1, i.p.) but unaffected by nitrendipine. 6. Injection of Bay K 8644 (60 microgram, i.c.v.) produced a significant increase in handling-induced convulsive behaviour. Felodipine (10 mg kg-1, i.p.) reduced this behaviour both 60 and 120 min later, while nitrendipine (50 mg kg-1) showed a modest reduction only at 120 min.7. In contrast, nitrendipine (50mg kg-1) and felodipine (10 mg kg-1) produced similar effects on the hyperexcitability produced by handling following administration of bicuculline. Hexamethonium(8 mg kg-1) had no effect on this response.8. No change was found in [3H]-isradipine or [125I]-w-conotoxin binding to cerebral tissue prepared from ethanol-dependent mice.9. These results demonstrate that while felodipine and nitrendipine have similar actions on some CNS-mediated effects (raising seizure thresholds to several convulsant drugs), felodipine, in contrast to nitrendipine, has no effect on the ethanol withdrawal syndrome. Suggested explanations for the results include the possibility that nitrendipine may protect against the ethanol withdrawal syndrome via sites other than dihydropyridine receptors: that felodipine has partial agonist actions at dihydropyridine receptors in the CNS or that felodipine has actions which mask its protective effect in ethanol withdrawal.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1993

Neurotransmitters and second messengers in aging and Alzheimer's disease.

A substantial loss of cortical cholinergic nerve endings, along with a much more circumscribed cortical degeneration of pyramidal neurons, almost certainly causes glutamatergic hypoactivity in live Alzheimer's patients. These selective pathologies are discussed in terms of therapy. An additional effect of some proposed treatments is emerging as there is evidence that processing pathways for beta-amyloid precursor proteins in cortical pyramidal neurons, a target cell for acetylcholine, are affected by neuronal activity.

Aging↗
PubMed1993

Chlormethiazole antagonises seizures induced by N-methyl-DL-aspartate without interacting with the NMDA receptor complex.

Administration to mice of N-methyl-DL-aspartate (NMDLA; 680-3400 mumol/kg IP) produced a behavioural syndrome of scratching, running, pawing, clonus, loss of righting and tonic convulsions. Measures of latency to appearance of the behaviours and percentage of animals displaying the behaviour (frequency) indicated that the latency to appearance of running behaviour, clonus and tonic convulsions were all dose dependant. Chlormethiazole (155-622 mumol/kg IP) given 15 min before NMDLA (3400 mumol/kg) dose-dependently inhibited all the behaviours, increasing the latency to appearance of scratching, running and clonus and reducing the incidence of pawing, loss of righting and tonic convulsions. Tonic seizures induced by NMDLA (3400 mumol/kg) were inhibited by the following drugs (ED50 values in mumol/kg in brackets): chlormethiazole (210); pentobarbitone (67); dizocilpine (0.9). The diazepam value (38) was estimated as complete inhibition was not obtained. Chlormethiazole (1 mM) did not affect the binding of [3H]-dizocilpine to rat cortical membranes or the stimulation of this binding by glutamate (10 microM), glycine (10 microM) or spermidine (100 microM). It is therefore concluded that whilst chlormethiazole effectively antagonises the convulsive behavioural syndrome induced by injection of NMDLA, it does not do so by interacting with the NMDA receptor complex but more probably by its known interaction with the GABAA receptor complex.

Animals↗
PubMed1993

Effect of chlormethiazole, dizocilpine and pentobarbital on harmaline-induced increase of cerebellar cyclic GMP and tremor.

Administration to mice of harmaline (100 mg/kg SC) resulted in a greater than two-fold increase in cyclic GMP in the cerebellum 15 min later. This response was inhibited by pretreatment 5 min before the harmaline with pentobarbital (ED50 6.5 mg/kg), chlormethiazole (ED50 10.4 mg/kg) and dizocilpine (ED50 0.5 mg/kg). Harmaline-induced tremor was inhibited by pentobarbital (ED50 30 mg/kg) and chlormethiazole (ED50 50 mg/kg) but not dizocilpine. The data demonstrate that the harmaline-induced tremor and cerebellar cyclic GMP rise are probably not associated. They also demonstrate that chlormethiazole is able to inhibit a biochemical response (the increase in cerebellar cyclic GMP) which results from increased glutamate function.

Animals↗
PubMed1993

The human neuroblastoma cell line, IMR-32 possesses a GABAA receptor lacking the benzodiazepine modulatory site.

GABAA receptors were identified in IMR-32 cell membranes by the binding of [35S]t-butyl-bicyclophosphorothionate ([35S]TBPS) to the chloride channel. GABA (IC50 2.2 microM), muscimol (IC50 0.8 microM), picrotoxin (IC50 1.7 microM), pentobarbitone (IC50 108 microM), etomidate (IC50 53 microM), chlormethiazole (IC50 98 microM) and Ro 5-3663 (IC50 280 microM) all inhibited [35S]TBPS binding. The potency of these drugs at the [35S]TBPS binding site in IMR-32 cell membranes did not correlate with their potency on [35S]TBPS binding to rat cortical membranes (linear correlation of pIC50 values, r = 0.75, NS). No specific binding of the benzodiazepine ligands [3H]flunitrazepam or [3H]Ro 15-4513 to IMR-32 cell membranes was observed. Chloride efflux from IMR-32 cells was studied using the fluorescent dye 6-methoxy-N-(3-sulphopropyl) quinolinium. Chloride efflux was stimulated by GABA and muscimol (0.1-100 microM) but not by the GABAB agonist baclofen (100 microM). In the absence of exogenous GABA chloride efflux was stimulated by chlormethiazole (1-100 microM) in a picrotoxin-sensitive manner. Flurazepam (1-100 microM) both alone and in the presence of GABA had no effect on chloride efflux. It is concluded that IMR-32 cells contain a functional GABAA receptor which differs from that in rat cortex both in its general pharmacology and specifically in the absence of the allosteric modulatory site sensitive to benzodiazepines.

Animals↗
PubMed1993

The effects of chlormethiazole and nimodipine on cortical infarct area after focal cerebral ischaemia in the rat.

Focal ischaemia in the rat cerebral cortex was produced by means of a photochemically induced thrombosis of cerebral arteries. This was achieved by intravenous infusion of the photosensitive dye Rose Bengal and illumination of the skull with focused green light. Initial experiments justified the use of tetrazolium staining as an index of infarct damage. Using this technique it was demonstrated that chlormethiazole (200 mg/kg, i.p.) given 5 min post ischaemia markedly reduced the area of infarcted cortical tissue. A second experiment replicated this observation and showed that, in contrast, nimodipine (0.5 mg/kg, i.p.) given 5 min post infarct was without effect on infarct size. The pattern of Evans Blue extravasation indicated that the infarct developed over a 24-h period with the major damage occurring in the first 4.5 h. The spread of the infarct beyond the initial core of damage was decreased by an estimated value of almost 50% by injection of chlormethiazole (200 mg/kg, i.p.) 5 min after the light exposure. These data indicate that chlormethiazole is an effective drug in protecting against the effects of focal ischaemia in the rat and, taken with earlier observations that chlormethiazole protects against the effects of global ischaemia in the gerbil, suggest that the drug may be an effective treatment against the ischaemic cell death that can occur following a stroke or cardiac arrest.

Animals↗
PubMed1993

Identification of the GABAA receptor alpha 3 subunit in the IMR-32 neuroblastoma cell line.

A previous report has described the presence of t-[35S]-butylbicyclophosphorothionate binding sites and GABA-gated Cl- flux in the human neuroblastoma IMR-32 cell line. We now report the further characterisation of this binding site and, even more important, the identification of the GABAA receptor alpha 3 sub-unit expressed in these cells. Cell membranes prepared from IMR-32 cells were screened by immunoblotting for reactivity with various GABAA receptor alpha subunit-specific antibodies. Of these, only anti-Cys alpha 3 454-467 antibodies recognised specifically and in a dose-dependent manner an immunoreactive band. This M(r) 58,000 immunoreactive species and the N-deglycosylated derivatives were both coincident with the respective homologues found in both calf cerebral cortex membranes and purified receptor preparations. This is the first report of the identification of a specific GABAA receptor subunit expressed in a human cell line, and it therefore provides a convenient model for the study of receptor structure and regulation.

Animals↗
PubMed1992

The immediate consequences of middle cerebral artery occlusion on GABA synthesis in mouse cortex and cerebellum.

The effect on gamma-aminobutyric acid (GABA) synthesis of focal ischaemia in the right cortex of the mouse was investigated by performing a right middle cerebral artery (MCA) occlusion. Synthesis of GABA was determined by measurement of the rate of GABA accumulation in tissue following injection of amino oxyacetic acid (AOAA; 30 mg/kg, i.p.). Five min following the MCA occlusion, the rate of GABA synthesis in the right (ischaemic) cortex was decreased by approximately 70% compared to either the left cortex or the right cortex of untreated controls. The basal GABA concentration was however unaffected. Four hours after the occlusion the rate of GABA synthesis was similar in the right and left cortex. The rate of GABA accumulation in the cerebellum was unchanged at both times after the right MCA occlusion compared with untreated control mice. The data suggest that there is a rapid but short lasting decrease in GABA synthesis following an ischaemic insult and it is suggested that this might be associated with the EEG spiking activity that occurs at this time.

Aminooxyacetic Acid↗