Chlormethiazole, dizocilpine and haloperidol prevent the degeneration of serotonergic nerve terminals induced by administration of MDMA ('Ecstasy') to rats.

An investigation has been made into the effect of 3,4-methylenedioxymethamphetamine (MDMA or 'Ecstasy') administration on the concentration of 5-hydroxytryptamine (5-HT), uptake of [3H]5-HT and [3H]paroxetine binding in rat cerebral cortex tissue. Four days after 2 injections of MDMA (20 mg/kg i.p., 6 hr apart) the concentrations of 5-HT and its metabolite 5-HIAA were reduced by 60%. The binding of [3H]paroxetine to the presynaptic 5-HT transporter was decreased and high affinity uptake of [3H]5-HT was reduced by a similar amount, indicating neurodegeneration of 5-HT terminals. Pretreatment with chlormethiazole (100 mg/kg i.p.), 10 min before each MDMA injection prevented the decrease in both [3H]parotextine binding and uptake of [3H]5-HT. The loss in 5-HT and 5-HIAA content was also attenuated. Pretreatment with dizocilpine (1 mg/kg i.p.) or haloperidol (2 mg/kg i.p.) also prevented the MDMA-induced loss of [3H]paroxetine binding and attenuated the loss of 5-HT and 5-HIAA content. All three compounds also decreased the degree of hyperthermia that follows MDMA administration, although previous studies suggest that the long term neurodegeneration is not associated with the acute hyperthermic response. These data support the findings of others that MDMA injection produces degeneration of 5-HT nerve terminals in the cortex, confirm that chlormethiazole, dizocilpine and haloperidol attenuate MDMA-induced neurotoxic loss of 5-HT and demonstrate for the first time that these compounds prevent the neurodegeneration of 5-HT nerve terminals that follows MDMA administration.

The use-dependent sodium channel blocker mexiletine is neuroprotective against global ischemic injury.

Mechanisms responsible for anoxic/ischemic cell death in mammalian CNS grey and white matter involve an increase in intracellular Ca2+, however the routes of Ca2+ entry appear to differ. In white matter, pathological Ca2+ influx largely occurs as a result of reversal of Na+-Ca2+ exchange, due to increased intracellular Na+ and membrane depolarization. Na+ channel blockade has therefore been logically and successfully employed to protect white matter from ischemic injury. In grey matter ischemia, it has been traditionally presumed that activation of agonist (glutamate) operated and voltage dependent Ca2+ channels are the primary routes of Ca2+ entry. Less attention has been directed towards Na+-Ca2+ exchange and Na+ channel blockade as a protective strategy in grey matter. This study investigates mexiletine, a use-dependent sodium channel blocker known to provide significant ischemic neuroprotection to white matter, as a grey matter protectant. Pentobarbital (65 mg/kg) anesthetized, mechanically ventilated Sprague-Dawley rats were treated with mexiletine (80 mg/kg, i.p.). Then 25 min later the animals were subjected to 10 min of bilateral carotid occlusion plus controlled hypotension to 50 Torr by temporary partial exsanguination. Animals were sacrificed with perfusion fixation after 7 days. Ischemic and normal neurons were counted in standard H&E sections of hippocampal CA1 and the ratio of ischemic to total neurons calculated. Mexiletine pre-treatment reduced hippocampal damage by approximately half when compared to control animals receiving saline alone (45 vs. 88% damage, respectively; P<0.001). These results suggest that mexiletine (and perhaps other drugs of this class) can provide protection from ischemia to grey matter as well as white matter.

The behaviour of schizophrenic day-patients at home: an assessment by relatives.

Relatives of 39 schizophrenic patients attending a day hospital in South Glamorgan assessed the patients' behaviour at home covering a period of one week. The results pointed to the existence of a sub-group of patients with severe behavioural problems. These patients had had more psychiatric admissions, and had spent a longer total time in hospital. The proportion of forms of behaviour regarded as problems by the relatives themselves was lower than that suggested by their assessments, except in the families where the patient exhibited severe behavioural difficulties. The findings are discussed in terms of the practical difficulties regarding home-management by relatives of the schizophrenic.

Evaluation of teaching methods in a home-based training scheme for developmentally delayed pre-school children.

Thirty-eight pre-school developmentally delayed children receiving the South Glamorgan Home Advisory Service were included in the study. The children were grouped according to developmental ability and manifesting problems. The effectiveness of three methods of teaching (activity charts, target setting, suggestion) were assessed under a balanced design. Weekly skill gain and increments on checklists were measured at the start and at the end of the study period. Parents' opinions on the different methods of teaching were requested and time samples of duration of home visiting were taken. On weekly skill gain, suggestion proved less effective than activity charts or target setting. Severely delayed children made least progress on weekly skill gains. Progress on checklists was independent of teaching method. However, group differences were observed in that severely delayed children (DQ range 22-61) and older (greater than 17 months) Down's syndrome children made least gains on the checklists. Activity charts were preferred by parents although they were also rated as being the most time consuming. Duration of home visits tended to be greater when activity charts were used. Implications of the findings are discussed with reference to ways of improving advice given to parents and alternative ways of evaluating pre-school educational programmes for particular groups of children.

Profiles of skill gain in delayed infants and young children.

Thirty-eight developmentally delayed preschool children were entered into a study to assess their developmental progress on skills checklists during a 3-month period. All children were receiving the South Glamorgan Home Advisory Service. Weekly tasks were set in a balanced manner. Children were assessed on twelve developmental checklists both prior to and following the study period. Results showed that in general children made greater progress in inspection/tracking and perceptual problem-solving skills than in motor, self-help and visuomotor areas. Separate analyses for Down's children and for children of different developmental levels indicated slightly altered developmental profiles. Results are discussed in terms of implications for early intervention programmes.

Cognitive and behavioural profiles of the elderly mentally handicapped.

In 148 mentally handicapped in-patients aged between 65 and 88 years, evidence was found for ongoing intellectual development in adulthood until late middle-age. This was usually followed by a decline in intellectual functioning which became significant in 18%. For these, intellectual deterioration was associated with deficient self-care skills, poor orientation and staff reports of deterioration. It was not related to previous ability levels or prolonged hospitalization. For the entire sample, competence in self-care skills was high though behaviour disturbance was present in about half. Results are discussed in terms of their implications for the care and training of the elderly mentally handicapped.

Ageing in Down's syndrome.

In a group of 23 hospital patients aged over 50 with Down's syndrome, psychological testing indicated that significant intellectual deterioration, which was un-related to chronological age, sex, length of hospitalisation, or earlier mental age, had occurred in nine. Clinically, there was no evidence in any patient of active physical illness, focal neurological signs, or dementia, but significant associations were found between intellectual deterioration and decreased visual acuity, hearing loss, and macrocytosis.

Down's syndrome: intellectual and behavioural functioning during adulthood.

Previous cross-sectional studies of Down's syndrome have suggested that deficits in cognitive and neurological functioning after the age of 35 years are symptomatic of Alzheimer's disease. It has been claimed that this pattern corresponds to post-mortem neuropathological findings of Alzheimer's disease in all Down's syndrome patients who die aged over 35 years. In the present study of Down's syndrome patients aged between 19 and 49 years, results showed that, for those over 35 years, intellectual deterioration had occurred in less than a third. No relationship was found between chronological age and the level of self care skills or the presence of disturbed behaviour. Results are discussed in terms of the interpretation of the existing neuropathological literature, the methodology of future studies and clinical decisions regarding hospitalized patients with Down's syndrome.

An investigation of the possible interaction of clomethiazole with glutamate and ion channel sites as an explanation of its neuroprotective activity.

The activity of the neuroprotective agent clomethiazole at glutamate and ion channel sites has been investigated. Dizocilpine (3.25 mg/kg intraperitoneally) provided almost total protection against the damage produced by infusion of N-methyl-DL-aspartate (NMDLA; 75 micrograms) into the right hippocampus. In contrast, clomethiazole (96 mg/kg intraperitoneally) was without effect. Using ligand binding techniques, no evidence was found for clomethiazole interacting with NMDA, AMPA or sigma binding sites. Clomethiazole did inhibit the stimulatory effect of the metabotropic glutamate receptor agonist 1S3R-aminocyclopentone-1,3-dicarboxylic acid (ACPD) on phosphoinositol hydrolysis, but only at a concentration of 10(-3) M, which is unlikely to have functional relevance. Clomethiazole was also without effect on ligand binding to Ca2+ channels (N- or L- type), Na+ channels or ATP-sensitive K+ channels. Potentiation of GABA function therefore remains the most plausible explanation for the neuroprotective activity of clomethiazole.

Selective coupling of mu-calpain activation with the NMDA receptor is independent of translocation and autolysis in primary cortical neurons.

Excessive mu-calpain activation has been linked to several cellular pathologies including excitotoxicity and ischemia. In erythrocytes and other non-central nervous system (CNS) cells, calpain activation is thought to occur following a Ca2+-induced translocation of inactive cytosolic enzyme to membranes and subsequent autolysis. In the present report, we show that transiently exposing primary rat cortical neurons to lethal (50 microM) N-methyl-D-aspartic acid (NMDA) caused protracted calpain activation, measured as increased spectrin hydrolysis, but this was independent of translocation or autolysis of the protease. An anti-mu-calpain antibody showed that calpain was largely membrane associated in cortical neurons, and, consequently, neither translocation nor autolysis of the protease was observed following ionomycin or lethal NMDA treatment. By contrast, in rat erythrocytes, calpain was largely cytosolic and underwent rapid translocation and autolysis in response to ionomycin. Calpain-mediated spectrin hydrolysis was specifically coupled to Ca2+ entry through the NMDA receptor because nonspecific Ca2+ influx via ionomycin or KCl-mediated depolarization failed to activate the enzyme. Thus, calpain appears selectively linked to glutamate receptors in cortical neurons and regulated by mechanisms distinct from that occurring in many non-CNS cells. The data suggest that intracellular signals coupled to the NMDA receptor are responsible for activating calpain already associated with cellular membranes in cortical cells.