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Biomedical subjects

B S Meldrum

Publications and source records attributed to B S Meldrum.

At least 109 records · Page 6Linked to original sources
PubMed1991

Anticonvulsant action of 2-chloroadenosine injected focally into the inferior colliculus and substantia nigra.

Focal injection of 2-chloroadenosine into the substantia nigra protects Sprague-Dawley rats against electroshock seizures (50 mA. 60 Hz, 0.2 s) and genetically epilepsy prone rats against audiogenic seizures. 2-Chloroadenosine infusion into the substantia nigra pars reticulata provided significant protection against electroshock seizures (1.66, 8.33 and 25 nmol) and audiogenic seizures (66, 331 pmol and 1.66 nmol). High doses of 2-chloroadenosine injected into the substantia nigra pars compacta resulted in a similar suppression of electroshock seizure activity (8.33 nmol) and audiogenic seizures (1.66 nmol). No anticonvulsant activity was observed when 2-chloroadenosine was infused into the entopeduncolar nucleus. Lower doses of 2-chloroadenosine provided significant protection against audiogenic seizures (66 and 331 pmol) when injected into the inferior colliculus. Aminophylline antagonised these effects, indicating that purinergic mechanisms are involved in both audiogenic and electroshock seizures. In addition, the similarity of these effects to those elicited by excitatory amino acid antagonists in the inferior colliculus and substantia nigra pars reticulata is consistent with 2-chloroadenosine acting by reducing excitatory transmission.

2-Chloroadenosine↗
PubMed1991

The high pressure neurological syndrome in genetically epilepsy prone rats: protective effect of 2-amino-7-phosphono heptanoate.

Genetically epilepsy prone rats (GEPR) are hypersensitive to various epileptogenic treatments and undergo characteristic generalized seizures when exposed to potent acoustic stimulation. We have studied the sensitivity of GEPR to high atmospheric pressure. Threshold pressures for behavioral symptoms of the high pressure neurological syndrome (HPNS) were recorded in normal Sprague-Dawley (SD) and GEPR (which originate from the SD strain) of both sexes. The threshold pressure (TP) for tremor and for convulsion was significantly lower in GEPR than in SD rats. The protective action of the NMDA receptor antagonist D-2-amino-7-phosphono-heptanoate (D-APH) was tested on both strains of rats. D-APH, 90 mg/kg ip was more protective against tremor in SD than in GEPR. Female GEPR were not protected against tremor. Protection against clonic seizures was similar in both sexes of GEPR and female SD rats while SD males were not significantly protected. None of the animals treated with D-APH developed the tonic phase of seizures. Blockade of the NMDA receptor with D-APH brought the threshold for convulsions in GEPR to a similar pressure to that obtained in SD vehicle-injected controls. This findings suggests the involvement of the excitatory amino acid system in the hypersensitivity of GEPR to high atmospheric pressure.

2-Amino-5-phosphonovalerate↗
PubMed1991

Brain nuclei and neurotransmitters involved in the regulation of the high pressure neurological syndrome in the rat.

The role of glutamatergic (NMDA), cholinergic and purinergic neurotransmission in the pedunculopontine nucleus, red nucleus, ventrolateral thalamic nucleus, entopeduncular nucleus, and the substantia nigra in the development of the high pressure neurological syndrome (HPNS) was investigated in the rat. Focal injection of D-2-amino-7-phosphonoheptanoate (D-APH, 5 nmol per side) into the red nucleus or the pedunculopontine nucleus was protective against HPNS-induced convulsions. Carbachol (10 nmol), injected into the red nucleus, did not influence the severity of the symptoms of HPNS. Injection of carbachol into the pedunculopontine nucleus, significantly lowered the threshold pressure for convulsions and increased the threshold pressure for tremor. 2-Chloroadenosine (5 nmol), injected into the red nucleus, produced a potent antitremorgenic effect and a similar but less pronounced effect when injected into the pedunculopontine nucleus. 2-Chloroadenosine, injected into the substantia nigra (12.5 nmol) or the ventrolateral thalamic nucleus (25 nmol), facilitated the development of tremor and, in the entopeduncular nucleus (25 nmol), facilitated the occurrence of convulsions. These results show the complexity of neurotransmitter interactions in different regions of the brain, under high pressure. They also indicate that the biochemical and anatomical substrates, involved in the convulsions produced by HPNS, differ substantially from those in other experimental models of epilepsy.

2-Amino-5-phosphonovalerate↗
PubMed1991

The effects of the competitive NMDA receptor antagonist CPP on the high pressure neurological syndrome in a primate model.

Neurophysiological interactions between the competitive N-methyl-D-aspartate (NMDA) preferring receptor antagonist, CPP (3-((+-)-2-carboxypiperazine-4-yl)-propyl-1-phosphonate) and the high pressure neurological syndrome (HPNS) have been investigated in the non-human primate Papio anubis. Eight animals were exposed on two occasions to environmental pressures of 81 atmospheres absolute (ATA) in a hyperbaric chamber, using helium and oxygen. One exposure followed pretreatment with CPP (either 5 or 10 mg/kg i.v. plus 5 mg/kg/hr infusion), the other a saline control. Pretreatment with CPP delayed moderate signs of face tremor and myoclonus and abolished severe signs of whole body tremor and seizure activity. By 81 ATA, scores representing severity of HPNS were significantly reduced by CPP to a mean score, reflecting a level of just mild to moderate limb tremoring (P less than 0.001). Changes in the EEG were observed in channels associated with the frontal, parietal and occipital regions of the left cortex. Amplitude and frequency spectra were calculated and changes with pressure in the 4 conventional wavebands were analysed. The most striking change was the complete prevention by CPP of the 100% increase in the amplitude of alpha waves at 81 ATA in the frontal region (P less than 0.001). It is concluded that NMDA transmission has a major role in the expression of HPNS.

Animals↗
PubMed1991

Changes in rat brain extracellular glutamate concentration during seizures induced by systemic picrotoxin or focal bicuculline injection: an in vivo dialysis study with on-line enzymatic detection.

An on-line enzymatic assay of dialysis fluid has been used to monitor the extracellular glutamate concentration in the rat hippocampus. Perfusion with artificial cerebrospinal fluid containing a glutamate uptake inhibitor (either dihydrokainate or 4,4'-diisothiocyanatostilbene-2,2' disulfonic acid) produced a marked stable increase in glutamate concentration; 10 min perfusion with 100 mM K+ produced a transient increase. Sustained epileptiform EEG discharges were induced in the hippocampus by focal injection of bicuculline into the piriform cortex or by systemic injection of picrotoxin. Extracellular glutamate did not change significantly during seizure activity, either in the absence or in the presence of glutamate uptake inhibitors. It is concluded that seizure activity is not necessarily accompanied by an overall increase in extracellular glutamate concentration.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1991

The anticonvulsant effect of the non-NMDA antagonists, NBQX and GYKI 52466, in mice.

The excitatory amino acid antagonists, NBQX (2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(F)quinoxaline) and GYKI 52466 (1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine) that act on non-NMDA receptors, provide potent anticonvulsant protection against AMPA [RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)-induced seizures in Swiss mice and against sound-induced seizures in seizure-susceptible DBA/2 mice. Maximal anticonvulsant protection is observed 5-30 min after the i.p. administration of NBQX and 5-15 min after the i.p. administration of GYKI 52466 in DBA/2 mice. The ED50 values for the protection against AMPA-induced seizures by NBQX (30 min, i.p.) and GYKI 52466 (15 min, i.p.) are 23.6 (11.6-48.0) and 18.5 (11.5-29.5) mumol/kg, respectively. The ED50 values at 15 min for the protection against sound-induced seizures in DBA/2 mice are 31.3 (24.9-39.4) mumol/kg (NBQX, i.p.), 37.8 (21.2-67.4) mumol/kg (NBQX, i.v.) and 13.7 (11.5-16.5) mumol/kg (GYKI 52466, i.p.). In DBA/2 mice the therapeutic index (ratio of ED50 values for impaired rotarod performance and anticonvulsant action) is 6.6 for NBQX (15 and 30 min, i.p.) and 2.0 for GYKI 52466 (15 min, i.p.).

Acoustic Stimulation↗
PubMed1991

L-glutamate diethyl ester and deaminated analogues as excitatory amino acid antagonists in rat cerebral cortex.

1. The effects of L-glutamate diethyl ester (GDEE) HCl, glutarate diethyl ester (GlrDEE) and glutarate dimethyl ester (GlrDME) on depolarizing responses to alpha-amino-3-hydroxy-5- methyl-4-isoxazolepropionate (AMPA), kainate (Kain), N-methyl-D-aspartate (NMDA) and quisqualate (Quis), and spontaneous paroxysmal discharges (SPDs) were examined. Experiments were performed on slices of rat cingulate cortex using the in vitro grease gap recording technique in nominally Mg(2+)-free Krebs medium. 2. GDEE HCl (3-14 mM) caused a concentration-dependent depolarization of the d.c. baseline potential. L-Glutamate (0.1-0.5 mM), HCl (15 mM) and sucrose (30 mM) also depolarized the baseline. GlrDEE (3-12 mM) and GlrDME (4-26 mM) had no consistent effect on baseline potential. 3. GDEE HCl (10 mM) had no effect on depolarizing responses to AMPA, Kain and NMDA, but caused potentiation of those to Quis with a dose-ratio of 0.53 (0.44-0.63) (n = 4). In two other experiments, where the depolarization of the baseline induced by GDEE HCl was large, a depression of Quis response amplitude was observed. 4. GlrDEE (10 mM) antagonized depolarizing responses to Kain, and to a lesser extent NMDA, with dose-ratios of 2.14 (1.92-2.38) and 1.61 (1.39-1.87), respectively. This concentration of GlrDEE had no effect on AMPA responses, but potentiated Quis responses, with a dose-ratio of 0.64 (0.58-0.71). 5. GlrDME (10 mM) antagonized depolarizing responses to Kain and to Quis, with dose-ratios of 1.66 (1.48-1.85) and 1.22 (1.15-1.29), respectively, and had no effect on responses to NMDA. 6. The SPDs were inhibited by GDEE HCI (IC50 6.7 +/- 0.37mM), GlrDEE (IC50 5.6 +/- 0.38 mM) and GlrDME (IC50 10.4 +/- 0.73 mM). 7. In conclusion, there is little evidence that GDEE HCI is an antagonist of the postsynaptic excitatory amino acid receptors in the rat neocortex, and its effects may result from its contamination with Lglutamate and increased osmolarity of the bathing medium at high concentrations. The deaminated analogues of GDEE are very weak Kain antagonists.

Amino Acids↗
PubMed1991

Excitatory amino acid transmitters in epilepsy.

For the majority of human epilepsy syndromes, the molecular and cellular basis for the epileptic activity remains largely conjectural. The principal hypotheses currently concern: defects in membrane ionic conductances or transport mechanisms; defects in gamma-aminobutyric acid (GABA)-mediated inhibitory processes; and enhanced or abnormal excitatory synaptic action. Substantial evidence exists in humans and animals for acquired abnormalities in excitatory amino acid neurotransmission that may participate in the abnormal patterns of neuronal discharge, and this could provide the morphological basis for a recurrent excitatory pathway sustaining seizure discharges in temporal lobe epilepsy. In practice, two approaches appear significant in the suppression of seizures. One is to act postsynaptically on receptors to decrease the excitation induced by glutamate, and the other is to decrease synaptic release of glutamate and aspartate. Agents acting upon adenosine or GABAB receptors decrease glutamate release in vitro but do not have significant anticonvulsant activity, probably because of their predominant actions at other sites. Lamotrigine blocks stimulated release of glutamate and shows anticonvulsant activity in a wide range of animal models.

Anticonvulsants↗
PubMed1991

Neurochemical substrates of ictal behavior.

Ictal activity is associated with (a) very marked changes in energy metabolism and neurotransmitter turnover and (b) complex secondary effects on second messenger systems and the control of protein synthesis. These events both reflect the abnormal patterns of excitatory and inhibitory activity and entail further modifications of neuronal function. More refined in vivo measurements of neurochemical changes and their anatomy will be required if we are to correlate the more subtle ictal behavioral abnormalities with their underlying events.

Animals↗
PubMed1990

Receptor site specificity for the acute effects of beta-N-methylamino-alanine in mice.

DL-beta-N-methylamino-alanine (DL-BMAA; 1-10 mumol i.c.v.) in mice induced a syndrome of: ataxia, ptosis, scratching, jumping, myoclonic jerks, clonic muscle spasms and tonic seizure, which was unaffected by pretreatment with D(-)-4-(3-phosphonoprop-2-enyl)-piperazine-2-carboxylate (D(-)-CPPene; i.p.), or by co-administration of gamma-D-glutamylamino-methylsulphonate (gamma-D-GAMS with DL-BMAA; i.c.v.). Pretreatment with 1-(aminophenyl)-4-methyl-7,8-methylendioxy-5H-2,3-benzodiazepine (GYKI 52466; i.v.) decreased the incidence of clonic seizures for DL-BMAA, kainic acid and RS-alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (RS-AMPA; i.c.v.). These results suggest an involvement of the AMPA/quisqualate subtype of excitatory amino acid receptors in acute BMAA toxicity.

Amino Acids, Diamino↗
PubMed1990

Potent oral anticonvulsant action of CPP and CPPene in DBA/2 mice.

CPP (3-(2-carboxypiperazine-4-yl)-1-phosphonate), and its unsaturated analogue, CPPene (3-(2-carboxypiperazine-4-yl)-1-propenyl-1-phosphonic acid), have potent anticonvulsant activity against sound-induced clonic seizures in DBA/2 mice. Following i.p. administration the protection is maximal at 1-2 h, and the ED50 values (mumol/kg) are: D(-)-CPPene, 1.54; D(-)-CPP, 2.75; D,L( +/- )-CPP, 4.36. Following oral administration the protection is maximal at 3-4 h and the ED50 (mumol/kg) values are: D(-)-CPPene, 40.19; D(-)-CPP, 65.80; D,L( +/- )-CPP, 108.1.

Acoustic Stimulation↗
PubMed1990

Effect of NMDA and 2-amino-7-phosphonoheptanoate focal injection into the ventrolateral thalamic nucleus on the high pressure neurological syndrome in the rat.

We report the effect of focal injections of N-methyl-D-aspartate (NMDA, 5 nmol) and 2-amino-7-phosphonoheptanoate (APH, 5 and 10 nmol) into the ventrolateral thalamic nucleus on behavioural symptoms of the high pressure neurological syndrome in rats. The injection of NMDA significantly lowers the threshold pressure for tremor and increases its intensity. The injection of APH significantly increases the threshold pressure for tremor and decreases its intensity. APH, 10 nmol, significantly increases the threshold pressure for myoclonus and convulsions. These protective effects are, however, less pronounced than those produced by either systemic injection of APH or its focal infusion into the basal ganglia output system.

2-Amino-5-phosphonovalerate↗
PubMed1990

The effects of MK801 on the high pressure neurological syndrome in the baboon (Papio anubis).

The in vivo neurophysiological interactions of the non-competitive NMDA receptor antagonist MK801 with the High Pressure Neurological Syndrome have been investigated in the primate Papio anubis. A hyperbaric chamber was used to achieve environmental pressures of 61 ATA (atmospheres absolute) over a period of 5 hr. Eight animals underwent 2 compressions each, one following pretreatment with 0.03 mg/kg (i.v.) MK801, the other a control. Half of the animals received MK801 on their first exposure. Mild signs of the high pressure neurological syndrome, e.g. paw and limb tremor were first observed between 10 and 20 ATA and more severe signs, e.g. whole body tremor, myoclonus and vomiting, appeared after 50 ATA. The onset pressures for the various signs were increased by 10-17 ATA when the animals received MK801 (P = 0.06) and the severity of the signs, over the whole range of pressures at which they appeared, was significantly reduced (P less than 0.001). Additional experiments showed that MK801 afforded considerable protection, at pressures up to 81 ATA, but doses larger than those used for the main experiment produced signs of tranquilisation and sedation. Changes in the EEG were observed in channels associated with the frontal, parietal and occipital regions. Amplitude and frequency spectra were calculated and trends with pressure in the 4 conventional wavebands were analysed. The most striking change was a decrease in amplitude of delta waves (P less than 0.001), which was ameliorated by MK801 (P less than 0.001).

Animals↗
PubMed1990

Modulation of experimentally induced epilepsy by intracerebral grafts of fetal GABAergic neurons.

Systemic administration of pilocarpine to rats induces seizures that resemble complex partial epilepsy in humans. Susceptibility to these seizures is increased by lesion of the GABAergic striatonigral projection. Transplantation of fetal GABAergic neurons, but also of control non-GABAergic tissue, to the deafferent substantia nigra can reduce such lesion-increased seizure susceptibility. These observations are consistent with prior evidence that GABAergic basal ganglia outflow plays an important role in controlling the spread of seizures, and raise the possibility that intracerebral grafts may be of use for therapy of medically-unresponsive epilepsies.

Animals↗
PubMed1990

Anticonvulsant properties of some calcium antagonists on sound-induced seizures in genetically epilepsy prone rats.

1. The anticonvulsant activity of calcium channel antagonists, was studied after intraperitoneal or oral administration in genetically epilepsy prone rats (GEPR). 2. Flunarizine, dihydropyridines and HA 1004, administered intraperitoneally, were the most potent compounds. Diltiazem, prenylamine, perhexiline, verapamil and methoxyverapamil, given intraperitoneally, were able to reduce the incidence of the tonic phase but were completely ineffective in preventing clonic and running phases of sound-induced seizures in GEPR. Similar anticonvulsant activity was observed when these compounds were administered orally. 3. After intracerebroventricular administration of some of the hydrosoluble calcium antagonists studied, the anticonvulsant effects were similar to those observed after systemic administration. 4. The systemic administration of Bay K 8644, a dihydropyridine analogue, having the ability to stimulate calcium entry into cells produced a dose-dependent increase in clonic and tonic convulsions and other epileptic phenomena, which were prevented by pretreatment with nimodipine or nitrendipine. 5. The possible role of purinergic, excitatory amino acid, GABA-benzodiapine mechanisms as well as the role of Ca2(+)-calmodulin and calcium channel binding sites on the anticonvulsant effects of some calcium antagonists are discussed.

Acoustic Stimulation↗
PubMed1990

Aspartate-like and glutamate-like immunoreactivities in the inferior olive and climbing fibre system: a light microscopic and semiquantitative electron microscopic study in rat and baboon (Papio anubis).

A post-embedding immunogold procedure was used to analyse, in a semiquantitative manner, the distributions of aspartate-like and glutamate-like immunoreactivities in the inferior olive and climbing fibre system in rats and baboons. The neurons in the inferior olive were uniformly labelled for aspartate as well as glutamate, indicating a 100% co-localization of these two amino acids in the cell bodies. The level of glutamate-like immunoreactivity in the climbing fibre terminals was similar to that in the parent cell bodies, as judged by a computer-assisted calculation of gold particle densities. In contrast, the level of aspartate-like immunoreactivity in the climbing fibre terminals was only one-seventh of that of the olivary neurons. No differences were found between the hemispheres and vermis. Nerve terminals in the inferior olive were generally moderately labelled with the aspartate antiserum, as were cell bodies of astrocytes. With a few exceptions, the results obtained in baboons were similar to those in rats. Notably, no evidence was found of an enrichment of aspartate-like immunoreactivity in climbing fibres. The present results do not support previous data suggesting that aspartate is the transmitter of the climbing fibres but indicate that glutamate or another excitatory compound should be considered as candidate for this role. Our findings show that the presence of aspartate-like immunoreactivity in cell bodies is an unreliable indicator of transmitter identity.

Afferent Pathways↗
PubMed1990

Protection by NMDA antagonists against selective cell loss following transient ischaemia.

We have administered antagonists acting competitively or noncompetitively at the N-methyl-D-aspartate receptor after a short period of incomplete ischaemia and evaluated selective neuronal loss in the CA1 region of the rat hippocampus. The competitive antagonists D-(-)-2-amino-7-phosphonoheptanoate (2APH); 100 or 330 mg/kg; 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonate (CPP); 3.3 or 10 mg/kg; and CGS 19755 (cis-4-phosphonomethyl-2-piperidine carboxylate) 3.3 or 10 mg/kg; and the noncompetitive antagonists MK801 [+)5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate), 0.3, 1, or 3 mg/kg, and dextrorphan, 2, 6, 18, or 54 mg/kg, were administered intraperitoneally 15 min and 5 h after a 10-min incomplete ischaemia period; additionally MK801 (1 or 3 mg/kg) and CGS 19755 (10 or 30 mg/kg) were administered 5 and 10 h postischaemia. Seven days after ischaemia, the brains were fixed by perfusion. CA1 pyramidal cell counts were performed on Nissl-stained sections using an ocular grid piece. Ventilated (no ischaemia) control animals had a mean of 406 +/- 13 CA1 neurones/3 grid lengths. Ischaemia reduced this mean to 157 +/- 23. A significant protective effect against this cell loss was seen after two injections (at 15 min and 5 h postischaemia) of 2APH, CPP (10 mg/kg), CGS 19755 (10 mg/kg), MK801 (1 mg/kg), and dextrophan (54 mg/kg). Delayed injection (5 and 10 h postischaemia) of CGS 19755 (10 and 30 mg/kg) and MK801 (1 and 3 mg/kg) did not provide any protection against pyramidal cell loss.

2-Amino-5-phosphonovalerate↗