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B S Meldrum

Publications and source records attributed to B S Meldrum.

At least 127 records · Page 7Linked to original sources
PubMed1990

Presynaptic glutamate/quisqualate receptors: effects on synaptosomal free calcium concentrations.

Intracellular free [Ca2+]i was measured using fura-2 in synaptosomes prepared from cerebral cortices of adult male rats (12 weeks). L-(+)-Glutamate, D-(-)-glutamate, and quisqualate produced similar dose-dependent increases in [Ca2+]i, with EC50 values of 0.38 microM, 0.74 microM, and 0.1 microM, respectively, and maximum increases of approximately 40%. Ibotenate showed less affinity (EC50 4.4 microM) but had a greater maximum effect (57%). N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) did not increase [Ca2+]i. The increases in [Ca2+]i induced by quisqualate and ibotenate were not diminished in the absence of extrasynaptosomal Ca2+. L-2-Amino-4-phosphonobutyrate (L-AP4) (1 microM) completely blocked the changes in [Ca2+]i induced by L-(+)-glutamate, D-(-)-glutamate, quisqualate, or ibotenate. The effects of quisqualate and ibotenate on [Ca2+]i were also blocked by coincubation of synaptosomes with L-(+)-serine-O-phosphate (L-SP) (1 mM) (which, like L-AP4, blocks the effects of quisqualate and ibotenate on inositol phospholipid metabolism). 6-Cyano-7-nitroquinoxaline-2,3-dione (CNQX) had no effect on agonist-mediated increases in [Ca2+]i when coincubated with either quisqualate or ibotenate. These data are consistent with the existence of presynaptic glutamate receptors (of the excitatory amino acid metabotropic type) which activate phospholipase C leading to the elevation of inositol 1,4,5-trisphosphate and release of Ca2+ from intracellular stores.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1990

Anticonvulsant action of the beta-carboline abecarnil: studies in rodents and baboon, Papio papio.

Abecarnil (ZK 112119; isopropyl-6-benzyloxy-4-methoxymethyl-beta-carboxylate) is a metabolically stable beta-carboline derivative with potent anxiolytic and few sedative and ataxic effects in rodents. The anticonvulsant and muscle relaxant actions of abecarnil have been evaluated in mice, rats, gerbils and baboons. Abecarnil raised the threshold for tonic electroconvulsions in mice after corneal but not after auricular application, had no effect on maximal electroshock-induced tonic convulsions triggered by either method, protected mice against the tonic hindlimb extension in PTZ-, picrotoxin- and 3-mercaptopropionate-induced seizures and blocked clonus after PTZ, DMCM (methyl-4-ethyl-6,7-dimethoxy-9H-pyrido-(3,4-b)-indol-3-carboxylate) and 3-mercaptopropionate. Abecarnil had no effect on convulsions induced by bicuculline and strychnine. Furthermore, abecarnil blocked kindled seizures after chronic administration of PTZ and FG 7142 (beta-carboline-3-carboxylic acid methylamide) and protected mice and rats against limbic convulsions induced by pilocarpine. Severity and afterdischarge duration of amygdala-kindled seizures were reduced in rats treated with abecarnil. Abecarnil also antagonized selectively convulsions induced by i.c.v. administration of kainate, but not those triggered by N-methyl-D-aspartate or quisqualate. In genetic models of reflex epilepsy, abecarnil was effective against sound-induced convulsions in DBA/2 mice, against air blast-induced generalized seizures in gerbils and against myoclonus in baboons Papio papio. The anticonvulsant effect of abecornil in a PTZ seizure model in mice was potentiated by ethosuximide, whereas no significant potentiation was found with diazepam, clonazepam, diphenylhydantoin, carbamazepine and phenobarbital. Electromyographic monitoring in a etorphine model of muscle rigidity in rats showed no or little muscle relaxant effect of abecarnil.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Excitotoxicity of NMDA and kainic acid is modulated by nigrostriatal dopaminergic fibres.

The excitotoxic action of N-methyl-D-aspartate (NMDA) and of kinase (KA) has been assessed by measuring glutamic acid decarboxylase (GAD) and choline acetyltransferase (ChAT) activity in the rat striatum 5 days after focal microinjections of NMDA or KA. Prior unilateral lesioning of the nigrostriatal dopaminergic pathway by focal injection of 6-hydroxydopamine decreases the excitotoxic effect of NMDA and of KA.

Animals↗
PubMed1989

Non-competitive N-methyl-D-aspartate antagonists protect against sound-induced seizures in DBA/2 mice.

Non-competitive antagonists of the N-methyl-D-aspartate (NMDA) receptor have been evaluated as anticonvulsants against sound-induced seizures in DBA/2 mice. The ED50 values for protection against sound-induced clonic seizures 15 min following the intracerebroventricular (i.c.v.) and intraperitoneal (i.p.) administration are: MK-801, ED50 = 0.5 nmol (i.c.v.); 0.14 mumol/kg (i.p.); phencyclidine, ED50 = 14 nmol (i.c.v.); 1.9 mumol/kg (i.p.); dextrorphan, ED50 = 35 nmol (i.c.v.); 18.5 mumol/kg (i.p.); tiletamine, ED50 = 40 nmol (i.c.v.); 5.6 mumol/kg (i.p.); SKF-10047, ED50 = 50 nmol (i.c.v.); 23.5 mumol/kg (i.p.); dextromethorphan, ED50 = 70 nmol (i.c.v.); 28.0 mumol/kg (i.p.); ketamine, ED50 = 110 nmol (i.c.v.); 15.5 mumol/kg (i.p.). The anticonvulsant effects of ketamine and tiletamine are of short duration (10-30 min), whereas the anticonvulsant effects of MK-801 and dextromethorphan last for 45 min or longer. The effects of phencyclidine, SKF-10047 and dextrorphan are of intermediate duration. Mild to moderate behavioural excitation is associated with the anticonvulsant activity of all the non-competitive NMDA antagonists. For MK-801, phencyclidine, dextrorphan, SKF-10047 and ketamine there is a close correlation between their relative anticonvulsant potencies and their potencies for displacing [3H]MK-801. The anticonvulsant effect is likely to be primarily mediated via NMDA antagonism at the PCP/MK-801 site.

Acoustic Stimulation↗
PubMed1989

Studies on the role of the NMDA receptor in the substantia nigra pars reticulata and entopeduncular nucleus in the development of the high pressure neurological syndrome in rats.

The effect of the focal injection of N-methyl-D-aspartate (NMDA) and 2-amino-7-phosphonoheptanoate (APH) into the substantia nigra pars reticulata (SNR) and entopeduncular nucleus (EP) on behavioural signs of the high pressure neurological syndrome (HPNS) in rats was studied. Doses of 1, 5 and 10 nmoles of NMDA or APH were injected into the SNR or EP, 10-30 min prior to the exposure of animals to a high pressure. Injection of NMDA into either SNR or EP results in a lowering of the threshold pressure for tremor by about 30%. Injection of NMDA into the SNR has no significant effect on clonic seizures whereas its injection into the EP results in a decrease of threshold pressure for clonic seizures. NMDA also facilitates the occurrence of forelimb clonus when injected into the EP. Injection of the NMDA antagonist, APH, into the SNR or EP significantly increases the threshold pressure of tremor (32.8 and 48.2% respectively). Seizure threshold is also increased by the injection of APH into either area, but nigral injections (especially the higher doses) are more protective against seizures than the EP injections. Comparing the two sites blockade of NMDA receptors within the EP is more protective against tremor, whereas in the SNR NMDA blockade is more protective against seizures.

2-Amino-5-phosphonovalerate↗
PubMed1989

N-methyl-D-aspartate receptors in the cortex and hippocampus of baboon (Papio anubis and Papio papio).

In vitro autoradiography was used to examine the N-methyl-D-aspartate receptor in the brain of a baboon species, Papio anubis, and compared to that of Papio papio which exhibits a photosensitive epilepsy. The epilepsy originates in the frontal cortex and is accompanied by an enhanced sensitivity to N-methyl-D-aspartate. In both Papio anubis and Papio papio, the density of N-methyl-D-aspartate receptors was greatest in the hippocampus, followed by associational areas including frontal cortex, and low in primary sensory areas such as the visual cortex. The receptors were concentrated in the outer cortical layers I-III, very low in layer IV except in primary visual cortex, and of intermediate density in layer V. The density of binding sites was approximately two-fold lower than previously observed in the rodent brain, whereas the affinity of the receptor for [3H]L-glutamate was greater in the primate versus the rodent brain. Glycine potentiated the binding of [3H]L-glutamate in both cortex and hippocampus. No significant differences in the properties of N-methyl-D-aspartate receptors were observed between the two baboon species, suggesting that the photosensitivity of Papio papio is not due to alterations in the binding of L-glutamate to the N-methyl-D-aspartate receptor complex.

Animals↗
PubMed1989

GABAergic mechanisms in the pathogenesis and treatment of epilepsy.

1. Evidence relating to the role of GABA in the pathogenesis of epilepsy is reviewed. 2. Impaired GABAergic function appears to contribute to seizure susceptibility in a variety of genetically-determined syndromes in animals, e.g. genetically epilepsy prone rats showing sound-induced seizures, gerbils with genetically determined epilepsy, and baboons, Papio papio, with photosensitive epilepsy. 3. In epilepsy secondary to a cerebral insult there is some morphological and biochemical evidence for impaired GABAergic function in experimental situations, but little definitive evidence in man. 4. Pharmacological approaches to enhancing GABAergic inhibition include the use of GABA agonists (or prodrugs), GABA-transaminase inhibition, GABA uptake inhibition, and action at the GABA/benzodiazepine allosteric site. 5. Experimental data suggest that the best prospect for potent anticonvulsant action with fewest side effects (myoclonus, sedation, ataxia) is at present offered by GABA-transaminase inhibitors or novel agents acting on the benzodiazepine receptor site.

Animals↗
PubMed1988

Susceptibility to pilocarpine-induced seizures in rats increases with age.

Systemic administration of high doses of the cholinergic agonist pilocarpine induces motor limbic seizures in rats. Susceptibility to the convulsant effects of pilocarpine increases during adult life: the threshold dose for generalized seizures is essentially constant from age 30 to 70 days, but decreases thereafter, particularly beyond age 100 days. The increase in seizure susceptibility continues up to at least age 200 days, (the oldest age studied).

Acetylcholine↗
PubMed1988

CGS 19755 is a potent and competitive antagonist at NMDA-type receptors.

The N-Methyl-D-aspartate (NMDA)-type receptor blocking properties of CGS 19755, a novel, rigid analog of 2-amino-5-phosphonopentanoate, were demonstrated in vitro by the ability of the compound to block NMDA-evoked [3H]acetylcholine release (pA2 = 5.93). CGS 19755 (0.045 and 0.224 mmol/kg i.p.) was shown to be active in vivo as well by its ability to block harmaline-induced increases in cerebellar cGMP. Finally, CGS 19755 blocked sound-induced seizures in DBA/2 mice completely at doses of 1.0 nmol i.c.v. or 0.1 mmol/kg i.p. Taken together, these data indicate that CGS 19755 is a potent and competitive NMDA antagonist in vitro which is also active in vivo.

Acetylcholine↗
PubMed1988

The involvement of excitatory amino acid receptors within the prepiriform cortex in pilocarpine-induced limbic seizures in rats.

The prepiriform cortex (PPCx) shows high sensitivity to the epileptogenic action of chemo-convulsants and to the protective action of the NMDA receptor antagonist, 2-amino-7-phosphono-heptanoate (APH) against pilocarpine-induced (motor) limbic seizures in rats. In this study the interaction between agonists acting selectively on the three main excitatory amino acid receptor subtypes in the PPCx and the muscarinic agonist, pilocarpine, within the PPCx have been investigated. Kainate (KA) or quisqualate (QUIS) injected focally into the PPCx (100 pmoles or 5 nmoles per side respectively) induced motor limbic seizures when administered after a subconvulsant dose of pilocarpine (250 mg/kg, i.p.). KA, 100 pmoles injected into the same site in olfactory-bulboectomized rats (bulbectomy results in protection against pilocarpine-induced seizures) also facilitated seizures. However, activation of the NMDA receptor in the PPCx by focal injection of NMDA (250 fmoles-10 nmoles) failed to produce seizures after a subconvulsant dose of pilocarpine. Moreover NMDA in the same range of doses injected into the PPCx protected rats against the seizures induced by a fully convulsant dose of pilocarpine.

Animals↗
PubMed1988

Decrease in excitatory transmission within the lateral habenula and the mediodorsal thalamus protects against limbic seizures in rats.

We have used limbic convulsions induced by systemic pilocarpine in rats combined with focal intracerebral injections concurrently to study the initiation and spread of seizure activity. Protection against pilocarpine-seizure development by antagonism of excitatory or facilitation of inhibitory neurotransmission at focal sites establishes the anatomical circuits involved in the propagation of seizures. The excitatory amino acid antagonist 2-amino-7-phosphonoheptanoate (APH, selective for the NMDA preferring glutamate receptor subtype) is potently anticonvulsant after bilateral focal injections into the habenula or mediodorsal thalamus. The dose of APH required to give sustained protection against pilocarpine-induced convulsions is 10 pmol for lateral habenula and 50 pmol for mediodorsal thalamus. The GABA agonist muscimol produces a similar sustained protection following focal injections (100 pmol/side) into either the lateral habenula or the mediodorsal thalamus. An overall decrease in the efferent neurotransmission of these two brain regions results in a strong anticonvulsant effect indicating their importance in modulating limbic seizure activity.

2-Amino-5-phosphonovalerate↗
PubMed1988

Excitant amino acids and audiogenic seizures in the genetically epilepsy-prone rat. I. Afferent seizure initiation pathway.

The afferent pathway involved in initiation of audiogenic seizures in the genetically epilepsy-prone rat was investigated by bilateral microinfusion of the excitant amino acid antagonist 2-amino-7-phosphonoheptanoate into the major brain stem and subcortical nuclei of the auditory system. This antagonist has been shown to possess anticonvulsant properties in other seizure models, and an excitant amino acid has been implicated as a putative neurotransmitter in several of these nuclei. Seizure severity was significantly reduced following infusion of this agent into the cochlear nucleus, superior olivary complex, inferior colliculus, and medial geniculate body. Many of these animals exhibited a complete blockade of seizures. The smallest effective dose in the cochlear nucleus and the medial geniculate body was 5 nmol per side. The smallest effective dose in the olive was 1 nmol, and in the inferior colliculus 0.1 nmol per side was protective. The onset of anticonvulsant effectiveness was earliest in the inferior colliculus. These findings showed that the inferior colliculus was the most sensitive auditory center to the anticonvulsant action of 2-amino-7-phosphonoheptanoate and that imbalance between inhibitory and excitatory transmission within this brain structure may be crucial in the initiation of audiogenic seizures in the genetically epilepsy-prone rat.

2-Amino-5-phosphonovalerate↗
PubMed1988

Excitant amino acids and audiogenic seizures in the genetically epilepsy-prone rat. II. Efferent seizure propagating pathway.

Previous studies indicate that the inferior colliculus is the brain stem auditory nucleus most sensitive to the chemical blockade of audiogenic seizures in the genetically epilepsy-prone rat. Other auditory structures do not appear to be as important. This study attempted to define the efferent pathways involved in propagation of the seizure from the colliculus to the spinal cord where the motor components of the convulsion are generated. This study also determined whether certain nuclei which have been implicated in the propagation of seizures in other epilepsy models are involved in audiogenic seizures. The excitant amino acid antagonist, 2-amino-7-phosphonoheptanoate, was infused bilaterally into several of those sites. The drug was effective in significantly reducing seizure severity with infusion of 5 nmol bilaterally into the midbrain and the pontine reticular formation or the substantia nigra. However, similar drug doses were not effective when infused into the entopeduncular nucleus even though prominent behavioral effects were observed with this infusion. Infusion of 2-amino-7-phosphonoheptanoate into the prepiriform cortex resulted in a small but significant reduction in seizure severity. These results suggest that inhibition of excitatory transmission within the substantia nigra and the reticular formation effectively blocks the output pathway for the audiogenic seizures, whereas the role of the prepiriform cortex in this process is relatively minor.

2-Amino-5-phosphonovalerate↗
PubMed1988

Regulation of seizure threshold by excitatory amino acids in the striatum and entopeduncular nucleus of rats.

The participation of excitatory neurotransmitter systems in the basal ganglia in the initiation and propagation of limbic seizures induced by pilocarpine has been investigated in the rat. Limbic seizures (electrographic and motor) occur in rats receiving bilateral microinjections into the entopeduncular nucleus of 12.5 nmol N-methyl-D-aspartate or 0.1 nmol kainate, 15 min prior to a subconvulsant dose of pilocarpine (150 mg/kg, intraperitoneally). N-Methyl-D-aspartate (12.5 nmol) or kainate (0.5 nmol), injected alone bilaterally into the entopeduncular nucleus, induce sniffing and grooming but no electrographic or behavioural seizures. Limbic seizures also occur after a subconvulsant dose of pilocarpine when it is preceded by injection of N-methyl-D-aspartate (12.5 nmol) or kainate (0.5 or 2 nmol) into the dorsal striatum. Behavioural and electrographic signs of limbic seizures following pilocarpine (380 mg/kg) are suppressed by the focal microinjection into the entopeduncular nucleus of the N-methyl-D-aspartate antagonist, 2-amino-7-phosphonoheptanoate (0.02 nmol) or the kainate antagonist, gamma-D-glutamylamino-methylsulphonate (40 nmol). Seizure threshold within the limbic system is modulated by excitatory systems controlling basal ganglia outputs. The relative importance of N-methyl-D-aspartate and non-N-methyl-D-aspartate receptor systems varies between different components of the basal ganglia.

Animals↗
PubMed1988

Long-term development of selective neuronal loss and the mechanism of protection by 2-amino-7-phosphonoheptanoate in a rat model of incomplete forebrain ischaemia.

Excitatory neurotransmission at the N-methyl-D-aspartate (NMDA) receptor is selectively blocked by 2-amino-7-phosphonoheptanoate acid (2-APH). Acute focal microinjection of 2-APH into the rat hippocampus partially protects against cytopathology developing in selectively vulnerable neurons after 30 min of ischaemia and 2 h of reperfusion. We show that this protective action of 2-APH does not involve alterations in local cerebral blood flow (CBF). Intermediate cytopathology and long-term neuronal survival has been assessed in rats receiving focal injections of (+/-) 2-APH, 20 micrograms in 1 microliter, into one dorsal hippocampus prior to and 4 and 10 h after a 10-min period of forebrain ischaemia. Cytopathology assessed 4 or 24 h after ischaemia shows no difference between the buffer and 2-APH-injected hippocampi. Assessment after 7 days survival shows a significant protection against neuronal loss in the CA1 zone of the 2-APH-injected hippocampus compared with the contralateral, buffer-injected hippocampus. Systemic injection of D(-)2-APH (675 mg/kg i.v. at 0 h, 4 h, and 10 h) affords significant protection to CA1 hippocampal neurones (as assessed after 7 days). These results suggest that maintained blockade of neurotransmission at the NMDA receptor in the postischaemic period can protect against delayed cell loss. The mechanism may be through antagonism of the excitotoxic action of an endogenous neurotransmitter acting in the postischaemic period.

2-Amino-5-phosphonovalerate↗
PubMed1988

Anticonvulsant effects of some calcium entry blockers in DBA/2 mice.

1. The behavioural and anticonvulsant effects of several drugs acting by various mechanisms on calcium-channels or affecting intracellular Ca2+ concentrations were studied after both systemic and intracerebroventricular administration in DBA/2 mice, a strain genetically susceptible to sound-induced seizures. 2. The anticonvulsant effects were evaluated on seizures evoked by means of auditory stimulation (109 dB) in animals placed singly under a perspex dome. 3. Flunarizine and dihydropyridine derivatives, belonging to class I of calcium entry blockers, administered intraperitoneally, were the most potent compounds. 4. Diltiazem, a benzothiazepine derivative belonging to class III, and HA 1004, a calcium antagonist, acting by inhibiting Ca2+ mobilization from intracellular stores, injected intraperitoneally, were 3-7.6 fold and 5.8-10.7 fold less potent than flunarizine respectively. 5. Verapamil and methoxyverapamil, two phenylalkylamine derivatives, given intraperitoneally, were completely ineffective in preventing sound-induced seizures in DBA/2 mice. In addition, high doses of verapamil and its methoxyderivative occasionally produced spontaneous tonic-clonic seizures. 6. After intracerebroventricular administration of the hydrosoluble calcium entry blockers, belonging to different classes, the anticonvulsant effects were similar to those observed after systemic administration. 7. 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 neurological side effects. 8. The present results strongly support the idea that some Ca2+ antagonists may be useful in human epilepsy.

Animals↗
PubMed1987

An adenosine analogue, 2-chloroadenosine, protects against long term development of ischaemic cell loss in the rat hippocampus.

Delayed ischaemic damage was assessed by light microscopy following 10 min of incomplete forebrain ischaemia and 7 days of reperfusion. Iterative focal injections of 2-chloroadenosine, a stable analogue of adenosine, protect against selective hippocampal CA1 loss (P less than 0.01), when given either immediately before ischaemia and after 4 and 10 h of reperfusion or after 1 min, 4 h and 10 h of reperfusion. Delayed focal injection of 2-chloroadenosine after 10 and 24 h of reperfusion fails to protect against CA1 cell loss. The mechanism of cerebroprotection may involve attenuation of excitatory neurotransmission.

2-Chloroadenosine↗