Biomedical subjects

B S Meldrum

Publications and source records attributed to B S Meldrum.

At least 145 records · Page 8Linked to original sources

PubMed1987

Anticonvulsant action and biochemical effects in DBA/2 mice of CPP (3-((+/-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonate), a novel N-methyl-D-aspartate antagonist.

CPP has a potent anticonvulsant effect against sound-induced seizures in audiogenic DBA/2 mice. Pretreatment with CPP (0.01-10 nmol i.c.v., 45 min) protects against successive phases of sound-induced seizures in a dose-dependent fashion (ED50, tonic phase, 0.023 nmol; clonic phase, 0.039 nmol; wild running, 0.17 nmol). Systemic administration of CPP (0.001-0.1 mmol/kg i.p., 45 min) produces a similar protection (ED50, tonic phase, 0.0012 mmol/kg; clonic phase, 0.0026 mmol/kg; wild running, 0.021 mmol/kg). Following the administration of a fully anticonvulsant dose of CPP (0.1 mmol/kg i.p., 45 min) to adult DBA/2 mice regional brain glucose (cerebellum and striatum) levels are elevated and lactate (striatum and hippocampus) levels decrease. The CPP-induced changes in alanine, serine and glycine paralleled those of lactate. Aspartate levels are significantly decreased by CPP in the striatum (-21%) and the hippocampus (-23%).

Amino Acids↗

PubMed1987

The effect of two novel dipeptide antagonists of excitatory amino acid neurotransmission on the high pressure neurological syndrome in the rat.

Intracerebroventricular injection in the rat of beta-D-aspartyl aminomethylphosphonate (Asp-Amp) 1 mumol, or Y-D-glutamylaminomethylsulphonate (GAMS) 1 mumol, increases the onset pressure for the initial tremor phase of the high pressure neurological syndrome (HPNS) by 50%. Asp-Amp also significantly increases the onset pressures for myoclonus and for tonic-clonic seizures. GAMS did not significantly change the onset pressures for myoclonus or tonic clonic seizures, but it caused the appearance of brief clonic seizures prior to the onset of the HPNS.

Animals↗

PubMed1987

Evidence that antagonism at non-NMDA receptors results in anticonvulsant action.

The effect of gamma-D-glutamylaminomethylsulphonate (gamma-D-GAMS) and 1-(p-bromobenzoyl)-piperazine-2,3-dicarboxylate (pBB-PzDA) on convulsions elicited by intracerebroventricular application of kainate (KA) and N-methyl-D-aspartate (NMDA) was studied in mice. gamma-D-GAMS, 0.0025-1.0 mumol, and pBB-PzDA, 0.001-0.2 mumol, were preferentially active against myoclonic seizures induced by kainate, but had also pronounced anticonvulsant action against NMDA. Although pBB-PzDA was a more potent anticonvulsant relative to gamma-D-GAMS, gamma-D-GAMS displayed higher kainate-selectivity. gamma-D-GAMS, 0.025 and 0.5 mumol, and pBB-PzDA, 0.1 mumol, blocked myoclonic seizures induced by kainate in the presence of 2-amino-7-phosphonoheptanoate, a selective antagonist at the NMDA receptor, with potency comparable to that for antagonism of seizures produced by kainate alone. These results indicate that antagonism at kainate receptors may contribute to anticonvulsant drug action.

Animals↗

PubMed1987

Neurotransmission in the pedunculopontine nucleus and pilocarpine-induced motor limbic seizures in rats.

Systemic injection of the cholinergic agonist, pilocarpine (380 mg/kg, i.p.) initiates a sequence of events leading to motor limbic seizure activity. Focal injection of the excitatory amino acid antagonist, 2-amino-7-phosphonoheptanoic acid (50 pmol-1 nmol) into the pedunculopontine nucleus (PPN), prior to pilocarpine injection, results in a powerful anticonvulsant action. The GABA agonist, muscimol (25-50 pmol) also afforded protection against pilocarpine-evoked convulsions when injected focally into the PPN. The results suggest that an overall inhibition of PPN output neurons is required for anticonvulsant action.

2-Amino-5-phosphonovalerate↗

PubMed1987

Kynurenate inhibition of cell excitation decreases stroke size and deficits.

Pharmacological inhibition of excitatory neurotransmission attenuates cell death in models of global ischemia/reperfusion and hypoglycemia. The current investigations extend these observations to a model of focal ischemia. Kynurenic acid, a broad-spectrum antagonist at excitatory amino acid receptors, was used as treatment (300 mg/kg; 3 doses at 4-hour intervals) before and after focal cerebral ischemia in rats (n = 54). Preischemia but not 1 hour postischemia treatment with kynurenate attenuated infarction size (p less than 0.001) and improved neurological outcome (p less than 0.001) studied at 24 hours after injury. These data support the role of excitatory neurotransmission in acute neuronal injury and support pharmacological inhibition of cell excitation as a potential therapy for stroke.

Animals↗

PubMed1987

Unusual interactions of excitatory amino acid receptor agonists: alpha- and beta-kainate antagonize motor responses to N-methyl-D-aspartate in rodents.

The alpha- and beta-stereoisomers of kainate correspond sterically to the L- and D-isomers of glutamate. Alpha-Kainate is a potent excitant at a specific membrane receptor site (kainate receptor). Beta-Kainate has been proposed as a functional N-methyl-D-aspartate antagonist in vivo. Because of the structural similarities between the alpha- and beta-stereoisomers of kainate we have investigated the interactions of both compounds with N-methyl-D-aspartate-mediated excitation in two well established animal models for assessing the action of excitatory amino acids and their antagonists in vivo: determination of CD50 (convulsant dose) for myoclonic seizures in mice and electromyographic measurement of muscle tone in genetically spastic rats. We find that alpha-kainate and beta-kainate produce myoclonic seizures in mice when given intracerebroventricularly and increase the muscle tone in genetically spastic rats when given intrathecally. Alpha-Kainate is about 5000 times more potent than beta-kainate as a convulsant and about 1000 times more active than beta-kainate in increasing the muscle tone. The excitatory actions of alpha-kainate and of beta-kainate are blocked by gamma-D-glutamylaminomethylsulphonate, a preferential kainate/quisqualate antagonist, but not by (+/-)-2-amino-7-phosphonoheptanoate, a specific N-methyl-D-aspartate antagonist. Surprisingly, alpha-kainate and beta-kainate antagonize the myoclonic seizures and the increase in muscle tone produced by N-methyl-D-aspartate, and potentiate both the anticonvulsant and myorelaxant actions of (+/-)2-amino-7-phosphonoheptanoate. Quisqualate induces myoclonic seizures in mice after intracerebroventricular application and increases muscle tone in genetically spastic rats following intrathecal injection.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1987

Redistribution of transmitter amino acids in rat hippocampus and cerebellum during seizures induced by L-allylglycine and bicuculline: an immunocytochemical study with antisera against conjugated GABA, glutamate and aspartate.

The effects of the convulsants L-allylglycine and bicuculline on the distribution of gamma-amino-butyric acid (GABA), glutamate and aspartate in rat brains were assessed immunocytochemically, using antisera raised against glutaraldehyde-protein conjugates of the respective amino acids. In accord with previous biochemical studies of GABA content, L-allylglycine treatment was followed by a decreased immunoreactivity for GABA in the hippocampus and cerebellum, whereas treatment with bicuculline led to an increased immunoreactivity in the hippocampus, but not in the cerebellum. Different cells and zones were affected differentially. With both convulsants the hippocampus showed the most pronounced changes in the neuropil of the pyramidal and granular cell layers. L-Allylglycine treatment led to a substantial decrease in the concentration of detectable GABA-immunoreactive bouton-like dots in the stratum oriens, radiatum and lacunosum-moleculare and in the deep hilar region, but did not produce statistically significant changes in this parameter in the outer and intermediate zones of the dentate molecular layer. In the cerebellum, the decrease in GABA immunoreactivity after L-allylglycine treatment was less in the basket cell terminals than in other GABA-containing elements. Neither convulsant altered the average staining intensity for aspartate or glutamate in the two regions studied, but L-allylglycine reduced the level of aspartate-like immunoreactivity in hippocampal hilar cells. All the changes described were evident after 20 min of seizure activity and were qualitatively similar after 60 min of seizure (animals paralysed and ventilated). Our results indicate that L-allylglycine or bicuculline given intravenously exerts specific effects on cerebral amino acid metabolism. The nature and magnitude of these effects show inter-regional variations and also differ among cellular compartments within each region. Amino acid immunocytochemistry may prove to be a valuable tool for the investigation of metabolic changes associated with epileptic seizures and should be particularly useful in regions showing heterogeneous changes that would tend to cancel each other in biochemical analyses.

Allylglycine↗

PubMed1987

Bidirectional effects of beta-carbolines in reflex epilepsy.

Derivatives of ethyl-beta-carboline-3-carboxylate, ZK 91296, ZK 93423 and ZK 95962 have potent anticonvulsant activity against sound-induced seizures in audiogenic DBA/2 mice and against photically-induced seizures in the baboon, Papio papio. The convulsant beta-carbolines, DMCM and beta-CCM, have proconvulsant and convulsant activity in the same animal models. DMCM and beta-CCM are similar in potency as convulsants in DBA/2 mice (ED50 value for DMCM: 1.3 mg/kg; ED50 value for beta-CCM; 0.8 mg/kg), but differ with respect to their profiles for protection by anticonvulsant drugs. The anticonvulsant potencies of diazepam and clobazam are similar against both types of beta-carboline-induced seizures, whereas quazepam protects better against beta-CCM seizures (4 fold elevation in ED50 value at 1 mg/kg quazepam IP) than against DMCM seizures (1.7 fold elevation in ED50 value), supporting a preferential action of beta-CCM on BZ1 receptors. Valproate (400 mg/kg) and gamma-vinyl-GABA (1.5 g/kg) protect better against beta-CCM seizures (9.5 and 5.9 fold elevations in ED50 values respectively) than against DMCM seizures (1.8 and 2.7 fold elevations in ED50 values respectively). The excitatory amino acid antagonist, 2-amino-7-phosphonoheptanoic acid, has significant anticonvulsant activity against DMCM seizures. The elevated regional GABA levels in brains of DBA/2 mice observed during beta-CCM seizures are eliminated by the pretreatment with Ro 15-1788, which also blocks the seizure activity.

Animals↗

PubMed1987

Paradoxical anticonvulsant activity of the excitatory amino acid N-methyl-D-aspartate in the rat caudate-putamen.

We used limbic seizures induced in rats by systemic injection of the cholinergic agonist pilocarpine (380 mg/kg; i.p.) to study the neuronal pathways within the basal ganglia that modulate seizure threshold. N-Methyl-D-aspartate (N-Me-D-Asp) is an excitatory amino acid derivative that is a powerful convulsant agent when injected into the cerebral cortex, amygdala, or hippocampus in rats. Bilateral microinjections of N-Me-D-Asp into the caudate-putamen, however, protected against limbic seizures induced by pilocarpine (injected systemically), with an ED50 of 0.7 nmol (range 0.5-1.0 nmol). Lesioning the caudate-putamen (by bilateral microinjection of the excitotoxin ibotenate) converted subconvulsant doses of pilocarpine into convulsant ones. The anticonvulsant action of N-Me-D-Asp in the caudate-putamen was reversed by blocking gamma-aminobutyrate-mediated inhibition in the substantia nigra pars reticulata or in the entopeduncular nucleus. The results suggest that the caudate-putamen and its gamma-aminobutyrate-dependent efferent pathways modulate the threshold for seizures in the limbic forebrain.

Animals↗

PubMed1987

2-Amino-7-phosphonoheptanoic acid inhibits insulin-induced convulsions and striatal aspartate accumulation in rats with frontal cortical ablation.

Pretreatment of rats with the excitatory amino acid antagonist 2-amino-7-phosphonoheptanoic acid (2-APH; 0.5 mmol/kg, i.p.) protected against insulin-induced clonic seizures. Complete protection was observed in 38% of the rats and partial protection in an additional 50%. Lesioning of the corticostriatal pathway by frontal cortical ablation caused decreases in the striatal levels of aspartate (-28%) and glutamate (-18%), an increase in striatal glutamine level (45%), and decreased high-affinity uptake of D-[3H]aspartate (-27%) in the lesioned dorsal neostriatum. Insulin-induced hypoglycemia caused a predicted sharp increase in aspartate level (165%) and decreased glutamate (-20%) and glutamine (-38%) levels in the intact striatum. Pretreatment of rats with 2-APH significantly reversed the insulin-induced changes in striatal aspartate, glutamate, and glutamine levels, especially in the intact hemisphere. In normoglycemic control rats, the "metabolic," i.e., concentration in the lesioned hemisphere, aspartate pool constituted 72% and the "synaptic," i.e., the concentration difference between the intact and lesioned hemispheres, 28% of the total striatal aspartate pool. 2-APH had no effect on the level of "metabolic" aspartate in the striata of normoglycemic rats but caused an almost complete suppression of "synaptic" aspartate. Following insulin-induced hypoglycemia, the "metabolic" aspartate pool doubled, whereas the "synaptic" aspartate pool increased 3.5-fold in the absence of 2-APH. The insulin-induced rise in "synaptic" aspartate level was almost completely blocked by 2-APH (a 5% rise instead of a 3.5-fold rise).(ABSTRACT TRUNCATED AT 250 WORDS)

2-Amino-5-phosphonovalerate↗

PubMed1987

Protection against hypoxic/ischaemic brain damage with excitatory amino acid antagonists.

Selective neuronal loss in the hippocampus following transient forebrain ischaemia appears to be excitotoxic in origin. The early cytological changes in the rat hippocampus (1-2 hours after 10 or 30 minutes of ischaemia) have the ultrastructural appearances of an excitotoxic lesion. Focal injection of an excitatory amino acid antagonist acting competitively on the N-methyl-D-aspartate (NMDA) receptor, 2-amino-7-phosphonoheptanoic acid (2-APH) in one hippocampus protects against the early cytopathology, and, when repeated 4 and 10 hours after the ischaemia, partially protects against selective nerve cell loss. Systemic administration of 2-APH or of a non-competitive antagonist at the NMDA receptor, ketamine, also protects against neuronal loss. Blockade of excitatory transmission at the NMDA receptor may provide a therapeutic approach to the acute treatment of cerebral ischaemia.

Amino Acids↗

PubMed1987

GABA uptake inhibitors. Synthesis and effects on audiogenic seizures of ester prodrugs of nipecotic acid, guvacine and cis-4-hydroxynipecotic acid.

The pivaloyloxymethyl esters 4 and 5 of the amino acid GABA uptake inhibitors guvacine and nipecotic acid, respectively, were synthesized as potential prodrugs. The half-lives of 4 and 5 for conversion into the parent amino acids were determined under approximate physiological conditions in the presence or absence of human serum. Under the former conditions the half-lives for 4 and 5 were 6.3 hr and 0.8 hr, and, in the absence of serum, 15.5 hr and 1.2 hr, respectively. The compounds 4 and 5 were administered intracerebroventricularly (i.c.v.) or intraperitoneally (i.p.) to DBA/2 mice and their effects on audiogenic seizures determined. In agreement with earlier findings for 5, all phases of the seizure response of the animals were suppressed by compound 4 at doses above 2mmol/kg i.p. At anticonvulsant doses of compound 4, as well as of 5, side effects such as sedation and impairments of motor activities were observed. The ethyl and pivaloyloxymethyl esters 9 and 11 of cis-4-acetoxynipecotic acid, designed as 'double' ester prodrugs of the GABA uptake inhibitor cis-4-OH-nipecotic acid, were synthesized and shown to have very weak anticonvulsant effects. Compounds 9 and 11 did, however, show a broad spectrum of cholinergic side effects. These apparent interactions of 9 and 11 with muscarinic cholinergic receptors have been explained on the basis of the similarity of the structures of 9 and 11 to that of the muscarinic agonist 1-methyl-4-acetoxypiperidine. Furthermore, the structural similarity of 9 and the muscarinic agonist nipecotic acid ethyl ester may, to some extent, underlie the cholinergic profile of 9.

Acoustic Stimulation↗

PubMed1986

Anticonvulsant action of a kainate antagonist gamma-D-glutamyl aminomethylsulphonic acid injected focally into the substantia nigra and entopeduncular nucleus.

Focal injection of gamma-D-glutamylaminomethylsulphonic acid (GAMS) into basal ganglia areas, the substantia nigra and entopeduncular nucleus, protects against electroshock (50 mA, 60 Hz, 0.2 s) and pilocarpine (380 mg/kg i.p.) induced seizures in rats. GAMS infusion into substantia nigra pars reticulata significantly protects against generalised (5, 10 nmol) and limbic (10, 50 nmol) seizures. The highest dose of GAMS results in similar suppression of seizure activity following injection into substantia nigra pars compacta against generalised (10 nmol) and limbic (50 nmol) seizures. The anticonvulsant action of GAMS is less marked after infusion into the entopeduncular nucleus. High doses of GAMS are required to provide protection against electroshock test (10 nmol) and limbic (40 nmol) seizures. Protection against limbic and electroshock seizures is more pronounced after infusion of GAMS into substantia nigra than into the entopeduncular nucleus. The substantia nigra pars reticulata is particularly sensitive to the anticonvulsant action of GAMS suggesting that antagonism at the kainate receptor is functionally important.

Animals↗

PubMed1986

Excitatory amino acid and calcium content of subarachnoid spinal fluid during hypoglycemia in the rat.

The concentrations of amino acids and calcium were measured in the subarachnoid cerebrospinal fluid (CSF) of rats prior to, and following, profound hypoglycemia. Calcium concentrations fell and amino acid changes were non-specific following hypoglycemia. In particular, elevations in excitatory amino acids did not occur, even though typical neuropathologic changes were found. These data do not support a role for excitatory amino acids or calcium as a 'CSF-borne toxin' in hypoglycemic brain injury. Moreover, the histopathological patterns of cell loss in the dentate gyrus often could not be reconciled with the concept of a CSF-borne toxin.

Amino Acids↗

PubMed1986

Olfactory bulbectomy protects against pilocarpine-induced motor limbic seizures in rats.

Systemic injection of pilocarpine (380 mg/kg) results in the development of motor limbic seizures in rats. Olfactory bulbectomy performed 7 days prior to pilocarpine administration has a strong protective effect against the seizures. Neuropathological changes which normally occur in this seizure model do not develop in the brains of bulbectomized animals.

Animals↗

PubMed1986

Distribution of [3H]kainic acid and binding sites in the rat brain: in vivo and in vitro receptor autoradiography.

Brain sections incubated in vitro with alpha-[3H]kainic acid (KA; spec. act. 62.5 Ci/mmol), reveal a heterogeneous distribution of low and high affinity KA binding sites in the brain. The highest density of KA binding sites was localised to the hippocampus CA3 region and to superficial layers of the entorhinal cortex (3.8-6.0 mu Ci/g tissue). Intravenous injection of [3H]KA (1 mu Ci/g) reveals limited overall penetration of [3H]KA across the blood-brain barrier. However, a dense labelling of the hippocampus, entorhinal cortex and lateral septal regions (2.5-3.8 mu Ci/g tissue) was observed. Behaviourally, these rats exhibited mild limbic seizure activity possibly as a result of a direct action of KA in the hippocampus or entorhinal cortex.

Animals↗

PubMed1986

Focal injection of 2-amino-7-phosphonoheptanoic acid into prepiriform cortex protects against pilocarpine-induced limbic seizures in rats.

Intraperitoneal injection of pilocarpine (380 mg/kg) produces motor limbic seizures in rats. Focal injection into the prepiriform cortex (PC) of an N-methyl-D-aspartate receptor antagonist, 2-amino-7-phosphonoheptanoic acid (APH), 1-10 pmol, potently protects against these seizures and their pathological consequences. Sites similarly sensitive to the protective action of APH are found along a substantial part of the anterior-posterior extension of the piriform cortex. More caudal injection sites, located at the level of lateral septum are less sensitive. The anticonvulsant action of APH along the extent of the PC is localised in the vicinity of the injection site, as shown by autoradiography following focal injection of tritiated APH.

2-Amino-5-phosphonovalerate↗

PubMed1986

2-Amino-7-phosphonoheptanoic acid (2-APH) infusion into entopeduncular nucleus protects against limbic seizures in rats.

Motor limbic seizures occur following a systemic injection of pilocarpine (380 mg/kg) in rats. Focal injection of the selective N-methyl-D-aspartate receptor antagonist, (+/-)-2-amino-7-phosphonoheptanoic acid (2-APH, 5-20 pmol), bilaterally into the entopeduncular nucleus (EP) prior to pilocarine blocks these seizures. Muscimol (50 pmol), a potent gamma-aminobutyric acid receptor agonist, injected bilaterally into EP produces a similar protection against pilocarpine-induced seizures. Thus by blocking excitatory neurotransmission or facilitating inhibition within the EP, the severity of limbic seizures can be reduced.

2-Amino-5-phosphonovalerate↗