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Biomedical subjects

B S Meldrum

Publications and source records attributed to B S Meldrum.

At least 163 records · Page 9Linked to original sources
PubMed1986

Does the excitatory amino acid receptor antagonist 2-APH exhibit anxiolytic activity?

The activity of 2-amino-7-phosphonoheptanoic acid (2-APH), an antagonist of the NMDA subtype of glutamate receptor, was tested in several animal models of anxiolytic activity in rats and mice and compared with the activity of the standard benzodiazepine anxiolytic, diazepam. 2-APH was effective, but about 100 times less potent than diazepam in antagonising the suppressive effects of punishment on locomotor activity in the four-plate test in mice. 2-APH was also effective in enhancing exploration of the open, exposed arms of a plus maze, without altering exploration of the enclosed arms. Again 2-APH was about 100 times less effective than diazepam. In contrast to diazepam, 2-APH was ineffective in antagonising the pro-punishment properties of the anxiogenic beta-carboline DMCM in a modified four-plate test, and in antagonising the discriminative stimulus provided by pentylenetetrazol. These results are discussed in the context of the equivalence of the antagonism of excitatory mechanisms and the enhancement of inhibitory systems as anxiolytic treatments.

2-Amino-5-phosphonovalerate↗
PubMed1986

Anticonvulsant action of 1,3-dimethyl-5-aminoadamantane. Pharmacological studies in rodents and baboon, Papio papio.

The anticonvulsant actions of memantine (1,3-dimethyl-5-aminoadamantane) have been evaluated in mice (seizures induced by maximal electroshock, pentylenetetrazol, bicuculline, picrotoxin, 3-mercaptopropionic acid and N-methyl-D,L-aspartic acid) and in photosensitive baboons, Papio Papio (clonic responses to intermittent photic stimulation). Memantine, 5-20 mg/kg, raised the threshold for electroconvulsions and protected mice against the tonic hind limb extension in pentylenetetrazol-, bicuculline-, picrotoxin- and 3-mercaptopropionic acid-induced seizures, but was ineffective against the clonic phase of chemically-induced seizures. In the baboons, no protection against photomyoclonic responses was observed within 5 h after the intravenous administration of memantine, 1-9 mg/kg. Amantadine, 100 mg/kg, reduced the protective effect of memantine against electroconvulsions. Apomorphine, haloperidol, pimozide, spiroperidol and bicuculline did not modify the anticonvulsant activity of memantine in electroconvulsions. These studies demonstrate an anticonvulsant action of memantine in rodents and suggest that dopaminergic mechanisms do not contribute to its mechanism of action.

Amantadine↗
PubMed1986

Induction of audiogenic seizure susceptibility by focal infusion of excitant amino acid or bicuculline into the inferior colliculus of normal rats.

N-Methyl-D-aspartate (NMDA) (10 to 20 nmol) or bicuculline (15 to 50 pmol) in 0.5 microliter was infused bilaterally into the inferior colliculus or the deep layers of superior colliculus (DLSC) in normal rats, and the response to high intensity acoustic stimulation was examined. Thirty-five percent of rats receiving NMDA infusions and 42% of animals receiving bicuculline infusions into the inferior colliculus exhibited sound-induced seizures exclusively that were behaviorally similar to audiogenic seizures displayed by genetically epilepsy-prone rats. Rats receiving microinjections into the DLSC did not display sound-specific seizures. A combined pattern of spontaneous and sound-induced seizures was seen in some rats with both drugs and loci of microinjection. These data and previous studies support a role for increased excitant amino acid action and decreased efficacy of GABA in the inferior colliculus as important mechanisms involved in genetic susceptibility to audiogenic seizures.

Acoustic Stimulation↗
PubMed1986

Anticonvulsant properties of flunarizine on reflex and generalized models of epilepsy.

The anticonvulsant activity of 1-bis(4-fluorophenyl)methyl-4-(3-phenyl-2-propenyl)-piperazine, flunarizine, was studied after intraperitoneal administration in DBA/2 mice (seizures induced by sound), intravenous administration in Papio papio (myoclonus induced by photic stimulation) and oral administration in Wistar rats (seizures induced by cefazolin). Protection against sound-induced seizures was observed after intraperitoneal administration of flunarizine (5-40 mg/kg). The ED50 for suppression of tonic, clonic and wild running phases of sound-induced seizures was 3.3, 9.8 and 17.5 mg/kg, respectively. This protective action was significantly reduced by pretreatment with aminophylline (50 mg/kg, i.p.). In photosensitive baboons flunarizine (0.5-1.0 mg/kg, i.v.) provided partial protection against myoclonic responses to stroboscopic stimulation. After flunarizine (2 mg/kg, i.v.) this protection lasted for more than 5 hr (and was complete at 2-3 hr). Cefazolin-induced seizures in rats were prevented by administration of flunarizine (20-40 mg/kg, orally). The ED50 for the suppression of tonic and clonic seizures evoked by subsequent intravenous administration of cefazolin was 25 mg/kg. The protective effects of flunarizine (40 mg/kg, orally) were maximal after 3-6 hr and were maintained for 16-24 hr. Behavioural effects of flunarizine included signs of sedation in both mice and rats. Tolerance to the antiepileptic effects of flunarizine was not seen after chronic treatment in rats. The role of purinergic receptors and of calcium entry blockade in the anticonvulsant action of flunarizine requires further study.

Acoustic Stimulation↗
PubMed1986

Excitatory neurotransmission within substantia nigra pars reticulata regulates threshold for seizures produced by pilocarpine in rats: effects of intranigral 2-amino-7-phosphonoheptanoate and N-methyl-D-aspartate.

Seizures produced by pilocarpine given i.p. to rats provide an animal model for studying the initiation, spread and generalisation of convulsive activity within the forebrain. Pilocarpine, 380 mg/kg, produces a sequence of behavioural and electroencephalographic alterations indicative of motor limbic seizures and status epilepticus, which is followed by widespread damage to the limbic forebrain resembling that occurring subsequent to prolonged intractable seizures. Microinjections of a selective antagonist at the N-methyl-D-aspartate receptor, (+/-)-2-amino-7-phosphonoheptanoate, into the substantia nigra pars reticulata, bilaterally, protects against the behavioural, electrographic and morphological features of seizures produced by pilocarpine, 380 mg/kg, with an ED50 of 0.0007 mumol (0.0004-0.0011). Microinjections of (+/-)-2-amino-7-phosphonoheptanoate, 0.005 or 0.01 mumol, into the substantia nigra pars compacta or into the dorsal part of mid-anterior striatum do not modify the electrographic and morphological sequelae of pilocarpine, 380 mg/kg. In rats pretreated with microinjections of N-methyl-D-aspartate into the substantia nigra pars reticulata, a non-convulsive dose of pilocarpine, 100 mg/kg, results in recurrent motor limbic seizures and status epilepticus. The ED50 of N-methyl-D-aspartate for the generation of seizures after pilocarpine, 100 mg/kg, is 0.0014 mumol (0.001-0.0019). Electrographic monitoring shows a pattern and sequence of evolution of convulsant activity within the hippocampus and cortex similar to that produced with pilocarpine, 380 mg/kg, alone. Morphological examination of brains from rats treated with N-methyl-D-aspartate in the substantia nigra pars reticulata and subsequently given pilocarpine, 100 mg/kg, which underwent status epilepticus, reveals widespread damage to the amygdala, thalamus, olfactory cortex, substantia nigra, neocortex, and hippocampus. Microinjections of N-methyl-D-aspartate, 0.002 mumol, into either the substantia nigra pars compacta or dorsal striatum, bilaterally, do not augment seizures produced by pilocarpine, 100 mg/kg. The results indicate that the threshold for pilocarpine-induced seizures in rats is modulated by excitatory amino acid neurotransmission within the substantia nigra pars reticulata.

2-Amino-5-phosphonovalerate↗
PubMed1986

Regional amino acid concentration in the brains of rats exposed to high pressures.

Regional amino acid concentrations were measured in rat brain fixed by microwave irradiation at three levels of elevated atmospheric pressure corresponding to different phases of the high-pressure neurological syndrome [20 atmospheres absolute (ATA), no clinical signs; 60 ATA, tremor; 85 ATA, severe tremor and myoclonic jerks]. No changes in amino acid content occurred at 20 or 60 ATA. At 85 ATA glutamine content increased in hippocampus, striatum, cerebellum, and substantia nigra, and gamma-aminobutyric acid content increased in hippocampus. It is suggested that enhanced glutamate release in various subcortical structures contributes to the myoclonic activity observed at 85 ATA.

Amino Acids↗
PubMed1986

Benzodiazepine receptors and their relationship to the treatment of epilepsy.

Benzodiazepines (BDZ) interact with components of neuronal membranes to modify excitability in three different ways. Action at a high affinity central receptor (dissociation constant, KD, of 3 nM) linked to the GABAA recognition site enhances the inhibitory action of GABA by increasing the number of openings of Cl- channels produced by a given concentration of GABA. This effect correlates with anticonvulsant activity as evaluated in the antipentylenetetrazol test in animals and with antimyoclonic activity in human beings. It also correlates with anxiolytic activity. Action at a lower affinity membrane site (KD 100 nM to 1 microM) limits repetitive firing as observed in isolated neurons (in a manner similar to the action of phenytoin or carbamazepine). This does not depend primarily on neurotransmitter mechanisms, but probably involves an increase in the population of sodium channels in the inactive state. Action at a lower affinity site (KD 45 microM) in presynaptic terminals decreases voltage sensitive Ca++ conductance and, by limiting Ca++ entry, decreases neurotransmitter release. The two lower affinity BDZ systems may be responsible for therapeutic action in status epilepticus and for sedative side-effects. The high affinity central benzodiazepine binding sites can be differentiated into BZ1 and BZ2 receptors by ligands (such as triazolopyridazines and Quazepam) that preferentially act on BZ1 sites. There are regional differences in the density of the two receptor subtypes, but these have not yet been correlated with specific actions of benzodiazepines. Differences between various 1,4- and 1,5-benzodiazepines in terms of therapeutic action in epilepsy and neurologic side-effects can probably be explained on the basis of variation in full or partial agonist action at the high affinity central receptor, or differing relative action at the high and low affinity receptors.

Animals↗
PubMed1986

Hyperglycemia does not augment neuronal damage in experimental status epilepticus.

The neuronal regions affected and the neuropathologic features of ischemia and status epilepticus are similar. Experimentally, elevated plasma glucose levels, increasing brain lactate, are associated with more severe neuropathologic damage from cerebral ischemia. We therefore studied the cytologic features and cerebral content of lactate and glucose in the selectively vulnerable neurons of rat hippocampus after 2 hours of L-allylglycine-induced status epilepticus in rats with mean plasma glucose concentrations of 65, 250, and 480 mg/100 ml. Brain lactate concentration was elevated in status and maximal in the high-glucose group, but the maximum levels (8 mumol/g) were less than those thought to augment cell death in ischemia. Using multiple linear regressions, only time-in-status predicted neuropathologic damage.

Animals↗
PubMed1986

Drugs acting on amino acid neurotransmitters.

The most potent agents currently available for suppressing myoclonic activity in animals and humans act to enhance GABA-mediated inhibition and/or to diminish amino acid-induced excitation. Postsynaptic GABA-mediated inhibition plays an important role at the cortical level, diminishing the effect of augmented afferent activity and preventing pathologically enhanced output. Enhancement of GABAergic inhibition, principally at the cortical level but also at lower levels, by clonazepam and by valproate appears to be a predominant element in their antimyoclonic action. Studies in various animal models, including photically induced myoclonus in the baboon, P papio, indicate the value of other approaches to enhancing GABA-mediated inhibition. Among such approaches meriting evaluation in humans are inhibition of GABA-transaminase activity by gamma-vinyl GABA and action at some of the benzodiazepine receptors to enhance the action of GABA, as by the novel anticonvulsant beta-carbolines. Excitatory transmission mediated by dicarboxylic amino acids appears to play a role in myoclonus, especially at the spinal level, but also in the brainstem, cerebellum, basal ganglia, and cortex. Among various novel agents that act at the postsynaptic receptor site to antagonize such excitation, those specifically blocking excitation induced by aspartate and/or NMDA prevent myoclonic activity in a wide range of animal models. Further research is required before such agents can be evaluated in humans.

Acoustic Stimulation↗
PubMed1986

Cell damage in epilepsy and the role of calcium in cytotoxicity.

Status epilepticus may be followed by the loss of selectively vulnerable neurons in the hippocampus and neocortex. The acute cytopathology preceding cell loss is that of "ischemic cell change" or "dark cell change." In the hippocampus, selectively vulnerable neurons (CA3 and CA1 pyramidal neurons, hilar polymorphic neurons) show swelling of mitochondria in the perikaryon and dendrites after 30 to 120 min of seizure activity. Electron-microscopic studies with the combined oxalate/pyroantimonate technique reveal dense calcium pyroantimonate deposits in the swollen mitochondria. Suppression of seizure activity for 30 to 60 min is sufficient to allow recovery of normal mitochondrial morphology and calcium load. A small proportion of vulnerable neurons develop ischemic cell change with multiple vacuoles containing calcium pyroantimonate deposits. Neurons prone to burst firing accumulate calcium during seizures, and eventually show massive "overloading" of mitochondria. Although by analogy with studies in muscle a cytotoxic role for raised cytosolic calcium concentration has been proposed, the link between increased [CA2+] activation of phospholipases and proteinases and ischemic cell change remains uncertain.

Animals↗
PubMed1986

Effect of 2-aminophosphonoheptanoic acid on the EEG of rats exposed to high pressure.

Excitatory amino acid neurotransmission may be involved in the tremor component of the high pressure neurological syndrome (HPNS). 2-Amino-7-phosphonoheptanoic acid (2-APH) is a novel antagonist of excitatory amino acids with preferential activity at the N-methyl-D-aspartate receptor. Rats were injected either i.p. or intracerebroventricularly with 2-APH and subsequently exposed to pressure. The EEG changes that occur after treatment with 2-APH at 1 ATA, namely, a marked increase in delta waves (1-4 Hz) in the centro-occipital region, continue at pressure. However, the apparent duration of action of 2-APH is shorter: the power spectra of delta waves reached its maximum value after a mean time of 37 min (SD 12) compared with 60 min (SD 5) in unpressurized rats. Behavioral results include an increase in the onset pressure for tremor--82.6 ATA (SEM 4.7) in treated rats compared with 49.4 ATA (SEM 3.4) in saline controls (P less than 0.005). It is probable that the antitremor effect and the EEG changes resulting from 2-APH are due to decreased postsynaptic activity of an excitatory neurotransmitter, and these data support the hypothesis that tremor may be central rather than peripheral in origin.

2-Amino-5-phosphonovalerate↗
PubMed1985

Anticonvulsant action of beta-kainic acid in mice. Is beta-kainic acid an N-methyl-D-aspartate antagonist?

An effect of the beta-stereoisomer of kainic acid on seizures produced by intracerebroventricular injections of excitatory amino acids was tested in mice. beta-Kainic acid preferentially antagonizes myoclonic seizures induced by N-methyl-D-aspartate and quinolinate, has less pronounced anticonvulsant action against alpha-kainate, D-homocysteinesulphinate and quisqualate, and no effect on convulsions induced by L-glutamate. The anticonvulsant activity of beta-kainic acid matches that of 2-amino-7-phosphonoheptanoic and kynurenic acids, both preferential N-methyl-D-aspartate receptor antagonists, and differs considerably from the profile of anticonvulsant action of gamma-D-glutamylaminomethylsulphonic acid, a preferential kainate/quisqualate antagonist.

Animals↗
PubMed1985

Anticonvulsant action of stereoisomers of gamma-glutamylaminomethylsulphonic acid in mice.

The effects of stereoisomers of gamma-glutamylaminomethylsulphonic acid (GAMS) on convulsions produced by intracerebroventricular injections of excitatory amino acids were studied in mice. gamma-D-GAMS preferentially blocked myoclonic seizures induced by kainate and had less pronounced anticonvulsant effect against quisqualate, N-methyl-D-aspartate, quinolinate, D-homocysteine sulphinate and L-glutamate. gamma-L-GAMS displayed only a relatively weak protective effect against kainate- and, to some extent, quisqualate-induced seizures, with little or no effect on the convulsant properties of the other excitatory amino acids. These results indicate that the D configuration of the gamma-carbon atom of excitatory amino acid antagonists is preferred not only for NMDA receptor antagonism but for antagonism at non-NMDA receptors as well.

Animals↗
PubMed1985

Anticonvulsant activity of two novel piperazine derivatives with potent kainate antagonist activity.

Two dicarboxylic piperazine derivatives, 1-(p-chlorobenzoyl)-piperazine-2,3-dicarboxylic acid (pCB-PzDA) and 1-(p-bromobenzoyl)-piperazine-2,3-dicarboxylic acid (pBB-PzDA), that block excitation at glutamate receptors have been evaluated as anticonvulsants in rodent models of epilepsy by i.c.v. or i.p. injection. In DBA/2 mice, pBB-PzDA (0.01 mumol i.c.v.) or pCB-PzDA (0.03 mumol i.c.v.) protects against the clonic and tonic seizures induced by loud sound. Protection is also seen following i.p. injection of pBB-PzDA (0.33-1.0 mmol/kg) or pCB-PzDA (0.66-1.0 mmol/kg). In Swiss S mice suppression of seizure activity induced by i.c.v. injection of excitatory amino acid agonists shows that both compounds are preferentially active against alpha-kainate, with the following rank orders (for pBB-PzDA); alpha-kainate greater than quisqualate greater than N-methyl-D-aspartate greater than quinolinate greater than L-glutamate; and (for pCB-PzDA): alpha-kainate greater than quinolinate greater than N-methyl-D-aspartate greater than quisqualate greater than L-glutamate. These compounds are the most potent preferential alpha-kainate antagonists so far tested. The relationship between antagonism at the various receptor subtypes and anticonvulsant action is not adequately defined.

Acoustic Stimulation↗
PubMed1985

Taurine in the hippocampal formation of the Senegalese baboon, Papio papio: an immunocytochemical study with an antiserum against conjugated taurine.

An antiserum raised against taurine conjugated to bovine serum albumin by glutaraldehyde produced intense staining of hippocampal pyramidal neurons at the CA1/CA3 transition (including CA2) and of a small proportion of the granule cells. Strongly immunoreactive neurons were also found in a zone overlapping the second reflected blade in the hilus. Most glial cells were unlabeled.

Animals↗
PubMed1985

Effects of 2-amino-7-phosphonoheptanoic acid on EEG of rats.

2-APH is an antagonist of excitation due to dicarboxylic amino acids and has a protective effect against several types of experimental seizures. We have studied its effect on EEG of rats. Following either intracerebroventricular or intraperitoneal administration of 2-APH produces slow waves of high voltage in central cortex. The anticonvulsant action of this drug may be related to altered activity in neurones of this area.

2-Amino-5-phosphonovalerate↗