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B S Meldrum

Publications and source records attributed to B S Meldrum.

At least 199 records · Page 11Linked to original sources
PubMed1984

Evaluation of anticonvulsant drugs in DBA/2 mice with sound-induced seizures.

The syndrome of sound-induced seizures in DBA/2 mice is described. Protection against seizure responses is provided by intraperitoneal administration of conventional anticonvulsant drugs with benzodiazepines being the most potent, and valproate, ethosuximide and trimethadione the least potent. Protection is also provided by intracerebroventricular administration of anticonvulsant drugs. GABAergic agents, antagonists of excitation due to dicarboxylic amino acids, alpha 2-noradrenergic agonists, and dopamine agonists all provide protection against the seizure responses. There is, however, no conclusive biochemical evidence that the syndrome is attributable to a defect in one or more of these neurotransmitter systems.

Acoustic Stimulation↗
PubMed1983

Antiepileptic action of excitatory amino acid antagonists in the photosensitive baboon, Papio papio.

Antagonists of excitation induced by dicarboxylic amino acids have been evaluated for acute anticonvulsant activity in baboons, Papio papio, with photosensitive epilepsy. 2-Amino-7-phosphonoheptanoic acid, 1 mmol/kg, i.v., abolishes myoclonic responses for 5 h. Less prolonged protection is seen after cis-2,3-piperidine-dicarboxylic acid, 1-3.3 mmol/kg; 2-amino-5-phosphonovaleric acid, 1-3.3 mmol/kg; or glutamic acid diethyl ester, 1-3.3 mmol/kg. Toxic side-effects are prominent after the latter two compounds. Antagonists of excitation due to N-methyl-D-aspartate possess acute anticonvulsant activity in a wider range of models epilepsy.

2-Amino-5-phosphonovalerate↗
PubMed1983

Anticonvulsant action in the photosensitive baboon, Papio papio, of a novel beta-carboline derivative, ZK 91296.

The anticonvulsant action of ethyl-5-benzyloxy-4-methoxymethyl-beta-carboline-3-carboxylate (ZK 91296) has been studied in Senegalese baboons, Papio papio, with photosensitive epilepsy. Myoclonic and paroxysmal electroencephalographic responses to stroboscopic stimulation are diminished or abolished for 2-4 h after ZK 91296, 0.25-4 mg/kg, i.v. Radioreceptor assay of plasma ZK 91296 indicates rapid clearance (t 1/2 alpha, 5-20 min and beta, 60-90 min). In this model of generalised epilepsy ZK 91296 is similar to diazepam in potency but has a longer duration of action.

Animals↗
PubMed1983

Uptake of a novel anticonvulsant compound, 2-amino-7-phosphono-[4,5-3H]heptanoic acid, into mouse brain.

The time course of radioactivity in plasma, liver and brain is described following the intraperitoneal injection of 2-amino-7-phosphono-[4,5-3H]heptanoic acid in mice. Using high performance liquid chromatography of dansylated extracts of mouse brain the radioactivity attributable to 2-amino-7-phosphono-[4,5-3H]heptanoic acid has been determined at 0.25-180 min after injection. The time course, with a peak concentration at 30 min, declining markedly between 90 and 180 min, corresponds to the anticonvulsant action.

2-Amino-5-phosphonovalerate↗
PubMed1983

Anticonvulsant activity of GABA uptake inhibitors and their prodrugs following central or systemic administration.

The activity of compounds inhibiting neuronal or glial GABA uptake has been assessed following intracerebroventricular (i.c.v.) or intraperitoneal (i.p.) administration in DBA/2 mice (sound-induced seizures) or Swiss S mice (pentylenetetrazol-induced seizures). Sound-induced seizures are suppressed by the i.c.v. injection of (+/-)-nipecotic acid, 3.2 mumol, or (+/-)-cis-4-hydroxynipecotic acid, 2 mumol, but not by i.p. injection of (+/-)-nipecotic acid, 3.2 mmol/kg or (+/-)-cis-4-hydroxynipecotic acid 4 mmol/kg. Pentylenetetrazol-induced seizures are not suppressed by i.c.v. injection of (+/-)-nipecotic acid 1-4 mumol, or (+/-)-cis-4-hydroxynipecotic acid, 2-4 mumol. THPO (4,5,6,7-tetrahydroisoxazolo[4.5-c]pyridin-3-ol), 1-5 mumol i.c.v. or 1-4 mmol/kg i.p., protects against sound-induced seizures. There is no protection against pentylenetetrazol seizures after i.c.v. THPO injection, but THPO, 2-8 mmol/kg i.p., is protective. Among prodrugs, (+/-)-nipecotic acid pivaloyloxymethyl ester protects against sound-induced seizures, when given i.c.v. (3.2 mumol) or i.p. (1.6-3.2 mmol/kg) and against pentylenetetrazol seizures when given i.p. (0.5-4 mmol/kg). (+/-)-cis-4-hydroxynipecotic acid methyl ester protects against sound-induced seizures when given i.p. (3.2 mmol/kg), but is only partially protective against pentylenetetrazol seizures, when given i.p. (4 mmol/kg). Some prodrugs induce myoclonus following either i.c.v. or i.p. administration.

Acoustic Stimulation↗
PubMed1983

Effect on cerebral D-[3H]aspartate release of 3-mercaptopropionic acid and methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate.

Minislices of rat brain cortex were preloaded with D-[3H]aspartate and spontaneous and potassium-induced (25 mM KCl) efflux of labelled compound into superfusate measured. 3-Mercaptopropionic acid, 100-220 microM did not modify the spontaneous efflux of D-[3H]aspartate, but augmented the K+-induced efflux. Methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate, 10 or 100 microM, enhanced both spontaneous and K+-induced efflux of D-[3H]aspartate. The convulsant action of both compounds may be due to enhanced synaptic release of aspartate or a related excitatory neurotransmitter.

3-Mercaptopropionic Acid↗
PubMed1983

Acute anticonvulsant activity of structural analogues of valproic acid and changes in brain GABA and aspartate content.

Ten analogues of valproic acid (substituted butyric, pentanoic and hexanoic acids) were tested for anticonvulsant activity against audiogenic seizures in DBA/2 mice. There is a consistent correlation between the structure of these branched-chain fatty acids and their anticonvulsant potency, the larger molecules being the more active. There is also a strong correlation between the anticonvulsant potency of these compounds and their ability to reduce cerebral aspartate levels. Cerebral GABA levels are elevated by most, but not all, of the actively anticonvulsant valproate analogues.

Acoustic Stimulation↗
PubMed1983

Comparative assessment of dopamine agonist aporphines as anticonvulsants in two models of reflex epilepsy.

The anticonvulsant action of various aporphine derivatives that act on dopamine receptors has been investigated in two genetically determined animal models--DBA/2 mice with sound-induced seizures and baboons Papio papio with photically-induced seizures. Protection against the clonic and tonic phases of the seizures response in DBA/2 mice was seen for 15-60 min after (-)2,10,11-trihydroxy-N-n-propylnoraporphine (1.25 mg/kg) and (-)10,11-methyl-enedioxy-N-n-propylnoraporphine (0.625-1.25 mg/kg) and for 30-60 min after (-)2,10,11-trihydroxyaporphine (31.25 mg/kg). Short-lasting protection (up to 30 min) was seen following (-)2,10,11-trihydroxy-N-ethyl-noraporphine (1.25-6.25 mg/kg). Changes in audiogenic seizure susceptibility were accompanied by piloerection, ptosis and loss of spontaneous locomotor and exploratory behaviour. No protection was seen after (-)norapomorphine (0.05-18.75 mg/kg). All the compounds (including norapomorphine) significantly lowered rectal temperature, although the time course of this effect was often longer than that of protection against audiogenic seizures. In baboons, marked reductions in photomyoclonic responses were seen following (-)10,11-methylenedioxy-N-n-propylnoraporphine (0.25 mg/kg, lasting up to 2h); (-)2,10,11-trihydroxy-N-n-propylnoraporphine (0.5-2.5 mg/kg, lasting up to 7 h); (-)2,10,11-trihydroxyaporphine (5 mg/kg, duration of action 1-4 h) and (-)2,10,11-trihydroxy-N-ethylnoraporphine (6.25 mg/kg, lasting 2 h). Little change in responsiveness followed administration of (-)norapomorphine 1.25 or 6.25 mg/kg. Changes in photosensitivity were accompanied by yawning and pupil dilatation. (-)10,11-Methylenedioxy-N-n-propylnoraporphine (0.5-6.25 mg/kg) was also administered orally in baboons.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1983

Changes in the sensitivity of the central alpha- and beta-adrenergic systems during desmethylimipramine treatment as assessed by plasma growth hormone response in the baboon.

The tricyclic antidepressant desmethylimipramine (DMI) 2.5 mg/kg IM was administered to adolescent baboons once daily for 21 days, to investigate changes in alpha- and beta-noradrenergic function. Prior to DMI treatment, plasma growth hormone (GH) responses to the intravenous infusion of an alpha 2-adrenergic receptor agonist, clonidine, or a beta 2-adrenergic antagonist, ICI 118,551, were determined. DMI, 2.5 mg/kg, administered acutely did not stimulate the release of GH (up to 4 h post injection). The GH response to clonidine was decreased 4 h after DMI, 2.5 mg/kg. Alterations in plasma GH response to clonidine and ICI 118,551 were evident during and after chronic DMI administration. The GH response to clonidine was significantly diminished after 2 days, and gradually returned to the pretreatment amplitude over 7-21 days of treatment, with an overshoot 2 days after DMI withdrawal. After 21 days of DMI administration the GH response to ICI 118,551 was significantly enhanced, and remained consistently elevated during a withdrawal period of 21 days. These changes in the response to an alpha-adrenergic agonist and a beta-adrenergic antagonist indicate that the long term regulatory changes in receptor sensitivity, occurring between 2 and 21 days of DMI treatment, compensate for the acute effects of DMI on these responses.

Animals↗
PubMed1983

Intracellular calcium accumulation in rat hippocampus during seizures induced by bicuculline or L-allylglycine.

Using electron microscopy and the combined oxalate-pyroantimonate technique, free calcium ions were located in the hippocampus of control rats and of those that had undergone status epilepticus induced by L-allylglycine or bicuculline. The validity of this technique was established by the use of the calcium chelating agent ethylene glycol bis(beta-aminoethyl ether), N,N'-tetra-acetic acid and by an X-ray microanalytical technique. In control material, calcium deposits were visible in synaptic vesicles and multivesicular bodies, in parts of the Golgi apparatus, mitochondria, lysosomes, and in glial and neuronal nuclei. Following 2 h of status epilepticus, cellular pathology included astrocytic swelling, and dark cell degeneration of pyramidal neurons. This was accompanied by a marked increase in the amount of calcium pyroantimonate deposits, particularly in swollen and disrupted mitochondria of CA1 and CA3 basal dendrites, and in selected neuronal cell bodies in the CA1 and CA3-4 regions. We propose that enhanced calcium entry into neurons and consequent overloading of the capacity of mitochondria for calcium sequestration is part of the cytotoxic mechanism leading to selective neuronal loss in the hippocampus in status epilepticus.

Allylglycine↗
PubMed1983

Effect of 2-amino-7-phosphonoheptanoic acid on regional brain amino acid levels in fed and fasted rodents.

2-Amino-7-phosphonoheptanoic acid, an antagonist of excitation caused by dicarboxylic amino acids with a selective action on N-methyl-D-aspartate receptors, has been administered in an anticonvulsant dose (1 mmol/kg i.p.) to fed or fasted rats and mice. The drug impaired motor activity in fasted mice. Glucose and amino acids were determined in dissected regions of brain fixed by microwave irradiation. Glucose content was low in the brains of fasted rats and mice but was restored to normal (fed) concentration 45 min after the administration of 2-amino-7-phosphonoheptanoic acid in fasted mice. In fed animals, 2-amino-7-phosphonoheptanoic acid did not change brain aspartate concentration. In fasted animals, aspartate concentration was raised in most brain regions. In fasted rats and mice, 2-amino-7-phosphonoheptanoic acid significantly increased glutamine in rat cortex and mouse striatum, decreased glutamate content in rat striatum, and decreased aspartate concentration in all regions except mouse cortex and striatum. GABA levels were significantly decreased in rat striatum and hippocampus. These changes are consistent with an increased synaptic release of glutamate and aspartate following blockage of their post-synaptic action at selected sites.

2-Amino-5-phosphonovalerate↗
PubMed1983

Noradrenergic regulation of growth hormone secretion in the baboon.

We have investigated the effects of iv administered noradrenergic agonists and antagonists on plasma GH concentration in the adolescent baboon, Papio papio, with the aim of defining the relative roles of adrenergic receptor subtypes (alpha 1, alpha 2, beta 1, and beta 2) in the regulation of GH release. Clonidine (0.02 mg/kg) or UK-14,304 (0.02 mg/kg), potent centrally acting alpha 2 noradrenergic agonists, were infused into 24 animals pretreated with either saline, or selective alpha 1 and alpha 2 noradrenergic antagonists. Both agonists potently augment plasma GH, producing peak levels of 30-60 ng/ml 15 min post infusion. These responses can be prevented by the prior infusion of the alpha 2 antagonist, piperoxane (1.0 mg/kg), but not by the alpha 1 antagonist, prazosin (2.0 mg/kg). Log dose response curves of the 2 agonists demonstrate a greater potency for UK-14,304 vs. clonidine on a molar basis. In animals pretreated with monoamine depleting agents (reserpine and alpha-methyl paratyrosine) the plasma GH response to an infusion of clonidine (0.02 mg/kg) is significantly enhanced (P less than 0.001). Beta-Adrenoreceptor antagonism by propranolol (0.02 or 1.0 mg/kg) or the more selective beta 2-adrenoreceptor antagonist, ICI 118,551 (0.02-1.0 mg/kg), results in a rapid and significant (P less than 0.01) increase in plasma GH. The beta 1-antagonist, practolol (0.2-2.0 mg/kg), does not alter plasma GH levels. It is proposed that in the baboon, noradrenaline acts on alpha 2-noradrenergic receptors to stimulate GH release and on beta 2-noradrenergic receptors to inhibit GH release.

Albuterol↗
PubMed1982

Intracellular sites of early calcium accumulation in the rat hippocampus during status epilepticus.

Using electron microscopy and the combined oxalate--pyroantimonate technique, calcium was located in hippocampal neurons of rats that had undergone L-allylglycine-induced status epilepticus. In control material, calcium deposits were prominent in nearly every synaptic vesicle, and to a lesser degree in mitochondria and the Golgi apparatus of pyramidal neurons and dentate granule cells. After status epilepticus, mitochondrial calcium deposits increased, particularly in the swollen mitochondria of the pyramidal cell bodies and basal dendrites of CA3 and CA1 neurones. These studies support the theory that enhanced calcium entry leading to calcium overload of mitochondria may be an important cytotoxic mechanism producing selective neuronal loss.

Allylglycine↗