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Biomedical subjects

B S Meldrum

Publications and source records attributed to B S Meldrum.

At least 181 records · Page 10Linked to original sources
PubMed1985

Plasma growth hormone responses to microinfusion of noradrenergic agents into or electrical stimulation of the hypothalamus and amygdala in baboons.

In nine baboons (Papio papio) guide cannulae and electrodes were stereotaxically implanted into the medial basal or lateral hypothalamus, the anterior hypothalamus or the dorsal amygdala. Plasma GH responses were measured after microinfusion (1 microliter) of the alpha2 adrenergic agonist, clonidine, or the beta adrenergic antagonist, propranolol, or electrical stimulation, in each of these sites. Clonidine, 100 nmol/microliter, infused into the medial basal or lateral hypothalamus elevated plasma GH levels by 5-30 ng/ml, 30-45 min post-infusion. Plasma GH responses to clonidine infused into the anterior hypothalamus or the dorsal amygdala were all less than 10 ng/ml. The prior, intravenous, administration of piperoxane, 1.0 mg/kg prevented GH responses to clonidine. Propranolol, 50 nmol/microliter, infused into the dorsal amygdala consistently increased plasma GH levels by 5-15 ng/ml. Electrical stimulation of the medial basal or lateral hypothalamus elevated plasma GH levels by 7-35 ng/ml, 15-45 min post stimulation. Electrical stimulation of anterior hypothalamus or dorsal amygdala did not alter plasma GH levels. The stimulation of alpha 2 adrenergic receptors in the medial basal or lateral hypothalamus of the baboons appears to facilitate GH release.

Amygdala↗
PubMed1985

Effects of two convulsant beta-carboline derivatives, DMCM and beta-CCM, on regional neurotransmitter amino acid levels and on in vitro D-[3H]aspartate release in rodents.

Clonic seizures were induced in Swiss or DBA/2 mice by methyl-6-7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM), 0.048 mmol/kg i.p., or by methyl-beta-carboline-3-carboxylate (beta-CCM), 0.044 mmol/kg i.p. Measurement of regional brain (cortex, hippocampus, striatum, and cerebellum) amino acid levels after 15 min of seizure activity showed increases in gamma-aminobutyric acid (GABA) (in all regions after beta-CCM, and in cortex and hippocampus after DMCM), and an increase in glycine in the striatum after beta-CCM. Aspartate levels fell (in cortex and hippocampus) after DMCM, but were unchanged in all regions after beta-CCM. Glutamate levels fell in cortex after beta-CCM and in striatum after DMCM. Pretreatment with the excitatory amino acid receptor antagonist, 2-amino-7-phosphonoheptanoic acid, 0.5 mmol/kg i.p., 45 min prior to the beta-carboline, significantly increased the ED50 for DMCM-induced clonic seizures (4.68 mumol/kg vs. 9.39 mumol/kg). Similar pretreatment did not significantly alter the ED50 for beta-CCM (4.22 mumol/kg vs. 6.6 mumol/kg). Pretreatment with 2-amino-7-phosphonoheptanoic acid, 1.0 mmol/kg, blocked the increase in GABA content produced by DMCM but not the fall in cortical aspartate content. Potassium-induced release of preloaded D-[3H]aspartate from rat cortical or hippocampal minislices was enhanced in the presence of DMCM (100 microM). In contrast, stimulated release of D-[3H]aspartate (from cortex or hippocampus) was not altered in the presence of beta-CCM (100 microM). Although DMCM and beta-CCM are both considered to induce convulsion by acting at the GABA--benzodiazepine receptor complex, the convulsions differ in several pharmacological and biochemical respects. It is suggested that enhanced release of excitatory amino acid neurotransmitters plays a more important role in seizures induced by DMCM.

2-Amino-5-phosphonovalerate↗
PubMed1984

gamma-D-Glutamylaminomethylsulphonic acid (GAMS), a kainate and quisqualate antagonist, prevents sound-induced seizures in DBA/2 mice.

The effect of gamma-D-glutamylaminomethylsulphonic acid (GAMS) on sound-induced seizures has been assessed in DBA/2 mice. All phases of the seizure response are suppressed following intracerebroventricular injection (ED50 values: 0.077 mumol for tonic seizure, 0.132 mumol for wild running) or intraperitoneal injection (ED50: 1.21 mmol/kg for tonic seizure, 4.95 mmol/kg for wild running). The results are discussed in relation to the involvement of 'kainate' and 'quisqualate' receptors in the generation and propagation of seizures.

Acoustic Stimulation↗
PubMed1984

Blockade of N-methyl-D-aspartate receptors may protect against ischemic damage in the brain.

In rats ischemia of the forebrain induced by a 30-minute occlusion of the carotid artery, followed by 120 minutes of arterial reperfusion, produced ischemic lesions of selectively vulnerable pyramidal cells in both hippocampi. Focal microinfusion into the dorsal hippocampus of 2-amino-7-phosphonoheptanoic acid, an antagonist of excitation at the N-methyl-D-aspartate-preferring receptor, before ischemia was induced protected against the development of ischemic damage. It is proposed that excitatory neurotransmission plays an important role in selective neuronal loss due to cerebral ischemia.

2-Amino-5-phosphonovalerate↗
PubMed1984

Anticonvulsant action of 2-amino-7-phosphonoheptanoic acid in the substantia nigra.

Focal injection of 2-amino-7-phosphonoheptanoic acid in the substantia nigra, pars reticulata or pars compacta, in rats produces a dose-dependent suppression of the tonic extensor seizure component in the electroshock test. Haloperidol pretreatment prevents stereotyped behaviour induced by 2-amino-7-phosphonoheptanoic acid, but does not change the effect on the electroshock test. This anticonvulsant effect of 2-amino-7-phosphonoheptanoic acid probably results from an antagonist action at a receptor site sensitive to N-methyl-D-aspartate leading to a decrease in activity in nigral efferent systems.

2-Amino-5-phosphonovalerate↗
PubMed1984

Kainic acid derivatives with anticonvulsant activity.

beta-Kainic acid, and the glycine and amino-methylphosphonate derivatives of alpha- and beta-kainic acid, have been injected intracerebroventricularly in DBA/2 mice, that show sound-induced seizure responses. An anticonvulsant effect is observed with marked protection against the tonic and clonic phases of the seizure response. ED50 values against clonus are (in mumol): beta-kainic acid, 0.09; beta-kainylglycine, 0.11; alpha-kainylglycine, 0.28; alpha-kainylaminomethylphosphonate, 0.31; beta-kainylaminomethylphosphonate, greater than 1.5. In addition a direct convulsant effect occurs after the alpha-kainyl derivatives.

Acoustic Stimulation↗
PubMed1984

Effect of excitatory amino acid antagonists on the high pressure neurological syndrome in rats.

The onset pressures for the tremor, myoclonus and convulsions seen in the high pressure neurological syndrome (HPNS) are increased following cis-2,3-piperidine dicarboxylic acid 1 mmol/kg in the rat. Glutamic acid diethyl ester 1-3 mmol/kg has no effect on tremor or myoclonus, but increases the convulsion pressure when 3 mmol/kg is given immediately before compression. These and earlier data with 2-amino-7-phosphonoheptanoic acid suggest that excitation at the N-methyl-D-aspartate receptor is important in HPNS tremor, and that excitation at the quisqualate receptor contributes to HPNS convulsions.

Animals↗
PubMed1984

The high pressure neurological syndrome and 2-amino-7-phosphonoheptanoic acid: differences between fed and fasted rats.

The elevated atmospheric pressure at which the main features of the high pressure neurological syndrome (HPNS), i.e. tremor, myoclonus and convulsions, successively appear, have been studied in fed and fasted rats with and without pretreatment with 2-amino-7-phosphonoheptanoic acid (180 mg/kg). The onset pressure for tremor is lower in fasted rats. 2-Amino-7-phosphonoheptanoic acid raises the onset pressure for all three phases of HPNS in fed rats, but only for tremor and convulsions in fasted rats. The results are interpreted in terms of changes in aspartergic and related excitatory neurotransmission.

2-Amino-5-phosphonovalerate↗
PubMed1984

Anticonvulsant activity of intracerebroventricularly administered valproate and valproate analogues. A dose-dependent correlation with changes in brain aspartate and GABA levels in DBA/2 mice.

Valproate and the branch-chain valproate analogues, 2-propyl-hexanoate and 2-ethyl-hexanoate, block sound-induced seizures in DBA/2 mice following their intracerebroventricular administration, the ED50 values for the suppression the clonic phase of the seizures being 6.0, 5.0, and 10.2 mumoles respectively. The straight-chain analogues, butyrate and pentanoate , have no anticonvulsant activity. Systemic administration of branched-chain valproate analogues has previously shown a progressive increase in the anticonvulsant activity of the analogues with an increase in the chain-length of the molecules. This relationship is abolished when the same analogues are injected directly into the ventricles. The icv administration of the 2 straight-chain, inactive analogues produces no effect on brain aspartate and GABA levels (with the exception of a butyrate-induced 34% rise in forebrain GABA level). There is a dose-dependent decrease in aspartate levels in cerebellum and forebrain (up to 45-55% reduction), and a dose-dependent increase in GABA levels in forebrain (up to 30-75% rise) 30 min after the icv administration of the 3 anticonvulsant branched-chain fatty acids. 2-Propyl-hexanoate does not affect the cerebellar GABA level significantly, while valproate and 2-ethyl-hexanoate administration produce 20-40% increases in cerebellar GABA levels.

Animals↗
PubMed1984

Regional brain glucose metabolism in chemically-induced seizures in the rat.

Measurement of regional brain glucose metabolism may give information concerning the mechanism of neuronal cell death developing after prolonged periods of epileptic activity. Regional brain glucose utilization was measured in paralyzed ventilated rats during seizures induced by L-allylglycine, kainic acid and bicuculline using the [14C]deoxyglucose method. Regional brain glucose concentration was measured in another series of rats, after similar periods of seizure activity, to permit a more accurate calculation of the lumped constant. In L-allylglycine-induced seizures regional brain glucose concentration did not vary from control values, so no correction of the lumped constant was necessary. Regional brain glucose utilization increased throughout the brain, the largest increase being in the hippocampus (control 36 +/- 6 mumol 100 g-1 min-1; seizure 120 +/- 12 mumol 100 g-1 min-1). In kainic acid-induced seizures, brain glucose concentration fell in the hippocampus, involving some correction of the lumped constant. Increases in glucose utilization were limited primarily to the hippocampus, with some involvement of the inferior colliculus. The ventral hippocampus showed the largest increase in glucose utilization (control 34 +/- 5 mumol 100 g-1 min-1; seizure 167 +/- 10 mumol 100 g-1 min-1). In bicuculline-induced seizures, in starved rats, brain glucose concentration fell in all regions investigated and no increase in regional glucose utilization was recorded. In L-allylglycine and kainic acid-induced seizures, the hippocampus, a region vulnerable to neuronal damage, shows the largest increase in glucose utilization. Studies involving bicuculline need further investigation, due to severe perturbation of brain and plasma glucose concentration.

Allylglycine↗
PubMed1984

Suppression of audiogenic seizures in DBA/2 mice by two new dipeptide NMDA receptor antagonists.

Two new phosphonate dipeptides, gamma-D- glutamylaminomethylphosphonate (Glu-Amp) and beta-D- aspartylaminomethylphosphonate (Asp-Amp), that are antagonists of excitation due to N-methyl-D-aspartate have been compared with omega-phosphonic-alpha-carboxylic amino acids as anticonvulsant agents in mice with sound-induced seizures. Compounds were injected intracerebroventricularly (i.c.v.) or intraperitoneally (i.p.) into DBA/2 mice 45 min prior to sound exposure, and ED50 values for suppression of the different phases of the seizure response were estimated. With i.c.v. injection Glu-Amp is 0.4-0.8 times as potent an anticonvulsant as (+/-)2-amino-7- phosphonoheptanoate and Asp-Amp is 1.3-2.5 times as potent. With i.p. injection Glu-Amp is 0.15-0.28 and Asp-Amp 0.23-0.58 times as potent as (+/-)2-amino-7-phosphonoheptanoic acid. These findings correspond to their known potency as N-methyl-D-aspartate antagonists, and are consistent with an anticonvulsant effect arising from action at a receptor sensitive to N-methyl-D-aspartate.

2-Amino-5-phosphonovalerate↗
PubMed1984

Specific effects of drugs at pressure: animal investigations.

The interactions of anaesthetics and other drugs with high pressure suggest that protection against the high pressure neurological syndrome (h.p.n.s.) can no longer be considered in terms of generalized non-specific mechanisms. The evidence from our work shows that anaesthetics may either protect, have no effect, or potentiate h.p.n.s. Structural analogues of the steroid anaesthetic Althesin have a protective effect against high pressure tremors in spite of the fact that they have no anaesthetic effects. Low doses of flurazepam are effective against tremor but can be antagonized by Ro 15-1788, which implies in this case a role for the benzodiazepine receptor complex. Pressure interactions with other drugs have included the classic anticonvulsants--which, in general, were relatively ineffective--and various agents perturbing the balance of specific neurotransmitter systems. Representative examples from different studies include 6-hydroxydopamine, muscimol, and sodium valproate. Finally, the potent protection against h.p.n.s. by 2-amino-phosphonoheptanoic acid, an antagonist with preferential action against excitation produced by aspartate and N-methyl-D-aspartate, provides the first evidence that enhanced excitatory amino acid neurotransmission may have an important role in the h.p.n.s.

Amino Acids↗
PubMed1984

Anticonvulsant actions of DS 103-282. Pharmacological studies in rodents and the baboon, Papio papio.

The anticonvulsant actions of DS 103-282 [5-chloro-4-(2-imidazolin-2-yl-amino)-2,1,3- benzothiadazole , tizanidine], have been evaluated after intraperitoneal administration in DBA/2 mice (seizures induced by sound), in Swiss S mice (seizures induced by N-methyl-D,L-aspartate; NMDLA ) and following intravenous or oral administration in Papio papio (seizure responses to intermittent photic stimulation). Protection against sound-induced seizures occurred after intraperitoneal administration of DS 103-282 (0.66-3.33 mg/kg). The ED50 doses for suppression of the tonic, clonic and wild-running phases of sound-induced seizures were 0.53, 0.79 and 1.3 mg/kg respectively. This protective effect of DS 103-282 (1.5 mg/kg, i.p.) was maximal after 30 min and was maintained for 60-120 min. Seizures induced by NMDLA were not suppressed by DS 103-282 (3.3-10 mg/kg, i.p.). In the baboons, a transient protection against photomyoclonic responses was observed 1 hr after intravenous administration of DS 103-282 (2-4 mg/kg). A similar profile of action was seen after oral administration of larger doses of DS 103-282 (16-32 mg/kg). Unwanted effects of DS 103-282 included transient piloerection, slight disturbance of gait and a fall in rectal temperature in mice, and muscular hypotonia and signs of sedation in baboons. These studies demonstrate an anticonvulsant action of DS 103-282, in both rodent and primate models of epilepsy, but do not support a postsynaptic blockade in excitatory neurotransmission as the mechanism of this action.

Acoustic Stimulation↗
PubMed1984

Anticonvulsant and proconvulsant properties of a series of structural isomers of piperidine dicarboxylic acid.

Anticonvulsant and convulsant effects of various piperidine dicarboxylic acids have been evaluated following their intracerebroventricular (i.c.v.) or intraperitoneal (i.p.) injection in DBA/2 mice, a strain of mice genetically susceptible to sound-induced seizures. Protection against sound-induced seizures occurred after intraventricular administration of (+/-)cis-2,3-piperidine dicarboxylic acid (0.017-0.045 mumol), (+/-)trans-2,3-piperidine dicarboxylic acid (0.018-0.33 mumol) and (+/-)cis-2,4-piperidine dicarboxylic acid (0.57-1.68 mumol). Protection against sound-induced seizures occurred after intraperitoneal injection of (+/-)cis-2,3-piperidine dicarboxylic acid (0.52-1.8 mmol/kg). Myoclonus or convulsions occurred at various times after the intraventricular injection of cis-2,3-piperidine dicarboxylic acid, trans-2,3-, cis-2,4-, cis-2,5- and cis-2,6-, piperidine dicarboxylic acids, and after the intraperitoneal injection of trans-2,3-piperidine dicarboxylic acid. The latter effect was blocked by pretreatment with 2-amino-7-phosphonoheptanoic acid (0.33 mmol/kg, i.p.) a potent and specific antagonist of excitation induced by N-methyl-D-aspartate. The anticonvulsant action of cis-2,3-piperidine dicarboxylic acid and the convulsant action of trans-2,3-piperidine dicarboxylic acid were associated with predominant antagonist and agonist actions respectively, at receptors preferring N-methyl-D-aspartate.

Acoustic Stimulation↗
PubMed1984

Status epilepticus: the reversibility of calcium loading and acute neuronal pathological changes in the rat hippocampus.

Light and electron microscopy (with the combined oxalate-pyroantimonate technique for the electron microscopic visualization of intracellular calcium) were used to compare the hippocampal pathology in rats killed immediately after 1.5-2 h of L-allylglycine-induced seizures with that in rats allowed 15-60 min of a seizure-free "recovery" period before perfusion fixation. Following 1.5 h of seizure activity, cellular pathology included astrocytic swelling and dark cell degeneration of pyramidal and polymorphic 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 certain neuronal cell bodies in the CA1 and CA3 regions and the hilus. After a seizure-free period of between 30 and 60 min the hippocampi showed almost complete recovery except for a few remaining dark, shrunken cells. The majority of these were presumed to be interneurons. The ultrastructural changes were consistent with the observations by light microscopy. By 60 min, excess calcium deposits had disappeared except in the dark cells in which intracellular vacuoles retained deposits. We conclude that most of the pathological changes observed after 1.5 h of L-allylglycine induced status epilepticus, including the mitochondrial calcium "overload" are reversible. At 1 h after termination of status epilepticus apparently irreversible pathology (dark cell change, "ischaemic cell change") concerns predominantly the polymorphic neurons.

Animals↗
PubMed1984

Calcium overload in selectively vulnerable neurons of the hippocampus during and after ischemia: an electron microscopy study in the rat.

Light and electron microscopy has been used to study the cytopathological changes in the rat hippocampus directly after a 30-min period of forebrain ischemia and after 30 or 120 min of reperfusion. The fine structural localization of calcium has been demonstrated using the oxalate/pyroantimonate procedure. Cellular changes considered typical of ischemia (swelling of astrocytic processes, distention of mitochondria, condensation of cytoplasm, "ischemic cell change") are most prominent after 30 min of reperfusion. At this time, dense calcium pyroantimonate deposits are evident in swollen mitochondria in pyramidal and hilar neurons. After 120 min of reperfusion, substantial restitution has occurred; most mitochondria appear normal and there are few calcium deposits. However, a small number of selectively vulnerable neurons (hilar and pyramidal neurons) show dense condensation (ischemic cell change) with multiple vacuoles containing calcium deposits. The role of excessive calcium entry and mitochondrial calcium overload during the reperfusion period in determining the death of selectively vulnerable neurons is discussed.

Animals↗
PubMed1984

Changes in regional neurotransmitter amino acid levels in rat brain during seizures induced by L-allylglycine, bicuculline, and kainic acid.

Changes in amino acid concentrations were studied in the cortex, cerebellum, and hippocampus of the rat brain, after 20 min of seizure activity induced by kainic acid, 47 mumol/kg i.v.; L-allylglycine, 2.4 mmol/kg i.v.; or bicuculline, 3.27 mumol/kg i.v. in paralysed, mechanically ventilated animals. Metabolic changes associated with kainic acid seizures predominate in the hippocampus, where there are decreases in aspartate (-26%), glutamate (-45%), taurine (-20%), and glutamine (-32%) concentrations and an increase in gamma-aminobutyric acid (GABA) concentration (+ 26%). L-Allylglycine seizures are associated with generalized decreases in GABA concentrations (-32 to -54%), increases in glutamine concentrations (+10 to +53%), and a decrease in cortical aspartate concentration (-14%). Bicuculline seizures, in fasted rats, are associated with marked increases in the levels of hippocampal GABA (+106%) and taurine (+40%). In the cerebellum, there are increases in glutamine (+50%) and taurine concentrations (+36%). These changes can be explained partially in terms of known biochemical and neurophysiological mechanisms, but uncertainties remain, particularly concerning the cerebellar changes and the effects of kainic acid on dicarboxylic amino acid metabolism.

Allylglycine↗