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G J Lees

Publications and source records attributed to G J Lees.

At least 37 records · Page 2Linked to original sources
PubMed1993

Differential effects of NBQX on the distal and local toxicity of glutamate agonists administered intra-hippocampally.

The ability of the non-NMDA glutamate antagonist NBQX (2,3-dihydroxy-6-nitro-7-sulphamoyl-benzo(F)quinoxaline) to protect the brain against the neuronal death caused by glutamate agonists was examined. Glutamate agonists and NBQX were co-injected into the dorsal region of the rat hippocampus and 4 days later the brain was examined histochemically for the loss of neurons. 95 nmol NBQX prevented the toxicity of glutamate agonists acting on the AMPA receptor (quisqualate and AMPA [L-alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate]), except for the higher dose of AMPA where toxicity was only partially reduced. This dose of NBQX also prevented about 50% of the toxicity of kainate, but produced a slight increase in the size of the lesions caused by NMDA (N-methyl-D-aspartate). With 190 nmol NBQX, a variable degree of non-specific damage resulted, but was mainly confined to the dentate region. Allowing for this damage, almost complete protection against the toxicity of non-NMDA glutamate agonists was obtained, with a partial protection against NMDA toxicity. Kainate, and a high dose of AMPA (2 nmol), consistently caused neuronal death in other limbic regions of the brain in addition to the hippocampal damage. About 50% of rats treated with 15 nmol quisqualate also showed damage to limbic regions. Both doses of NBQX prevented this distal damage caused by quisqualate, but not that caused by kainate. With AMPA, only the high dose of NBQX blocked the distal toxicity. Diazepam also blocked the distal toxicity of AMPA, but had only a minor effect on the hippocampal damage.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

The possible contribution of microglia and macrophages to delayed neuronal death after ischemia.

Macrophages have long been known to be involved in cytotoxic actions in many tissues in the body following infection. Knowledge of the post-injury actions of blood-borne macrophages in the brain, and their resident counterparts, the microglia, have been limited to the "mopping-up" of cellular debris. However, other functions are now coming to light and there is evidence that they contribute to both growth promotion and cytotoxicity following injury in the brain. This review raises the possibility that macrophages may contribute to delayed neuronal death following ischemia. Growth factors including certain cytokines produced by these cells protect against ischemia-induced neuronal death. In contrast, cytokines can also induce macrophages to synthesize nitric oxide synthase and indoleamine-2,3-dioxygenase which results in the production of the cytotoxins nitric oxide and quinolinic acid. It is hypothesized that viable cells produce or concentrate growth factors which prevent the induction of these enzymes, whereas damaged cells cannot.

Animals↗
PubMed1992

The non-NMDA glutamate antagonist NBQX blocks the local hippocampal toxicity of kainic acid, but not the diffuse extrahippocampal damage.

The neuronal lesion caused locally by the injection of 0.47 nmol kainic acid into the dorsal hippocampus was greatly reduced by the co-administration of 190 nmol 2,3-dihydro-6-nitro-7-sulphamoyl-benzo(F)quinoxaline (NBQX). Protection was particularly marked for the neurons present in the CA3 and dentate hilar regions which are the neurons most vulnerable to kainic acid. On the other hand, systemic administration of NBQX (3 doses of 30 mg/kg i.p.) was completely ineffective in blocking neuronal loss in the CA3 and hilar regions. Furthermore, neither hippocampal nor systemic NBQX could prevent the diffuse neuronal damage to other regions in the limbic system outside of the dorsal hippocampus.

Animals↗
PubMed1992

Biphasic changes in NCAM level after an NMDA lesion to the hippocampal formation: a quantitative dot-immunobinding assay.

With a quantitative dot-immunobinding assay, the time course changes of neuronal cell adhesion molecule (NCAM) concentrations and total tissue content were monitored in the rat hippocampus after a 40 nmol NMDA injection. A biphasic alteration was observed; a decrease occurred at day 3, an increase at day 30. The time course of changes differed from that of the glial fibrillary acidic protein (GFAP), a marker for reactive astroglial cell, but was similar to that for the markers of sprouting neurites, i.e., low (L) and high (H) molecular weight subunits of the neurofilament polypeptides. It is suggested that NCAM is implicated in the onset of neurite sprouting in the hippocampus after an excitotoxic trauma.

Animals↗
PubMed1992

Proteolysis of filament proteins in glial and neuronal cells after in vivo stimulation of hippocampal NMDA receptors.

An intrahippocampal injection of N-methyl-D-aspartate induced the appearance of degradation products of both the 68 kiloDalton neurofilament protein and the glial fibrillary acidic protein, as revealed by immunoblot techniques. The degradation of these two filament proteins was maximal at 10 days after the lesion. The degradation patterns were similar to those induced with calpains or calcium in vitro. There were no degradation effects on the 200 kD neurofilament protein as tested with both mono- and polyclonal antibodies. Consequently, the neuronal degeneration after excessive activation of NMDA receptors appears to involve calcium activation of proteolytic enzymes. The effects on the glial proteins are probably secondary to neuronal damage but could be related to calcium dependent processes.

Animals↗
PubMed1992

Effects of anaesthetics, anticonvulsants and glutamate antagonists on kainic acid-induced local and distal neuronal loss.

A semi-quantitative estimation has been made of the effect of anaesthetics, anticonvulsants and glutamate antagonists on the extent of neuronal loss in the hippocampus caused by the local injection of the excitotoxin kainic acid, and on the vulnerability of neurons in various extrahippocampal regions due to the resulting seizure activity. Following the intrahippocampal injection of 0.47 nmol kainic acid (a submaximal dose), the amount of neuronal loss in the dorsal hippocampus was greater when given under the short-acting anaesthetics halothane and ketamine (a non-competitive glutamate antagonist), than when given under pentobarbital anaesthesia (with or without co-administration of ketamine (30 mg/kg)). When kainic acid was injected under halothane or ketamine anaesthesia a greater number of extrahippocampal limbic regions (distal toxicity) were also affected, usually on the ipsilateral side, and the extent of damage in each of these regions was generally more extensive. The anticonvulsants MK 801 and diazepam, or multiple injections of ketamine over a period of 5 h, decreased both the local and distal toxicity of kainic acid injected under short duration anaesthesia, to levels similar to those found under pentobarbital anaesthesia. However, these compounds, even at high doses, could not reliably prevent all seizure-related damage in extrahippocampal areas.

Anesthetics↗
PubMed1991

The effect of an N-methyl-D-aspartate lesion in the hippocampus on glial and neuronal marker proteins.

The study employed an immunochemical quantification of brain cell marker proteins in addition to quantitative morphology in order to provide a more multifacetted and characterized model for an excitotoxic CNS lesion. The importance of the approach in the evaluation of the potential of neuroprotective agents is emphasized. The S-100 protein, the glial fibrillary acidic (GFA) protein, neuron specific enolase (NSE) and neuronal intermediary filament polypeptides (NF 68 and NF 200) were measured with a dot-immunobinding assay, 3-30 days after a unilateral injection of N-methyl-D-aspartate (NMDA) in the left dorsal hippocampus of the rat. After 3 days, the neuronal cell loss averaged 80% in the hippocampus. The S-100 content was reduced 3 days after injection, but was 150% of control at 30 days. GFA increased constantly from days 3 to 30. The neuronal marker proteins were all markedly reduced 7 days after injection. However, at 30 days, NF 68 and NF 200 were close to control (80%). Increasing content would reflect regeneration and sprouting of neurites. The content of the neuronal cytoplasmic marker, NSE, was significantly lower than control also at 10 and 30 days, although a gradual recovery could be traced.

Animals↗
PubMed1991

Evoked field potential changes in the rat hippocampus produced by toxic doses of glutamate agonists and metabolic inhibitors: correlation with subsequent neuronal death.

The perforant path evoked field potentials in the dentate gyrus of the rat hippocampus are distinctive and thus were used as a marker for the accurate positioning of injection cannulae. The time course of the changes in these potentials caused by various toxins were determined and correlated with the extent of neuronal loss produced subsequently. Glutamate and the glutamate receptor agonists, kainate and N-methyl-D-aspartate (NMDA), caused an immediate loss of the evoked field potentials, suggesting a massive depolarization block. After the glutamate agonists there was only a small recovery in potentials over a period of 8 h, whereas after glutamate the potentials recovered within 5 h. Short-term decreases in evoked potential (up to 2 h) were also found after saline injections. Hippocampal evoked potentials were still reduced 8 h after NMDA, even in areas not showing subsequent neuronal loss. Sodium iodoacetate (10 nmol) caused a delayed loss of evoked potentials, reaching a minimum 15 min after injection and lasting for at least 8 h, whereas after sodium cyanide (10 nmol) the potentials decreased immediately to a similar extent to those found 15 min after iodoacetate, but recovery was reversible over 8 h. There was a significant correlation between the degree to which the evoked potentials were decreased and the extent of death of the granule cell neurons, examined histologically four days later.

Animals↗
PubMed1990

The neurotoxicity of zinc in the rat hippocampus.

Intrahippocampal injections of zinc chloride (5-10 nmol) caused a discrete lesion in the rat hippocampus, involving all neuronal perikarya. In addition to the necrosis, the lesion was also characterized by a decrease in staining of the neuropil, the presence of pyknotic neurons, and occasionally infarction. Pathological changes occurred within 8 h of an injection, and neuronal loss, as judged by the loss of Nissl staining, was complete within 24 h. On the other hand, the loss of acidophilic staining of the neurons was more gradual, as acid fuchsin staining was still present in neurons in the periphery of the damaged area 4 days later. In comparison with an excitotoxic lesion, glial infiltration into the damaged area was minimal, even up to 3 weeks later, suggesting that some glial cell toxicity also occurred.

Animals↗
PubMed1990

The neurotoxicity of ouabain, a sodium-potassium ATPase inhibitor, in the rat hippocampus.

Intrahippocampal injection of 1 nmol ouabain, a sodium/potassium (Na+,K(+)-)ATPase inhibitor, produced a necrotic lesion within 4 days, characterised by a massive invasion by foaming macrophages. A lower dose of ouabain (0.1 nmol) produced a more discrete lesion of all groups of neuronal perikarya in the hippocampus, with only a minimal degree of glial infiltration. The neuronal perikaryal death produced in the subicular, CA1 and CA2 regions was only partially decreased by intraperitoneal injections of the anticonvulsants diazepam and MK-801; these drugs were without effect in the CA3 or hilar interneuronal regions. At neither dose of ouabain was there any indication of neuronal loss in brain regions outside the hippocampus, typically produced by prolonged seizure activity. It is suggested that ouabain has a two-fold action, a release of toxic acidic amino acids and a prolonged depolarization of neurons leading to osmolysis or calcium necrosis.

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

Halothane anaesthesia reverses the neuroprotective effect of ketamine against ibotenic acid toxicity in the rat hippocampus.

The neurodegenerative effect of ibotenic acid injected into the rat hippocampus was unaffected by the anaesthetics halothane or pentobarbital, apart from a trend to an increased toxicity at higher doses of pentobarbital (60-72 mg/kg). Its toxicity was substantially blocked only by high anaesthetic doses of the indirect acting N-methyl-D-aspartic acid antagonist, ketamine (150-180 mg/kg, i.p.). This is in contrast to its previous reported ability to protect at low concentrations in vitro. On the other hand, the protective effect of ketamine was modified under halothane or pentobarbital anaesthesia. Thus, under halothane anaesthesia, ketamine at 60 mg/kg, i.p. caused a large increase in ibotenic acid-induced neuronal death.

Anesthesia↗
PubMed1989

Trypan blue in vivo stains nigral dopaminergic neurons killed by 6-hydroxydopamine.

Dopaminergic neurons in the substantia nigra killed by 6-hydroxydopamine were stained in vivo by intracerebral injections of trypan blue. Such staining appeared specific for dead neurons, although a proportion of these retained the ability to stain with Nissl dyes for at least 2 days. Neurons retained trypan blue in vivo for periods of up to 9 days. Trypan blue staining of some neurons outside the substantia nigra demonstrated the use of this dye in determining the degree of non-specific toxicity of 6-hydroxydopamine. Twenty-four hours after infusion of trypan blue almost no background staining was present and individually stained neurons were clearly visible. Thus the use of trypan blue may have a general application as a sensitive method for estimating discrete areas of toxin-induced neuronal death, and for estimating the degree of specificity of a toxin.

Animals↗
PubMed1989

In vivo and in vitro staining of acidophilic neurons as indicative of cell death following kainic acid-induced lesions in rat brain.

An in vivo method for positively staining dead neurons was developed and compared with an in vitro staining method using acid fuchsin. Neurons previously killed by intracerebral injections of kainic acid were selectively stained by trypan blue within 15 min of its injection in vivo into the central nervous system of rats. Such staining persisted for at least 4 days in vivo, and there was no evidence that trypan blue itself was toxic to the remaining cells. Intense staining of neurons with acid fuchsin in vitro was first observed in brain sections of rats killed about 6h after kainic acid injection. This time was approximately 2-3 h before trypan blue, in vivo, was able to stain neurons. Thus, the loss of transport mechanisms (at least for trypan blue) apparently occurs subsequent to the development of basic products stainable with acidic dyes. At the earliest times, acid fuchsin stained neurons which had not yet lost Nissl substance, whereas the majority of trypan blue-stained neurons were not stained with Nissl dyes. After 24 h the majority of neurons stained with either acid fuchsin or trypan blue were Nissl-stain negative. The combination of staining with trypan blue in vivo with subsequent counterstaining of brain sections with acid fuchsin in vitro may have a potential use in the determination of the time of neuronal death in vivo.

Animals↗
PubMed1987

Effects of ketamine on the in vivo toxicity of quinolinate and N-methyl-D-aspartate in the rat hippocampus.

Systemic injections of ketamine (30 mg/kg, i.p.) decreased the neurotoxicity of the NMDA agonists NMDA (N-methyl-D-aspartic acid) and quinolinic acid injected into the hippocampus of the rat, although such protection was incomplete. Simultaneous injections of ketamine into the hippocampus decreased rather than increased these protective effects. In contrast, almost complete protection was provided by intra-hippocampal injections of DL-2-amino-5-phosphonovaleric acid (DL-APV). The duration of anaesthesia was not responsible for the protective effects of systemic ketamine, as the intracerebral injections of the NMDA agonists produced similar neuronal lesions under both halothane or nembutal anaesthesia.

2-Amino-5-phosphonovalerate↗
PubMed1987

Gross electrocortical activity as a linear wave phenomenon with variable temporal damping, regulated by ascending catecholamine neurones.

We report critical tests for a theory of electrocortical wave processes, in which telencephalic dendritic potentials reflect the mass action of coupled oscillatory circuits exhibiting complicated and unspecified non-linearities, the whole system being driven by active cell firing. Specific assumptions were: stochastic independence for instantaneous coupling parameters in the system, an individual central tendency to the cycle time for each circuit, and the maintenance of steady state conditions. Application of the central limit theorem to the state transition matrix shows that the gross electrocortical waves should be linear waves, exhibiting a multitude of invariant resonant modes, with the natural frequencies of all the modes being clustered about a smaller number of center values. Ascending brain-stem neurones of at least the dopaminergic and noradrenergic classes should regulate both the power of noise-like signals driving the telencephalic resonant patterns, and the temporal damping of each resonance. We devised tests which involved between hemisphere comparisons of electrocortical spectra, before and after unilateral lesion of transhypothalamic ascending fibres, thus obtaining ratio power changes attributable to post lesion asymmetry of damping and driving, in modes of equivalent left-right center-frequencies. These ratio spectra were curve-fitted to an approximate theoretical expression, and the parameters obtained enabled tests of several specific predictions. Estimates of the center values for resonant mode frequencies, comparison of the relative changes in left/right phase with that expected from the ratio changes in power, and estimates of the surface-to-signal transformation of left and right signals made by a back-calculation, all conform to expectation from the theory, and are consistent across lesion of different types of ascending neurone.

Animals↗
PubMed1985

Inhibition of the retrograde axonal transport of dopamine-beta-hydroxylase antibodies by the calcium ionophore A23187.

High levels of calcium, as well as calcium ionophores, have been reported to inhibit the anterograde transport of proteins. The effect of the calcium ionophore, A23187, on the retrograde axonal transport of proteins was therefore investigated. The uptake of antibodies to dopamine-beta-hydroxylase (anti-D beta H) by sympathetic nerve terminals in the iris and their subsequent accumulation in the superior cervical ganglion was inhibited by up to 65% by A23187 (6 nmol, i.o.). At this dose, catecholamine fluorescence in the iris was reduced, indicating a high rate of exocytosis, but tyrosine hydroxylase levels and the capacity of the treated irides to take up noradrenaline were unaffected. Higher amounts of A23187 (28 nmol, i.o.) did not cause a greater degree of inhibition of retrograde transport. However, this dose was toxic to the neurons, as shown by a 68% decrease in the ability of the nerve terminals in the iris to take up [3H]noradrenaline. This loss of function occurred gradually over a 12-h period. On the other hand, tyrosine hydroxylase levels were unaffected by 28 nmol A23187. The toxicity of A23187 may be a consequence of a build up in intracellular calcium, but such toxicity did not lead to any apparent loss of nerve terminals within a 3-day period.

Animals↗