Biomedical subjects

G J Lees

Publications and source records attributed to G J Lees.

At least 19 recordsLinked to original sources

PubMed2003

Simulated electrocortical activity at microscopic, mesoscopic, and global scales.

Simulation of electrocortical activity requires (a) determination of the most crucial features to be modelled, (b) specification of state equations with parameters that can be determined against independent measurements, and (c) explanation of electrical events in the brain at several scales. We report our attempts to address these problems, and show that mutually consistent explanations, and simulation of experimental data can be achieved for cortical gamma activity, synchronous oscillation, and the main features of the EEG power spectrum including the cerebral rhythms and evoked potentials. These simulations include consideration of dendritic and synaptic dynamics, AMPA, NMDA, and GABA receptors, and intracortical and cortical/subcortical interactions. We speculate on the way in which Hebbian learning and intrinsic reinforcement processes might complement the brain dynamics thus explained, to produce elementary cognitive operations.

Animals↗

PubMed2001

Comparative effects of metal chelating agents on the neuronal cytotoxicity induced by copper (Cu+2), iron (Fe+3) and zinc in the hippocampus.

The ability of metal chelating agents to prevent neuronal death caused by intra-hippocampal injections of cupric sulphate, ferric citrate and zinc chloride was investigated. Ammonium tetrathiomolybdate was itself toxic after injection into the hippocampus, but this toxicity was reduced by formation of a metal ion/tetrathiomolybdate complex with Cu+2. Disodium bathocuproine disulphonate (BCDS) prevented neuronal death caused by Cu+2, but not that induced by Fe+3 or Zn+2. Desferrioxamine prevented death caused by Fe+3, had no significant effect of the toxicity of Zn+2, and increased that caused by Cu+2. Even though N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN) has a higher affinity for Cu+2 than for Zn+2, TPEN had no effect on the toxicity of Cu+2 while totally preventing damage caused by Fe+3 or Zn+2. Ethylenediaminetetra-acetic acid (EDTA) prevented the toxicity of all three metal ions. Motor seizure activity occurred in most rats after injections of Fe+3; or combinations of Cu+2 plus TPEN, or 4 nmol Fe+3 plus 0.1 nmol desferrioxamine. However, apart from the low dose desferrioxamine/Fe+3 combination, only the occasional brain contained seizure-induced neuronal loss in limbic regions outside the injected hippocampus, and these brains were not used for analysis. Seizure activity was found even with very low levels of Cu+2 with a fixed amount of TPEN (a ratio of Cu+2/TPEN of 1:100), but the extent of hippocampal damage in these brains was not significantly different to that caused by injections of saline. These studies demonstrate that idiosyncratic interactions can occur between metal ions and chelating agents. Thus further investigations are needed before chelating agents can be examined for their protective properties in various neurodegenerative diseases.

Animals↗

PubMed2001

In vivo, the direct and seizure-induced neuronal cytotoxicity of kainate and AMPA is modified by the non-competitive antagonist, GYKI 52466.

The 2,3-benzodiazepine GYKI 52466, administered intracerebrally or systemically, was assessed for its ability to protect against the neuronal death in the brain caused by intra-hippocampal injections of the non-N-methyl-D-aspartate (NMDA) receptor agonists, kainate and L-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA). In contrast to a previous report, a low intra-hippocampal dose of GYKI 52466 (25 nmol) did not protect against kainate toxicity. In order to achieve higher doses of GYKI 52466, solubilization in 2-hydroxypropyl-beta-cyclodextrin was used, and limited protection against AMPA, but not kainate toxicity was found. There was a commensurate reduction in seizure-related neuronal loss in the limbic regions of the brain. When diazepam was used to prevent seizures, GYKI 52466 had no effect on hippocampal neuronal loss caused by the direct toxicity of AMPA and kainate on hippocampal neurons. Systemic administration of GYKI 52466 had only a minimal effect on preventing neuronal death caused by AMPA. In vivo, GYKI 52466 is only weakly effective as a neuroprotective agent.

Animals↗

PubMed2000

Pharmacology of AMPA/kainate receptor ligands and their therapeutic potential in neurological and psychiatric disorders.

It has been postulated, consistent with the ubiquitous presence of glutamatergic neurons in the brain, that defects in glutamatergic neurotransmission are associated with many human neurological and psychiatric disorders. This review evaluates the possible application of ligands acting on glutamate alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) and kainate (KA) receptors to minimise the pathology and/or symptoms of various diseases. Glutamate activation of AMPA receptors is thought to mediate most fast synaptic neurotransmission in the brain, while transmission via KA receptors contributes only a minor component. Variants of the protein subunits forming these receptors greatly extend the pharmacological and electrophysiological properties of AMPA/KA receptors. Disease and drug use can differentially affect the expression of the subunits and their variants. Ligands bind to AMPA receptors by competing with glutamate at the glutamate binding site, or non-competitively at other sites on the proteins (allosteric modulators). Ligands showing selective competitive antagonist actions at the AMPA/ KA class of glutamate receptors were first reported in 1988, and the systemically active antagonist 2,3-dihydroxy-6-nitro-7-sulphamoyl-benzo(F)quinoxaline (NBQX) was first shown to have useful therapeutic effects on animal models of neurological diseases in 1990. Since then, newer antagonists with increased potency, higher specificity, increased water solubility, and a longer duration of action in vivo have been developed. Negative allosteric modulators such as the prototype GYKI-52466 also block AMPA receptors but have little action at KA receptors. Positive allosteric modulators enhance glutamatergic neurotransmission at AMPA receptors. Polyamines and adamantane derivatives bind within the ion channel of calcium-permeable AMPA receptors. The latest developments include ligands selective for KA receptors containing Glu-R5 subunits. Evidence for advantages of AMPA receptor antagonists over N-methyl-D-aspartate (NMDA) receptor antagonists for symptomatic treatment of neurological and psychiatric conditions, and for minimising neuronal loss occurring after acute neurological diseases, such as physical trauma, ischaemia or status epilepticus, have been shown in animal models. However, as yet AMPA receptor antagonists have not been shown to be effective in clinical trials. On the other hand, a limited number of clinical trials have been reported for AMPA receptor ligands that enhance glutamatergic neurotransmission by extending the ion channel opening time (positive allosteric modulators). These acute studies demonstrate enhanced memory capability in both young and aged humans, without any apparent serious adverse effects. The use of these allosteric modulators as antipsychotic drugs is also possible. However, the long term use of both direct agonists and positive allosteric modulators must be approached with considerable caution because of potential adverse effects.

Animals↗

PubMed1998

Nitric oxide generators produce accumulation of chelatable zinc in hippocampal neuronal perikarya.

While zinc is essential for health, it has also been implicated in the neuropathology of several disease states such as Alzheimer's disease, epilepsy and cerebral ischemia. Recent studies have shown that oxidative and nitrosylative stresses can liberate zinc from metalloproteins in vitro. Thus, nitric oxide (NO.), a radical molecule which serves as a retrograde messenger, was studied for its effects on the in vivo accumulation of zinc in neurons. Three NO. -donors, sodium nitroprusside (SNP; >/=5 nmol), spermine-nitric oxide complex (SPER-NO; </=200 nmol), and 3-morpholino-sydnonimine (SIN-1; </=200 nmol) were administered into the dorsal hippocampus of rats. Brain tissue was stained by both the Timm's method, and with N-(6-methoxy-8-quinolyl)-para-toluenesulfonamide (TSQ), a histochemical stain for metal ions and a selective fluorescent probe for zinc ions, respectively. A sporadic pattern of zinc accumulation within the perikarya, axons, and dendritic processes of certain pyramidal neurons, interneurons, and dentate granule cells was found 2 h after administrations of SNP and SPER-NO, but not with SIN-1. With SNP, sporadic perikaryal zinc staining of the pyramidal neurons and interneurons at strata oriens (SO), pyramidale (SP), and radiatum (SR) was consistently observed, but with SPER-NO, the granule cells of the dentate gyrus were preferentially stained. Administration of sodium ethylenediamine tetraacetic acid (NaEDTA, 10 nmol) 10 min before SNP resulted in a marked reduction of sporadic perikaryal zinc staining in the SO and SR. The more selective metal chelator, N,N,N', N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN, 10 nmol) injected 10 min before SNP abolished the staining of neuronal perikarya and surrounding neuropil. In addition, SNP, but not SPER-NO, induced convulsive activity. Groups of rats that manifested continuous wet dog shakes and/or generalized convulsions for at least 4-5 h after SNP were found to have generalized perikaryal Timm's staining of all neurons in the pyramidal cell layer of the subicular and cornu ammonis regions, similar to the staining found after seizures induced by kainic acid. However, after kainic acid-, but not SNP-induced seizures, Timm's staining of neuronal perikarya in the piriform cortex and amygdala was also observed. This is the first evidence that NO. can induce accumulation of zinc in neuronal perikarya and processes in the hippocampus in vivo. As a mechanism underlying the possible involvement of zinc in neurodegenerative disorders caused by excitotoxicity and/or oxidative stress, it is an alternative to release of synaptic vesicle zinc and uptake by damaged hippocampal neuronal perikarya.

Aminoquinolines↗

PubMed1998

Diverse effects of metal chelating agents on the neuronal cytotoxicity of zinc in the hippocampus.

Abnormal metabolism of metal ions such as zinc may contribute to neuropathology. Complexing zinc could reduce this pathology. Thus, to examine the effectiveness of metal chelating agents in vivo, a model system was used. This involved determining the ability of chelating agents to prevent neuronal death caused by zinc chloride injected into the rat hippocampus. Significant protection against zinc toxicity was obtained with pyrithione, inositol hexakisphosphate, ethylenediamine tetraacetate (EDTA) and N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN). The affinity of these agents for zinc varied between 106 M-1 and 1018 M-1. Thus, the affinity for zinc within this range does not appear to be a major factor affecting the ability of chelators to provide neuroprotection. While almost complete protection was found with EDTA and TPEN given simultaneously with zinc chloride, poor protection was obtained if TPEN was given before or after zinc chloride. Other agents either did not protect against zinc-induced neuronal death (zincon), or exacerbated zinc toxicity (BTC-5N and about 40% of rats injected with a combination of zinc chloride and diethylenetriamine pentaacetate [DTPA]). Rats showing increased damage after zinc plus BTC-5N or DTPA suffered wet dog-like shakes (WDS), suggesting that these zinc chelate complexes can induce seizures resulting in seizure-related damage. In contrast, in the 60% of rats treated with zinc chloride and DTPA that had no WDS, there was about an 80% reduction in the size of the zinc-induced lesion. The ability of chelators to cross cell membranes was examined by determining whether Timm's staining for vesicular zinc was reduced following the injection of a chelator into the hippocampus. TPEN and pyrithione reduced Timm's staining for zinc. However, cell permeability was not necessary for a chelator to protect against zinc toxicity.

Animals↗

PubMed1998

Effect of metal chelating agents on the direct and seizure-related neuronal death induced by zinc and kainic acid.

The ability of metal chelating agents to affect seizure-induced neuronal death caused by intra-amygdaloid injections of kainic acid was investigated. N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN), diethyldithiocarbamate (DEDTC) and diphenylthiocarbazone (dithizone), administered simultaneously or within 30 min of a kainate injection, all failed to affect the amount of neuronal loss in the ipsilateral hippocampus. This failure was not due to an inability to complex endogenous zinc as all these chelating agents quenched staining for endogenous zinc by the Timm method. However, the period for which this quenching occurred was short for DEDTC and dithizone (a maximum of 1.5 h) although it lasted for 8 h with TPEN. TPEN, but not DEDTC or dithizone prevented the neuronal loss caused by intra-hippocampal injections of zinc chloride. In the presence of diazepam to prevent seizures, co-injection of TPEN and kainate into the hippocampus also failed to prevent the direct cytotoxicity of kainate. Endogenous zinc, released from mossy fibres in the hippocampus by seizure activity, does not appear to modify seizure activity sufficiently to alter the extent of the resulting neuronal death.

Amygdala↗

PubMed1997

Zinc metabolism in the brain: relevance to human neurodegenerative disorders.

Zinc is an important trace element in biology. An important pool of zinc in the brain is the one present in synaptic vesicles in a subgroup of glutamatergic neurons. In this form it can be released by electrical stimulation and may serve to modulate responses at receptors for a number of different neurotransmitters. These include both excitatory and inhibitory receptors, particularly the NMDA and GABA(A) receptors. This pool of zinc is the only form of zinc readily stained histochemically (the chelatable zinc pool), but constitutes only about 8% of the total zinc content in the brain. The remainder of the zinc is more or less tightly bound to proteins where it acts either as a component of the catalytic site of enzymes or in a structural capacity. The metabolism of zinc in the brain is regulated by a number of transport proteins, some of which have been recently characterized by gene cloning techniques. The intracellular concentration may be mediated both by efflux from the cell by the zinc transporter ZrT1 and by complexing with apothionein to form metallothlonein. Metallothionein may serve as the source of zinc for incorporation into proteins, including a number of DNA transcription factors. However, zinc is readily released from metallothionein by disulfides, increasing concentrations of which are formed under oxidative stress. Metallothionein is a very good scavenger of free radicals, and zinc itself can also reduce oxidative stress by binding to thiol groups, decreasing their oxidation. Zinc is also a very potent inhibitor of nitric oxide synthase. Increased levels of chelatable zinc have been shown to be present in cell cultures of immune cells undergoing apoptosis. This is very reminiscent of the zinc staining of neuronal perikarya dying after an episode of ischemia or seizure activity. Thus a possible role of zinc in causing neuronal death in the brain needs to be fully investigated. intraventricular injections of calcium EDTA have already been shown to reduce neuronal death after a period of ischemia. Pharmacological doses of zinc cause neuronal death, and some estimates indicate that extracellular concentrations of zinc could reach neurotoxic levels under pathological conditions. Zinc is released in high concentrations from the hippocampus during seizures. Unfortunately, there are contrasting observations as to whether this zinc serves to potentiate or decrease seizure activity. Zinc may have an additional role in causing death in at least some neurons damaged by seizure activity and be involved in the sprouting phenomenon which may give rise to recurrent seizure propagation in the hippocampus. In Alzheimer's disease, zinc has been shown to aggregate beta-amyloid, a form which is potentially neurotoxic. The zinc-dependent transcription factors NF-kappa B and Sp1 bind to the promoter region of the amyloid precursor protein (APP) gene. Zinc also inhibits enzymes which degrade APP to nonamyloidogenic peptides and which degrade the soluble form of beta-amyloid. The changes in zinc metabolism which occur during oxidative stress may be important in neurological diseases where oxidative stress is implicated, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS). Zinc is a structural component of superoxide dismutase 1, mutations in which give rise to one form of familiar ALS. After HIV infection, zinc deficiency is found which may be secondary to immune-induced cytokine synthesis. Zinc is involved in the replication of the HIV virus at a number of sites. These observations should stimulate further research into the role of zinc in neuropathology.

Animals↗

PubMed1997

Zinc and Alzheimer's disease: is there a direct link?

Zinc is an essential trace element in human biology, but is neurotoxic at high concentrations. Several studies show that zinc promotes aggregations of beta-amyloid protein, the main component of the senile plaques typically found in Alzheimer's disease brains. In other neurological disorders where neurons appear to be dying by apoptosis (gene-directed cell death), chelatable zinc accumulates in the perikarya of neurons before, or during degeneration. As there is evidence for apoptotic death of neurons in Alzheimer's disease, an involvement of zinc in this process needs to be investigated. Zinc interacts with enzymes and proteins, including transcription factors, which are critical for cell survival and could be linked to apoptotic processes. While controversial, some studies indicate that total tissue zinc is markedly reduced in several brain regions of Alzheimer's patients. At face value, it seems that a paradox exists between reports of a decrease in zinc in the Alzheimer's brain and the putative link to aberrant high zinc levels promoting plaque formation. An hypothesis to explain this inconsistency is presented. Neuropathological changes mediated by endogenous or exogenous stressors may be relevant factors affecting abnormal zinc metabolism. This paper reviews current investigations that suggest a role of zinc in the etiology of Alzheimer's disease.

Alzheimer Disease↗

PubMed1996

Neuronal cytotoxicity of inositol hexakisphosphate (phytate) in the rat hippocampus.

D-myo-Inositol hexakisphosphate (InsP6, phytate), a normal cellular constituent, was found to be toxic to neuronal perikarya when injected into the rat hippocampus. However, the extrinsic cholinergic innervation of the hippocampus (as estimated by staining for acetylcholinesterase) was unaffected. Its potency as a toxin was approximately equal to that of the excitotoxin quinolinate. Other highly charged derivatives of inositol (inositol hexakissulphate, inositol monophosphate) were not toxic. The cytotoxicity of InsP6 was not due to a high osmolality, or to seizure-induced lesions, but was reduced by calcium. Nevertheless, the toxicity was not due to chelation of brain calcium by InsP6, as another calcium chelator with a higher affinity for calcium, 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA), produced only a very mild lesion. Thus, abnormal metabolism of InsP6 might possibly contribute to neuronal death in neurodegenerative diseases.

Animals↗

PubMed1996

Prevention of zinc neurotoxicity in vivo by N,N,N',N'-tetrakis (2-pyridylmethyl) ethylene-diamine (TPEN).

Intrahippocampal injections of zinc chloride (10 nmol) produce lesions in the rat hippocampus. A heavy metal chelator N,N,N',N'-tetrakis(2-pyridylmethyl)-ethylene-diamine (TPEN), co-injected with zinc chloride in vivo, totally prevented zinc-induced neuronal loss. Furthermore, intrahippocampal injections of TPEN (10 nmol) were non-toxic when compared with controls. TPEN injections in vivo quenched the in vitro staining of brain sections for zinc (Timm's stain), particularly the staining of the hippocampal mossy fibres. This demonstrates that TPEN is taken up by zinc-containing neurones in vivo. The use of TPEN to block the actions of zinc could help define the possible role of zinc in the pathology of various neurological disorders.

Animals↗

PubMed1996

Interactions between excitotoxins and the Na+/K+-ATPase inhibitor ouabain in causing neuronal lesions in the rat hippocampus.

A possible indirect role of glutamate in causing the neuronal death found after intracerebral administration of a low dose of ouabain (0.1 nmol) has been evaluated. This dose of ouabain produces a more extensive neuronal lesion than those caused by glutamate receptor agonists (kainate at an equimolar dose, or NMDA (N-methyl-D-aspartate) at a 50-fold higher dose). The selective glutamate receptor antagonists, dizocilpine (MK-801) and NBQX (2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline), in doses which blocked the direct toxicity of glutamate receptor agonists acting on either the NMDA and non-NMDA classes of glutamate receptor, failed to provide more than a minor protection against ouabain-induced neuronal death in the rat dorsal hippocampus. In contrast, the non-selective glutamate receptor antagonist, kynurenate (100 nmol) reduced the damage by around 70%. The difference in neuroprotection found between the glutamate receptor antagonists suggests that kynurenate may protect by a non-glutamatergic mechanism. Co-administration of ouabain and glutamate receptor agonists (kainate, NMDA or glutamate) resulted in additive rather than synergistic damage to hippocampal neurons. The results suggest that in vivo, ouabain and excitotoxins probably cause neuronal death by independent mechanisms.

Animals↗

PubMed1995

The sodium-potassium ATPase inhibitor ouabain is neurotoxic in the rat substantia nigra and striatum.

Injection of ouabain, a potent and selective inhibitor of Na+/K+ ATPase, into the rat striatum and substantia nigra caused a selective neuronal loss in up to 70% of the lesioned area. However, there was a glial cell/macrophage proliferation in the core of the lesion. Neuronal loss was demonstrated by staining in vivo with Trypan Blue, a marker for dead cells. Cholinesterase staining was also lost, but in the striatum this was revealed only after pre-existing enzyme was irreversibly inhibited in vivo.

Animals↗

PubMed1995

Influence of ketamine on the neuronal death caused by NMDA in the rat hippocampus.

The protection provided by ketamine against the neuronal cytotoxicity of NMDA was investigated and compared with that provided by dizocilpine (MK 801). A massive anaesthetic dose of ketamine (180 mg/kg) was required for substantial protection (about 70%) of rat dorsal hippocampal neurons. Protection was markedly decreased if the ketamine was given in three divided doses of 60 mg/kg over a period of 2 hr, rather than as a bolus injection of 180 mg/kg. A lower dose (60 mg/kg i.p.) gave no protection when given 10 min prior to NMDA, but some protection (up to 30%) was found when administration was delayed for 1-2 hr. After 3 hr, ketamine at this dose did not protect. In comparison, the toxicity of NMDA was reduced by about 70% by prior treatment with dizocilpine at 1 mg/kg, and completely eliminated at 10 mg/kg. The lack of protection when ketamine at 60 mg/kg was administered prior to NMDA may be due to a proconvulsant action of ketamine, as diazepam in the presence but not in the absence of ketamine significantly reduced the toxicity of NMDA. However, there was no behavioural or histological evidence of increased seizure activity in the presence of ketamine. Neuroprotectant effects may prevail with massive anaesthetic doses of ketamine or when diffusion has reduced the concentration of NMDA. The heroic doses of ketamine required for protection diminish its attractiveness as a potential anti-ischaemic agent.

Animals↗

PubMed1994

Neurone-specific enolase persists in some hippocampal cells 24 hours after an NMDA injection.

Neurone-specific enolase immunoreactivity (NSE-IR) was examined in the hippocampal dentate gyrus 5 h, 24 h and 6 days following local injection of N-methyl-D-aspartate (NMDA), and was compared with Nissl substance and acid fuchsin staining. Five and 24 hours post-injection extracellular NSE-IR was increased, and the number of NSE-IR neurones in the granule cell layer was decreased. However, at 24 h post-injection only, 10-15% of the granule cells were strongly NSE-IR, in contrast to the Nissl/acid fuchsin staining which showed a homogeneous population of degenerating neurones. By 6 days there were no viable neurones in the lesion area stained by either method. These results show that neuronal degeneration after an excitotoxic insult occurs in a non-uniform way in an apparently homogeneous group of central neurones.

Animals↗

PubMed1994

Synergy between diazepam and NBQX in preventing neuronal death caused by non-NMDA agonists.

The non-N-methyl-D-aspartate (NMDA) glutamate receptor agonists kainate and L-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA), when injected into the rat dorsal hippocampus, cause neuronal death directly by activating non-NMDA receptors and as a consequence of initiating seizure activity. Co-injection of the non-NMDA antagonist 2,3-dihydroxy-6-nitro-7-sulphamoyl-benzo(F)quinoxaline (NBQX; 12.5-95 nmol) was partially effective in preventing up to about 60% of the direct excitotoxicity. On the other hand, diazepam (6 x 5 mg kg-1, i.p.) had only a minor protective effect against the direct neuronal damage, but was effective in preventing almost all the extra-hippocampal loss of neurones caused by seizure activity. The combination of intracerebral NBQX and systemic diazepam reduced the toxicity of kainate or AMPA to a greater extent than that found in the presence of either protectant alone. At optimum doses the neuronal cytotoxicity caused by non-NMDA agonists in the hippocampus was completely prevented.

Animals↗

PubMed1994

NBQX prevents contralateral but not ipsilateral seizure-induced cytotoxicity of kainate but not AMPA-reversal at high doses of NBQX.

The non-N-methyl-D-aspartate (NMDA) glutamate agonists are potent convulsants, and cause neuronal loss in many regions of the limbic system in the brain. Kainate or L-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) and the non-NMDA antagonist 2,3-dihydroxy-6-nitro-7-sulphamoyl-benzo(F)quinoxaline (NBQX) were concomitantly injected unilaterally into the rat dorsal hippocampus. Kainate with low doses of NBQX (12.5-25 nmol) almost completely prevented damage to the contralateral but not ipsilateral limbic areas (distal toxicity). In most animals, damage was still found in the contralateral midline thalamic nuclei. In contrast, high doses of NBQX (95-190 nmol) gave no protection to either side. AMPA showed a trend for a reduction in limbic damage to both sides with increasing dose of NBQX. At the highest doses, NBQX prevented damage to both sides.

Animals↗

PubMed1994

Brain lesions induced by specific and non-specific inhibitors of sodium-potassium ATPase.

The cytotoxicity in the brain of potent selective and non-selective inhibitors of Na+/K+ ATPase has been assessed. Following injection of cardiac glycosides into the dorsal hippocampus of rats, the extent of neuronal loss roughly paralleled their potencies as inhibitors of the enzyme. Dihydroouabain was less potent than ouabain as a cytotoxin by an order of magnitude, similar to their relative affinities for Na+/K+ ATPase. The non-specific inhibitors, melittin, erythrosin B and zinc (chloride) were less neurocytotoxic than the selective inhibitors having equivalent potencies. The toxicity of a low dose of ouabain appeared to be selective for neuronal perikarya as staining for acetylcholinesterase (present on the nerve terminals of the afferent cholinergic innervation) was unaffected. A higher dose of ouabain caused a non-specific necrosis including damage to the neuropil and a loss of cholinesterase staining. Concurrently, there was an invasion of the tissue by cells resembling foaming macrophages. Other inhibitors of the enzyme caused a mixed pathology with both types of responses evident. It is suggested that the pathological response may depend on the relative degrees to which the glial and neuronal activities of the enzyme are affected.

Acetylcholinesterase↗