Neuroprotective efficacy of AR-A008055, a clomethiazole analogue, in a global model of acute ischaemic stroke and its effect on ischaemia-induced glutamate and GABA efflux in vitro

@article{Nelson2001NeuroprotectiveEO,
  title={Neuroprotective efficacy of AR-A008055, a clomethiazole analogue, in a global model of acute ischaemic stroke and its effect on ischaemia-induced glutamate and GABA efflux in vitro},
  author={R. M. Nelson and A. Hainsworth and D. Lambert and J. A. Jones and T. K. Murray and D. Richards and J. Gabrielsson and A. Cross and A. Green},
  journal={Neuropharmacology},
  year={2001},
  volume={41},
  pages={159-166}
}
We have investigated the neuroprotective properties of AR-A008055 [(+/-)-1-(4-methyl-5-thiazolyl-1-phenyl-methylamine], a novel compound structurally related to clomethiazole. Administration (i.p.) of (+/-)-AR-A008055 60 min after 5 min of global cerebral ischaemia in gerbils produced a dose-dependent protection of the hippocampus from damage. Both enantiomers [(R)-(+)-AR-A008055 and (S)-(-)- AR-A008055] at 600 micromol/kg produced similar protection to that following clomethiazole (600… Expand
The interaction of AR-A008055 and its enantiomers with the GABAA receptor complex and their sedative, muscle relaxant and anticonvulsant activity
TLDR
The current data suggest that the proposed GABA uptake inhibitory property of (R)-(+)-AR-A008055 fails to produce significant sedative, myorelaxant or anticonvulsant activity. Expand
Mechanisms Underlying Neuroprotection by the NSAID Mefenamic Acid in an Experimental Model of Stroke
TLDR
In vitro, the fenamates, MFA, meclofenamic acid, niflumic acid, and flufenamic Acid each reduced glutamate-evoked excitotoxicity in cultured embryonic rat hippocampal neurons supporting the idea that this is a drug class action. Expand
Electrophysiological actions of γ-aminobutyric acid and clomethiazole on recombinant GABAA receptors
Clomethiazole is a gamma-aminobutyric acid (GABA)-mimetic agent with anticonvulsant, sedative and neuroprotective properties. The pharmacological actions of clomethiazole that underlie its functionalExpand
Design and synthesis of neuroprotective methylthiazoles and modification as NO-chimeras for neurodegenerative therapy.
TLDR
Assessment data suggest that these chimeric nomethiazoles may be of use in treatment of multiple components of neurodegenerative disorders, such as AD. Expand
Pharmacology of ischemia-induced glutamate efflux from rat cerebral cortex in vitro
TLDR
The data indicate that the early phase of ischemia-induced glutamate efflux is in part Ca(2+) dependent, while the later phase involves volume activated anion currents and both phases involve excitatory amino acid transporters. Expand
Pharmacological manipulation of cGMP and NO/cGMP in CNS drug discovery.
TLDR
There is no evidence that nitrate tolerance is a phenomenon relevant to the CNS actions of NO-chimeras, and studies on nitroglycerin in the periphery continue to challenge the dogma of nitrateolerance mechanisms. Expand
Re-engineering a neuroprotective, clinical drug as a procognitive agent with high in vivo potency and with GABAA potentiating activity for use in dementia
TLDR
The findings show that NMZ embodies a promising pharmacological approach targeting synaptic dysfunction and opens new avenues for neuroprotective intervention strategies in mixed pathology AD, neurodegeneration, and dementia. Expand
Opposing needling promotes behavior recovery and exerts neuroprotection via the cAMP/PKA/CREB signal transduction pathway in transient MCAO rats
TLDR
It is demonstrated that ON markedly protected the brain against transient cerebral ischemic injury, and this effect was possibly mediated by the activation of the GABAB/cAMP/PKA/CREB signal transduction pathway, implying that ON may be a potential therapeutic method for treating stroke. Expand
Modulating nitric oxide signaling in the CNS for Alzheimer's disease therapy.
  • Qin Zhihui
  • Biology, Medicine
  • Future medicinal chemistry
  • 2013
TLDR
The search for effective NO-donating hybrid drugs, CNS-targeting sGC stimulators/activators and selective PDE inhibitors is an important goal for pharmacotherapy that manipulates NO biochemical pathways involved in cognitive function and neuroprotection. Expand
Novel analogues of chlormethiazole are neuroprotective in four cellular models of neurodegeneration by a mechanism with variable dependence on GABAA receptor potentiation
TLDR
Using CMZ as a lead compound, neuroprotective methiazole analogues were developed, and neuroprotection and GABAA receptor dependence were studied. Expand
...
1
2
...

References

SHOWING 1-10 OF 23 REFERENCES
The interaction of AR-A008055 and its enantiomers with the GABAA receptor complex and their sedative, muscle relaxant and anticonvulsant activity
TLDR
The current data suggest that the proposed GABA uptake inhibitory property of (R)-(+)-AR-A008055 fails to produce significant sedative, myorelaxant or anticonvulsant activity. Expand
Neuroprotective activity of chlormethiazole following transient forebrain ischaemia in the gerbil
TLDR
The data suggest that chlormethiazole may be a useful treatment in the prevention of neurodegeneration following stroke or cardiac arrest. Expand
The protective action of chlormethiazole against ischaemia‐induced neurodegeneration in gerbils when infused at doses having little sedative or anticonvulsant activity
TLDR
It is suggested that neuroprotection depends on both dose and duration of chlormethiazole administration and that excellent neuroprotection is possible in the absence of the sedative and anticonvulsant effects of the drug. Expand
Attenuation by chlormethiazole administration of the rise in extracellular amino acids following focal ischaemia in the cerebral cortex of the rat
TLDR
The data strengthen the evidence for the neuroprotective effect of chlormethiazole in this model of focal ischaemia and suggest that the attenuated rise in the concentration of all the amino acids is reflective of neuroprotection and therefore decreased cell death. Expand
GABA potentiation: a logical pharmacological approach for the treatment of acute ischaemic stroke
TLDR
The evidence that GABAergic function is acutely depressed following an ischaemic insult is examined, and the data that suggest that increasing cerebral GABA concentration has a neuroprotective effect, as does the administration of some (but not all) GABAmimetic agents are reviewed. Expand
Two distinct interactions of barbiturates and chlormethiazole with the GABAA receptor complex in rat cuneate nucleus in vitro
TLDR
It is suggested that a specific site of action in the GABAA receptor complex is involved in the reduction of picrotoxin effect and that this may be relevant to the anticonvulsant properties of chlormethiazole, phenobarbit one and (−)‐methylphenobarbitone. Expand
μ- and κ-opioids inhibit K+ evoked glutamate release from rat cerebrocortical slices
Abstract We have examined the effects of a range of opioid receptor subtype selective agonists on K + evoked glutamate release from perfused rat cerebrocortical slices. Dual application (S 1 and S 2Expand
[35S]-t-butylbicyclophosphorothionate binding sites are constituents of the gamma-aminobutyric acid benzodiazepine receptor complex
  • P. Supavilai, M. Karobath
  • Chemistry, Medicine
  • The Journal of neuroscience : the official journal of the Society for Neuroscience
  • 1984
TLDR
Using conventionally prepared washed membrane fractions from rat cerebral cortex, it is confirmed that in the presence of 200 mM NaBr [35S] TBPS binds to a high affinity population of binding sites and that muscimol inhibits [ 35S]TBPS binding (IC50 0.32 microM) allosterically. Expand
Clomethiazole is neuroprotective in models of global and focal cerebral ischemia when infused at doses producing clinically relevant plasma concentrations
TLDR
Clomethiazole is thus neuroprotective in both global and focal ischemia at plasma concentrations known to be well tolerated in stroke patients. Expand
GABA Agonist "Muscimol" Is Neuroprotective in Repetitive Transient Forebrain Ischemia in Gerbils
TLDR
The study shows that potentiation of inhibitory mechanisms may be important mechanisms of neuronal protection from the effects of repetitive ischemia and the effects are not limited to the SNr. Expand
...
1
2
3
...