Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Br J Pharmacol
2014 Jan 01;1712:389-402. doi: 10.1111/bph.12454.
Show Gene links
Show Anatomy links
Novel analogues of chlormethiazole are neuroprotective in four cellular models of neurodegeneration by a mechanism with variable dependence on GABA(A) receptor potentiation.
Vandevrede L
,
Tavassoli E
,
Luo J
,
Qin Z
,
Yue L
,
Pepperberg DR
,
Thatcher GR
.
???displayArticle.abstract???
Chlormethiazole (CMZ), a clinical sedative/anxiolytic agent, did not reach clinical efficacy in stroke trials despite neuroprotection demonstrated in numerous animal models. Using CMZ as a lead compound, neuroprotective methiazole (MZ) analogues were developed, and neuroprotection and GABA(A) receptor dependence were studied. Eight MZs were selected from a novel library, of which two were studied in detail. Neuroprotection, glutamate release, intracellular calcium and response to GABA blockade by picrotoxin were measured in rat primary cortical cultures using four cellular models of neurodegeneration. GABA potentiation was assayed in oocytes expressing the α1β2γ2 GABA(A) receptor. Neuroprotection against a range of insults was retained even with substantial chemical modification. Dependence on GABAA receptor activity was variable: at the extremes, neuroprotection by GN-28 was universally sensitive to picrotoxin, while GN-38 was largely insensitive. In parallel, effects on extracellular glutamate and intracellular calcium were associated with GABA(A) dependence. Consistent with these findings, GN-28 potentiated α1β2γ2 GABA(A) function, whereas GN-38 had a weak inhibitory effect. Neuroprotection against moderate dose oligomeric Aβ₁₋₄₂ was also tolerant to structural changes. The results support the concept that CMZ does not contain a single pharmacophore, rather that broad-spectrum neuroprotection results from a GABA(A)-dependent mechanism represented by GN-28, combined with a mechanism represented in GN-38 that shows the least dependence on GABA(A) receptors. These findings allow further refinement of the neuroprotective pharmacophore and investigation into secondary mechanisms that will assist in identifying MZ-based compounds of use in treating neurodegeneration.
Abdelhamid,
Benzothiophene Selective Estrogen Receptor Modulators Provide Neuroprotection by a novel GPR30-dependent Mechanism.
2011, Pubmed
Abdelhamid,
Benzothiophene Selective Estrogen Receptor Modulators Provide Neuroprotection by a novel GPR30-dependent Mechanism.
2011,
Pubmed
Alexander,
The Concise Guide to PHARMACOLOGY 2013/14: overview.
2013,
Pubmed
Alvarez,
Serum TNF-alpha levels are increased and correlate negatively with free IGF-I in Alzheimer disease.
2007,
Pubmed
Baldwin,
Attenuation by chlormethiazole administration of the rise in extracellular amino acids following focal ischaemia in the cerebral cortex of the rat.
1994,
Pubmed
Brito-Moreira,
Aβ oligomers induce glutamate release from hippocampal neurons.
2011,
Pubmed
Clarkson,
Clomethiazole: mechanisms underlying lasting neuroprotection following hypoxia-ischemia.
2005,
Pubmed
Clarkson,
Mitochondrial involvement in transhemispheric diaschisis following hypoxia-ischemia: Clomethiazole-mediated amelioration.
2007,
Pubmed
Colado,
Studies on the neuroprotective effect of the enantiomers of AR-A008055, a compound structurally related to clomethiazole, on MDMA ("ecstasy")-induced neurodegeneration in rat brain.
2001,
Pubmed
Cross,
The protective action of chlormethiazole against ischaemia-induced neurodegeneration in gerbils when infused at doses having little sedative or anticonvulsant activity.
1995,
Pubmed
Cross,
The modulation by chlormethiazole of the GABAA-receptor complex in rat brain.
1989,
Pubmed
De Felice,
Abeta oligomers induce neuronal oxidative stress through an N-methyl-D-aspartate receptor-dependent mechanism that is blocked by the Alzheimer drug memantine.
2007,
Pubmed
De Keyser,
Clinical trials with neuroprotective drugs in acute ischaemic stroke: are we doing the right thing?
1999,
Pubmed
Farooque,
Clomethiazole (ZENDRA, CMZ) improves hind limb motor function and reduces neuronal damage after severe spinal cord injury in rat.
1999,
Pubmed
Gladstone,
Toward wisdom from failure: lessons from neuroprotective stroke trials and new therapeutic directions.
2002,
Pubmed
Green,
The interaction of AR-A008055 and its enantiomers with the GABA(A) receptor complex and their sedative, muscle relaxant and anticonvulsant activity.
2001,
Pubmed
Green,
GABA potentiation: a logical pharmacological approach for the treatment of acute ischaemic stroke.
2000,
Pubmed
Green,
Clomethiazole (Zendra) in acute ischemic stroke: basic pharmacology and biochemistry and clinical efficacy.
1998,
Pubmed
Haass,
Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid beta-peptide.
2007,
Pubmed
Hankey,
Clomethiazole: an unsuccessful bachelor, but perhaps a prosperous married man?
2002,
Pubmed
Harmon,
The effect of clomethiazole on plasma concentrations of interleukin-6, -8, -1beta, tumor necrosis factor-alpha, and neutrophil adhesion molecule expression during experimental extracorporeal circulation.
2003,
Pubmed
Kilkenny,
Animal research: reporting in vivo experiments: the ARRIVE guidelines.
2010,
Pubmed
LECHAT,
[RELATIONS BETWEEN CHEMICAL STRUCTURE AND PHYSIOLOGICAL ACTIVITY OF SOME THIAZOLE DERIVATIVES. I. CASE OF 4-METHYL BETA-HYDROXY-5-ETHYL THIAZOLE].
1965,
Pubmed
Lambert,
Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins.
1998,
Pubmed
Lechat,
[Relations between chemical structure and physiological action of some thiazole derivatives. II. Influence of the length of the carbon chain attached at position 5 in 4-methyl-5-(omega-chloroalkyl)-thiazoles].
1965,
Pubmed
Lechat,
[Pharmacological study of a quaternary ammonium compound possessing preponderant ganglionic stimulating properties].
1965,
Pubmed
Liang,
Effects of clomethiazole on radial-arm maze performance following global forebrain ischemia in gerbils.
1997,
Pubmed
Limon,
Loss of functional GABA(A) receptors in the Alzheimer diseased brain.
2012,
Pubmed
,
Xenbase
Lindberg,
Studies on hypnotic and anticonvulsant agents related to the thiazole part of thiamine.
1971,
Pubmed
Lindberg,
Compounds related to clomethiazole. IV. 4-Methylthiazoles and oxazoles with polar side-chains and some other analogues of clomethiazole.
1971,
Pubmed
Marshall,
Functional benefit from clomethiazole treatment after focal cerebral ischemia in a nonhuman primate species.
1999,
Pubmed
Marshall,
Clomethiazole protects against hemineglect in a primate model of stroke.
2000,
Pubmed
Mattson,
beta-Amyloid peptides destabilize calcium homeostasis and render human cortical neurons vulnerable to excitotoxicity.
1992,
Pubmed
McAlpine,
Inhibition of soluble TNF signaling in a mouse model of Alzheimer's disease prevents pre-plaque amyloid-associated neuropathology.
2009,
Pubmed
McGrath,
Guidelines for reporting experiments involving animals: the ARRIVE guidelines.
2010,
Pubmed
Moody,
Chlormethiazole: neurochemical actions at the gamma-aminobutyric acid receptor complex.
1989,
Pubmed
Mucke,
Neurotoxicity of amyloid β-protein: synaptic and network dysfunction.
2012,
Pubmed
Mucke,
Clomethiazole (Astra Arcus AB).
1999,
Pubmed
Muir,
Neuroprotection for acute stroke: making clinical trials work.
1999,
Pubmed
Möhler,
The rise of a new GABA pharmacology.
2011,
Pubmed
Nelson,
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.
2001,
Pubmed
Olsen,
Drug interactions at the GABA receptor-ionophore complex.
1982,
Pubmed
Qin,
Design and synthesis of neuroprotective methylthiazoles and modification as NO-chimeras for neurodegenerative therapy.
2012,
Pubmed
Rissman,
Implications for treatment: GABAA receptors in aging, Down syndrome and Alzheimer's disease.
2011,
Pubmed
Rudolph,
Beyond classical benzodiazepines: novel therapeutic potential of GABAA receptor subtypes.
2011,
Pubmed
Santos,
Mitophagy in neurodegeneration: an opportunity for therapy?
2011,
Pubmed
Shi,
Anti-TNF-α reduces amyloid plaques and tau phosphorylation and induces CD11c-positive dendritic-like cell in the APP/PS1 transgenic mouse brains.
2011,
Pubmed
Snape,
The effects of chlormethiazole and nimodipine on cortical infarct area after focal cerebral ischaemia in the rat.
1993,
Pubmed
Stine,
In vitro characterization of conditions for amyloid-beta peptide oligomerization and fibrillogenesis.
2003,
Pubmed
Strum,
Rosiglitazone induces mitochondrial biogenesis in mouse brain.
2007,
Pubmed
Sydserff,
The neuroprotective effect of chlormethiazole on ischaemic neuronal damage following permanent middle cerebral artery ischaemia in the rat.
1995,
Pubmed
Sydserff,
The effect of chlormethiazole on neuronal damage in a model of transient focal ischaemia.
1995,
Pubmed
Usala,
Activity of chlormethiazole at human recombinant GABA(A) and NMDA receptors.
2003,
Pubmed
,
Xenbase
Vellas,
EHT0202 in Alzheimer's disease: a 3-month, randomized, placebo-controlled, double-blind study.
2011,
Pubmed
Wahlgren,
Clomethiazole acute stroke study (CLASS): results of a randomized, controlled trial of clomethiazole versus placebo in 1360 acute stroke patients.
1999,
Pubmed
Wahlgren,
Results in 95 hemorrhagic stroke patients included in CLASS, a controlled trial of clomethiazole versus placebo in acute stroke patients.
2000,
Pubmed
Wilby,
The pharmacology of chlormethiazole: a potential neuroprotective agent?
2004,
Pubmed
Yu,
Endocytic pathways mediating oligomeric Abeta42 neurotoxicity.
2010,
Pubmed
Yue,
Robust photoregulation of GABA(A) receptors by allosteric modulation with a propofol analogue.
2012,
Pubmed
,
Xenbase
