Novel analogues of chlormethiazole are neuroprotective in four cellular models of neurodegeneration by a mechanism with variable dependence on GABA A receptor potentiation

Lawren Vandevrede, Ehsan Tavassoli, Jia Luo, Zhihui Qin, Lan Yue, David R. Pepperberg, Gregory R. Thatcher

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

Background and Purpose 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 GABAA receptor dependence were studied. Experimental Approach 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 GABAA receptor. Key Results 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 GABAA dependence. Consistent with these findings, GN-28 potentiated α1β2γ2 GABAA function, whereas GN-38 had a weak inhibitory effect. Neuroprotection against moderate dose oligomeric Aβ1-42 was also tolerant to structural changes. Conclusions and Implications The results support the concept that CMZ does not contain a single pharmacophore, rather that broad-spectrum neuroprotection results from a GABAA-dependent mechanism represented by GN-28, combined with a mechanism represented in GN-38 that shows the least dependence on GABAA 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.

Original languageEnglish (US)
Pages (from-to)389-402
Number of pages14
JournalBritish Journal of Pharmacology
Volume171
Issue number2
DOIs
StatePublished - Jan 2014
Externally publishedYes

Keywords

  • Alzheimer's disease
  • chlormethiazole
  • excitotoxicity
  • GABA
  • GABA receptor
  • neurodegeneration
  • neuroprotection
  • stroke

ASJC Scopus subject areas

  • Pharmacology

Fingerprint

Dive into the research topics of 'Novel analogues of chlormethiazole are neuroprotective in four cellular models of neurodegeneration by a mechanism with variable dependence on GABA A receptor potentiation'. Together they form a unique fingerprint.

Cite this