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 GABA(A) 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 GABA(A) 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 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. CONCLUSIONS AND IMPLICATIONS: 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.
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 GABA(A) 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 GABA(A) 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 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. CONCLUSIONS AND IMPLICATIONS: 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.
Authors: A R Green; A H Hainsworth; A Misra; T A Debens; D M Jackson; T K Murray; R M Nelson; A J Cross Journal: Neuropharmacology Date: 2001-08 Impact factor: 5.250
Authors: Mauricio O Nava-Mesa; Lydia Jiménez-Díaz; Javier Yajeya; Juan D Navarro-Lopez Journal: Front Cell Neurosci Date: 2014-06-25 Impact factor: 5.505
Authors: Jia Luo; Sue H Lee; Lawren VandeVrede; Zhihui Qin; Manel Ben Aissa; John Larson; Andrew F Teich; Ottavio Arancio; Yohan D'Souza; Ahmed Elharram; Kevin Koster; Leon M Tai; Mary Jo LaDu; Brian M Bennett; Gregory R J Thatcher Journal: Mol Neurodegener Date: 2016-04-29 Impact factor: 14.195
Authors: Rachel C Knopp; Sue H Lee; Michael Hollas; Emily Nepomuceno; David Gonzalez; Kevin Tam; Daniyal Aamir; Yueting Wang; Emily Pierce; Manel BenAissa; Gregory R J Thatcher Journal: Redox Biol Date: 2020-03-02 Impact factor: 11.799