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

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 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: Lawren Vandevrede, Ehsan Tavassoli, Jia Luo, Zhihui Qin, Lan Yue, David R Pepperberg, Gregory R Thatcher
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 171 Issue 2 Pg. 389-402 (Jan 2014) ISSN: 1476-5381 [Electronic] England
• PMID: 24116891 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2013 The British Pharmacological Society.

Chemical References

• Excitatory Amino Acid Agonists
• GABA Agonists
• Neuroprotective Agents
• Receptors, GABA-A
• Chlormethiazole
• Glutamic Acid
• gamma-Aminobutyric Acid
• N-Methylaspartate
• Glucose
• Calcium

Topics

• Animals
• Biological Availability
• Brain (metabolism)
• Calcium (metabolism)
• Cell Hypoxia
• Chlormethiazole (analogs & derivatives, pharmacology)
• Chromatography, High Pressure Liquid
• Excitatory Amino Acid Agonists (toxicity)
• Female
• GABA Agonists (pharmacology)
• Glucose (deficiency)
• Glutamic Acid (metabolism, toxicity)
• Mice
• Mice, Inbred C57BL
• N-Methylaspartate (toxicity)
• Nerve Degeneration (prevention & control)
• Neurons (drug effects)
• Neuroprotective Agents (pharmacology)
• Oocytes (drug effects)
• Pregnancy
• Primary Cell Culture
• Rats
• Rats, Sprague-Dawley
• Receptors, GABA-A (drug effects)
• Xenopus laevis
• gamma-Aminobutyric Acid (pharmacology)