Etazolate, a neuroprotective drug linking GABA(A) receptor pharmacology to amyloid precursor protein processing

• Published in: Journal of neurochemistry Vol. 106; no. 1; pp. 392 - 404
• Main Authors: Marcade, Maryline, Bourdin, Jérôme, Loiseau, Nadia, Peillon, Hélène, Rayer, Aurélie, Drouin, Dominique, Schweighoffer, Fabien, Désiré, Laurent
• Format: Journal Article
• Language: English
• Published: England 01.07.2008
• Subjects: Alzheimer Disease - drug therapy; Alzheimer Disease - metabolism; Alzheimer Disease - physiopathology; Amyloid beta-Peptides - antagonists & inhibitors; Amyloid beta-Peptides - biosynthesis; Amyloid beta-Peptides - toxicity; Amyloid beta-Protein Precursor - metabolism; Amyloid Precursor Protein Secretases - drug effects; Amyloid Precursor Protein Secretases - metabolism; Animals; Cells, Cultured; Cerebral Cortex - drug effects; Cerebral Cortex - metabolism; Dose-Response Relationship, Drug; Etazolate - pharmacology; GABA Agents - pharmacology; GABA Agonists - pharmacology; GABA Antagonists - pharmacology; Guinea Pigs; Male; Neurons - drug effects; Neurons - metabolism; Neuroprotective Agents - pharmacology; Peptide Fragments - antagonists & inhibitors; Peptide Fragments - biosynthesis; Peptide Fragments - toxicity; Phosphodiesterase Inhibitors - pharmacology; Protein Structure, Tertiary - physiology; Rats; Rats, Wistar; Receptors, GABA-A - drug effects; Receptors, GABA-A - metabolism; Signal Transduction - drug effects; Signal Transduction - physiology
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2008.05396.x

Pharmacological modulation of the GABA(A) receptor has gained increasing attention as a potential treatment for central processes affected in Alzheimer disease (AD), including neuronal survival and cognition. The proteolytic cleavage of the amyloid precursor protein (APP) through the alpha-secretase pathway decreases in AD, concurrent with cognitive impairment. This APP cleavage occurs within the beta-amyloid peptide (Abeta) sequence, precluding formation of amyloidogenic peptides and leading to the release of the soluble N-terminal APP fragment (sAPPalpha) which is neurotrophic and procognitive. In this study, we show that at nanomolar-low micromolar concentrations, etazolate, a selective GABA(A) receptor modulator, stimulates sAPPalpha production in rat cortical neurons and in guinea pig brains. Etazolate (20 nM-2 microM) dose-dependently protected rat cortical neurons against Abeta-induced toxicity. The neuroprotective effects of etazolate were fully blocked by GABA(A) receptor antagonists indicating that this neuroprotection was due to GABA(A) receptor signalling. Baclofen, a GABA(B) receptor agonist failed to inhibit the Abeta-induced neuronal death. Furthermore, both pharmacological alpha-secretase pathway inhibition and sAPPalpha immunoneutralization approaches prevented etazolate neuroprotection against Abeta, indicating that etazolate exerts its neuroprotective effect via sAPPalpha induction. Our findings therefore indicate a relationship between GABA(A) receptor signalling, the alpha-secretase pathway and neuroprotection, documenting a new therapeutic approach for AD treatment.