title: Etazolate, a neuroprotective drug linking GABA(A) receptor pharmacology to amyloid precursor protein processing.
abstract: 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.
authors.affiliation: Department of Neurology, ExonHit Therapeutics, Paris, France.
authors.forename: Maryline
authors.initials: M
authors.lastname: Marcade
authors.forename: Jérôme
authors.initials: J
authors.lastname: Bourdin
authors.forename: Nadia
authors.initials: N
authors.lastname: Loiseau
authors.forename: Hélène
authors.initials: H
authors.lastname: Peillon
authors.forename: Aurélie
authors.initials: A
authors.lastname: Rayer
authors.forename: Dominique
authors.initials: D
authors.lastname: Drouin
authors.forename: Fabien
authors.initials: F
authors.lastname: Schweighoffer
authors.forename: Laurent
authors.initials: L
authors.lastname: Désiré
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D053829:Amyloid Precursor Protein Secretases / Q000187:drug effects / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000633:toxicity; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004974:Etazolate / Q000494:pharmacology*; D018682:GABA Agents / Q000494:pharmacology; D018755:GABA Agonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D006168:Guinea Pigs; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000633:toxicity; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D017434:Protein Structure, Tertiary / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D018682:GABA Agents; D018755:GABA Agonists; D018756:GABA Antagonists; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D010726:Phosphodiesterase Inhibitors; D011963:Receptors, GABA-A; C078592:amyloid beta-protein (1-40); D053829:Amyloid Precursor Protein Secretases; D004974:Etazolate