Etazolate, a neuroprotective drug linking GABAA receptor pharmacology to amyloid precursor protein processing
Article first published online: 5 APR 2008
© 2008 ExonHit Therapeutics
Journal of Neurochemistry
Volume 106, Issue 1, pages 392–404, July 2008
How to Cite
Marcade, M., Bourdin, J., Loiseau, N., Peillon, H., Rayer, A., Drouin, D., Schweighoffer, F. and Désiré, L. (2008), Etazolate, a neuroprotective drug linking GABAA receptor pharmacology to amyloid precursor protein processing. Journal of Neurochemistry, 106: 392–404. doi: 10.1111/j.1471-4159.2008.05396.x
- Issue published online: 5 APR 2008
- Article first published online: 5 APR 2008
- Received February 7, 2008; revised manuscript received March 6, 2008; accepted March 28, 2008.
- alpha secretase;
- Alzheimer’s disease;
- amyloid β protein;
- soluble APP ectodomain
Pharmacological modulation of the GABAA 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 α-secretase pathway decreases in AD, concurrent with cognitive impairment. This APP cleavage occurs within the β-amyloid peptide (Aβ) sequence, precluding formation of amyloidogenic peptides and leading to the release of the soluble N-terminal APP fragment (sAPPα) which is neurotrophic and procognitive. In this study, we show that at nanomolar-low micromolar concentrations, etazolate, a selective GABAA receptor modulator, stimulates sAPPα production in rat cortical neurons and in guinea pig brains. Etazolate (20 nM–2 μM) dose-dependently protected rat cortical neurons against Aβ-induced toxicity. The neuroprotective effects of etazolate were fully blocked by GABAA receptor antagonists indicating that this neuroprotection was due to GABAA receptor signalling. Baclofen, a GABAB receptor agonist failed to inhibit the Aβ-induced neuronal death. Furthermore, both pharmacological α-secretase pathway inhibition and sAPPα immunoneutralization approaches prevented etazolate neuroprotection against Aβ, indicating that etazolate exerts its neuroprotective effect via sAPPα induction. Our findings therefore indicate a relationship between GABAA receptor signalling, the α-secretase pathway and neuroprotection, documenting a new therapeutic approach for AD treatment.