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- W2002305576 abstract "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 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 GABA A 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 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 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 GABA A receptor signalling, the α‐secretase pathway and neuroprotection, documenting a new therapeutic approach for AD treatment." @default.
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- W2002305576 date "2008-04-05" @default.
- W2002305576 modified "2023-10-16" @default.
- W2002305576 title "Etazolate, a neuroprotective drug linking GABA<sub>A</sub>receptor pharmacology to amyloid precursor protein processing" @default.
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- W2002305576 doi "https://doi.org/10.1111/j.1471-4159.2008.05396.x" @default.
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