Etazolate, a neuroprotective drug linking GABA_A receptor pharmacology to amyloid precursor protein processing

Abstract

Alzheimer's disease (AD) is characterized neuropathologically by the extracellular deposition of the 4 kDa b-amyloid peptide (Ab), a 39-43 amino acid peptide that is neurotoxic (Borchelt et al. 1996) and accumulates in neuritic plaques and in cerebral and meningeal microvessels (Wahrle et al. 2002). Amyloid precursor protein (APP) is the precursor of Ab and can be processed via alternative pathways. A nonamyloidogenic secretory pathway includes cleavage of APP to soluble APP (sAPPa) by a-secretases from the a disintegrin and metalloprotease (ADAM) family of proteases within the Ab peptide sequence, thus precluding the formation of Ab. In contrast, the formation of the amyloidogenic Ab peptides is regulated by the sequential action of b-and c-secretases (Checler 1995;Nunan and Small 2000). A primary strategy proposed to treat AD is to prevent the formation of Ab peptides, and their deposition as senile plaques in the brain. Recently, Postina et al. (2004) showed that activation of a-secretase significantly reduces AD-like pathology in an animal model of AD. This raises the possibility that a pharmacological approach to increase a-secretase activity and sAPPa levels, and thus reduce Ab formation may be suitable for AD treatment (Bandyopadhyay et al. 2007).This approach is consistent with the observation that profound changes occur in APP processing with aging and the development of AD. In particular, a reduction in the activity of the non-amyloidogenic pathway leading to Received February 7, 2008; revised manuscript received March 6, 2008; accepted March 28, 2008. Address correspondence and reprint requests to Laurent Désiré, Department of Neurology, Exonhit Therapeutics, 63 Bd Massena, 75013 Paris, France. E-mail: laurent.desire@exonhit.comAbbreviations used: Ab, beta amyloid; ADAM, a disintegrin and metalloprotease; AD, Alzheimer's Disease; APP, amyloid precursor protein; BACE, beta-site APP-cleaving enzyme; DAPT, N-[N-(3,5-difluorophenacetyl-L-alanyl)]-S-phenylglycine t-butyl ester; IP, immunoprecipitation; LTP, long-term potentiation; PDE4, phosphodiesterase 4; PTX, picrotoxin; sAPPa, soluble APP ectodomain; SDS-PAGE, sodium dodecyl sulfate-polyacrylamide gel electrophoresis; TAPI-1, TNF-a Protease Inhibitor-1. AbstractPharmacological 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 a-secretase pathway decreases in AD, concurrent with cognitive impairment. This APP cleavage occurs within the b-amyloid peptide (Ab) sequence, precluding formation of amyloidogenic peptides and leading to the release of the soluble N-terminal APP fragment (sAPPa) which is neurotrophic and procognitive. In this study, we show that at nanomolar-low micromolar concentrations, etazolate, a selective GABA A receptor modulator, stimulates sAPPa production in rat cortical neurons and in guinea pig brains. Etazolate (20 ...

Loss of functional GABA A receptors in the Alzheimer diseased brain

“…However, it remains to be determined how those reductions affected the function of GABA A Rs in cellular membranes. This lack of information is a critical void, considering the correlation between cortical hyperexcitability, the pathological state of patients with AD (12,13), and the protective effects of GABA A R agonists against Aβ-induced injury (14). In the present study, we have extended our previous observations and report clear evidence of functional remodeling of native human GABA A Rs in AD.…”

Amyloid-modifying therapies for Alzheimer’s disease: therapeutic progress and its implications

“…ExonHit Therapeutics has developed EHT 0202, a pyrazolopyridine compound that is believed to increase co-localization of APP and α-secretase at the plasma membrane, thereby facilitating cleavage of APP by α-secretase and protecting against Aβ-induced neurotoxicity in cortical cell culture (Marcade et al 2008). Guinea pigs treated with clinically relevant dose of EHT0202 (10 mg/kg) exhibited a 20% reduction in total Aβ and a three-fold increase in sAPPα relative to controls.…”

Disease-modifying treatments for Alzheimer’s disease

“…Etazolate (EHT 0202, ExonHit Therapeutics) stimulates the neurotrophic a-secretase (nonamyloidogenic) pathway and inhibits Ab-induced neuronal death, providing symptomatic relief and modifying disease progression. In vitro, it is neuroprotective against Ab42, and neuroprotection is associated with sAPPa induction [Marcade et al 2008]. After a phase I study in healthy volunteers, a phase II clinical trial has been recently completed that assessed safety, tolerability and preliminary efficacy on cognition and behaviour in AD patients, as well as quantification of sAPPa in blood (see http://www.alzforum.org).…”