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- W2235607549 abstract "Tramiprosate (3-amino-1-propanesulfonic acid), currently in phase III clinical trials for Alzheimer's disease, was shown to bind to soluble amyloid-β (Aβ) involved with amyloid deposition in the brain and to be neuroprotective against Aβ-mediated toxicity. Because tramiprosate is structurally related to the neurotransmitter γ-amino butyric acid (GABA), we assessed the involvement of GABAA receptors (GABAAR) in the neuroprotective effect of tramiprosate. The binding affinity of tramiprosate to the GABAAR was determined using a competitive binding assay on crude rat brain membranes employing 3H-muscimol, a potent GABAAR agonist. To establish whether tramiprosate behaves as a functional agonist at the GABAAR on primary rat neurons, we measured membrane potential depolarization and calcium influx triggered by GABAergic drugs or allopregnanolone (neurosteroid). The neuroprotective activity of tramiprosate was assessed on Aβ42-induced caspase 3/7 activation. We show that tramiprosate bound to the GABAAR with high affinity (Ki ∼ 18 nM) as compared to taurine, a structural analog (Ki ∼ 70 μM) and other structurally similar molecules. Tramiprosate, muscimol and allopregnanolone, but not taurine, induced a dose-dependent membrane depolarization and calcium flux. The affinity of these GABAergic compounds for the GABAAR correlated with their EC50 in the membrane potential assay. The effect of tramiprosate was significantly decreased when neurons were pretreated with GABAAR antagonists (bicucculine, picrotoxin) confirming the specificity of these responses for the GABAAR. Finally, tramiprosate and muscimol decreased basal and Aβ42-induced caspase 3/7 activity. The effect of tramiprosate on Aβ-induced caspase 3/7 activation was significantly reduced by pretreating the cells with specific GABAAR antagonists. These results demonstrate that tramiprosate behaves as a functional agonist for the GABAAR, and this GABAergic activity may be involved in the neuroprotective effects against Aβ-induced caspase 3/7 activation in rat primary neurons. Tramiprosate was also reported to be neuroprotective in rat neurons at least in part via inhibition of Aβ42-induced ERK1/2 activation by a GABAA-independent mechanism (see Fallon et al., poster presentation at this meeting). Together, these results demonstrate that the neuroprotective actions of tramiprosate involve at least two independent and potentially complementary mechanisms, one GABAergic and the other non-GABAergic." @default.
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- W2235607549 date "2007-07-01" @default.
- W2235607549 modified "2023-09-26" @default.
- W2235607549 title "P-190: GABA-dependent pathways in the neuroprotective effect of tramiprosate against amyloid-β toxicity" @default.
- W2235607549 doi "https://doi.org/10.1016/j.jalz.2007.04.153" @default.
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