Neomycin Is an Agonist at a Polyamine Site on the N‐Methyl‐D‐Aspartate Receptor

Abstract

Neomycin appears as a full agonist and spermidine as a partial agonist at the site where polyamines enhance 1‐[1‐(2‐thienyl)cyclohexyl][3H]piperidine ([3H]TCP) binding on the N‐methyl‐D‐aspartate (NMDA) receptor. Other aminoglycosides also enhance [3H]TCP binding with efficacies roughly proportional to the number of primary amine groups. The polyamine antagonists ifenprodil and arcaine inhibit enhancement of [3H]TCP binding by spermidine or neomycin. The inhibition of [3H]TCP binding by arcaine is apparently competitively reduced by neomycin and spermidine, supporting a common site. Diethylenetriamine (previously described as a polyamine antagonist) may be a partial agonist. Enhancement by neomycin or spermidine is not additive to that of Mg2+, consistent with competition of Mg2+ and spermidine or neomycin at the site where these compounds enhance [3H]TCP binding. Polyamines also enhance the binding of the competitive antagonist 2 ‐ (2 ‐ carboxypiperazin ‐ 4 ‐ yl)[3H]propyl ‐ 1 ‐ phosphonic acid ([3H]CPP). Neomycin, which does not enhance [3H]CPP binding, inhibits the enhancement by spermidine. That this site is distinct from the site where spermidine and neomycin increase [3H]TCP binding is supported by different pharmacology. Arcaine and diethylenetriamine do not inhibit spermidine enhancement of [3H]CPP binding. Mg2+ also does not compete with the spermidine enhancement of [3H]CPP binding. Ifenprodil inhibits the spermidine enhancement of [3H]CPP binding. The data suggest two or more polyamine sites, with arcaine selective for the site that enhances [3H]TCP binding. Neomycin is an agonist at one polyamine site and an antagonist to the second.

Pasireotide prevents nuclear factor of activated T cells nuclear translocation and acts as a protective agent in aminoglycoside‐induced auditory hair cell loss

“…Evidence from other systems indicates that aminoglycosides mimic the modulatory actions of polyamines on NMDA receptors, causing excitotoxicity and cell death (Choi ; Pullan et al . ). Consistent with this, we found that OCs treated with gentamicin demonstrated significant repression of Nmda1 mRNA, and the induction of PI3K mRNA, suggesting a cellular response attempting to minimize or overcome the NMDA excitotoxicity induced by gentamicin.…”

Molecular Pathways Involved in Apoptotic Cell Death in the Injured Cochlea: Cues to Novel Therapeutic Strategies

“…Evidence has been obtained indicating that aminoglycosides can mimic the modulatory actions of polyamines on the NMDA receptor, causing excitotoxicity on SGNs and death of HCs [171][172][173] (see chapter Noise trauma). Treatment of aminoglycosideexposed animals with NMDA antagonists, such as MK-801, gave only a partial protection of hearing [172,174].…”

Early gene expression in the organ of Corti exposed to gentamicin

“…Furthermore, another gene with no known function to date, which exhibited differential expression following gentamicin exposure in our microarrays, shows significant sequence homology to the human NMDA receptor subtype 2D. Evidence from other studies indicates that aminoglycosides can mimic the modulatory actions of polyamines on the NMDA receptor causing excitotoxicity and cell death (Choi, 1992;Pullan et al, 1992). Moreover, it has been shown that aminoglycoside-induced HC loss could be significantly reduced by NMDA antagonists (Basile et al, 1996).…”