Aminoglycoside neurotoxicity involves NMDA receptor activation

Previous studies have led to the hypothesis that the ototoxicity produced b y aminoglycoside antibiotics involves the excitotoxic activation of cochlea r NMDA receptors. If this hypothesis is correct, then these antibiotics sho uld also injure neurons within the brain. Because aminoglycosides do not re adily penetrate the blood brain barrier, we examined the effects of the ami noglycoside neomycin following intrastriatal injection. Neomycin (10-250 nm ol) produced dose-dependent striatal damage manifested as an increased glio sis as measured by: (1) [H-3]PK-11195 binding, (2) staining for the astrocy tic marker glial fibrillary acidic protein (GFAP) and (3) staining for OX-6 , an MHC class II antigen expressed by microglia and macrophages. Go-inject ion of subthreshhold doses of NMDA potentiates the striatal damage produced by neomycin (10 nmol). Moreover, neomycin-induced striatal damage is atten uated by a combination of the NMDA antagonists ifenprodil and 5,7-dichlorok ynurenic acid. Intrastriatal administration of compounds structurally relat ed to neomycin, but devoid of modulatory actions at NMDA receptors (paromam ine and 2-deoxystreptamine), fail to produce neuronal damage. These data su pport the hypothesis that aminoglycoside-induced ototoxicity is, in part, a n excitotoxic process involving the activation of NMDA receptors. Moreover, aminoglycosides may damage the central nervous system in individuals with compromised blood brain barriers. (C) 1999 Published by Elsevier Science B. V. All rights reserved.