Aminoglycoside neurotoxicity involves NMDA receptor activation.
Previous studies have led to the hypothesis that the ototoxicity produced by aminoglycoside antibiotics involves the excitotoxic activation of cochlear NMDA receptors. If this hypothesis is correct, then these antibiotics should also injure neurons within the brain. Because aminoglycosides do not readily penetrate the blood brain barrier, we examined the effects of the aminoglycoside neomycin following intrastriatal injection. Neomycin (10-250 nmol) produced dose-dependent striatal damage manifested as an increased gliosis as measured by: (1) [3H]PK-11195 binding, (2) staining for the astrocytic marker glial fibrillary acidic protein (GFAP) and (3) staining for OX-6, an MHC class II antigen expressed by microglia and macrophages. Co-injection of subthreshhold doses of NMDA potentiates the striatal damage produced by neomycin (10 nmol). Moreover, neomycin-induced striatal damage is attenuated by a combination of the NMDA antagonists ifenprodil and 5, 7-dichlorokynurenic acid. Intrastriatal administration of compounds structurally related to neomycin, but devoid of modulatory actions at NMDA receptors (paromamine and 2-deoxystreptamine), fail to produce neuronal damage. These data support the hypothesis that aminoglycoside-induced ototoxicity is, in part, an excitotoxic process involving the activation of NMDA receptors. Moreover, aminoglycosides may damage the central nervous system in individuals with compromised blood brain barriers.
Segal
J A
JA
Laboratory of Neuroscience, National Institute on Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA. segalj@lilly.com
Harris
B D
BD
Kustova
Y
Y
Basile
A
A
Skolnick
P
P
D000617:Aminoglycosides / Q000633:toxicity*; D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D003342:Corpus Striatum / Q000737:chemistry / Q000187:drug effects / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005904:Glial Fibrillary Acidic Protein / Q000032:analysis; D007150:Immunohistochemistry; D007276:Injections, Intraventricular; D007546:Isoquinolines / Q000378:metabolism; D008297:Male; D016202:N-Methylaspartate / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology; D009355:Neomycin / Q000008:administration & dosage / Q000494:pharmacology; D009498:Neurotoxins / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*
D000617:Aminoglycosides; D005904:Glial Fibrillary Acidic Protein; D007546:Isoquinolines; D009498:Neurotoxins; D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate; D009355:Neomycin; C037850:PK 11195