Mechanism of suramin toxicity in stable myelinating dorsal root ganglion cultures.
Suramin is an experimental chemotherapeutic agent which produces a severe dose-related neuropathy. Suramin inhibits axonal growth from rat dorsal root ganglion neurons. This inhibition is dose dependent and reversed by increasing nerve growth factor concentrations. In this study, myelinating dorsal root ganglion cultures were exposed to various concentrations of suramin and nerve growth factor. Effects were assessed with quantitative light and electron microscopy. Using a systematic sampling technique, suramin was observed to produce dose and time-dependent myelinated fiber degeneration. With 9-day exposure, there was no effect with suramin concentrations of 100 microM or less. At 200 microM, 17% of the myelinated fibers were degenerating at 4 days and 53.3% by 9 days. At 300 microM, 72.7% of the myelinated fibers and at 1316 microM, 88.7% of the myelinated fibers were degenerating at 4 days. It appeared that secondary demyelination was the major process. Large multilamellar inclusion bodies filled Schwann cells, particularly those investing unmyelinated fibers and dorsal root ganglia neuron cell bodies. The size and frequency of these inclusions increased with prolonged exposure to suramin (300 microM). Immunohistochemistry revealed that the inclusions were composed primarily of GM1 ganglioside. These effects were not influenced by increasing nerve growth factor up to 500 ng/ml. We conclude that suramin causes injury to both axons and Schwann cells that is not prevented by NGF and produces and experimental form of GM1 gangliosidosis.
Gill
J S
JS
Molecular Neuroscience Doctoral Program, Mayo Clinic, Rochester, Minnesota 55905, USA.
Hobday
K L
KL
Windebank
A J
AJ
D000818:Animals; D046508:Culture Techniques; D005727:Ganglia, Spinal / Q000187:drug effects* / Q000503:physiopathology* / Q000648:ultrastructure; D007150:Immunohistochemistry; D008854:Microscopy, Electron; D009186:Myelin Sheath / Q000502:physiology*; D051381:Rats; D013498:Suramin / Q000633:toxicity*
D013498:Suramin