Role of nerve growth factor in suramin neurotoxicity studied in vitro.
We determined whether suramin neurotoxicity can be prevented by nerve growth factor (NGF) and if this interaction occurs at the level of the NGF receptor. Neurite outgrowth from rat dorsal root ganglia in vitro was measured serially in the presence of suramin (100-600 microM) alone or with beta-NGF (50-1,000 ng/ml). Competitive NGF receptor-binding studies were done with 125I-labeled NGF in the presence or absence of suramin. Neurite growth was inhibited in a dose-dependent manner, but at usual neurotoxic levels this inhibition could be overcome completely by increasing the concentration of NGF. Receptor-binding assays showed similar dose-dependent inhibition of 125I-labeled NGF binding. In the presence of suramin, the dissociation constant for high-affinity binding was decreased from 1.2 x 10(-11) to 3.9 x 10(-10) and low-affinity binding from 2.7 x 10(-9) to 1.2 x 10(-8). Increasing doses of suramin inhibited 125I-labeled NGF specific binding in a dose-dependent fashion, and doses of suramin > or = 1,000 microM were able to completely inhibit 125I-labeled NGF specific binding. Suramin-induced dorsal root ganglia damage can be ameliorated by high-dose NGF. This effect is most likely due to competition between suramin and NGF at the high-affinity NGF receptor.
Russell
J W
JW
Department of Neurology, Mayo Clinic, Rochester, MN 55905.
Windebank
A J
AJ
Podratz
J L
JL
D000818:Animals; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D009414:Nerve Growth Factors / Q000378:metabolism / Q000627:therapeutic use*; D016501:Neurites / Q000187:drug effects / Q000502:physiology; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000188:drug therapy*; D051381:Rats; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism; D013498:Suramin / Q000009:adverse effects*
D009414:Nerve Growth Factors; D017475:Receptors, Nerve Growth Factor; D013498:Suramin