Uptake of circulating insulin-like growth factors (IGFs) into cerebrospinal fluid appears to be independent of the IGF receptors as well as IGF-binding proteins.
Peripheral administration of human insulin-like growth factor (hIGF) results in both uptake of hIGF into the cerebrospinal fluid (CSF) and amelioration of brain injury. We tested the hypotheses that IGF uptake into CSF is independent of IGF receptors and IGF-binding proteins (IGFBP). Adult rats were injected sc with various concentrations of hIGF-I or structural analogs, and serum and CSF were withdrawn for assay 90 min later. An enzyme-linked immunoassay was used that detected immunoreactive hIGF-I and its analogs, but not rat IGF-I, IGF-II, or insulin. Plasma hIGF-I levels increased linearly (r = 0.97) with hIGF-I dose between 25-300 microgram/rat. By contrast, uptake into CSF reached saturation above 100 microgram, suggesting carrier-mediated uptake. hIGF-II reduced the uptake of hIGF-I into CSF (P < 0.02). Des(1-3)hIGF-I is a hIGF-I analog missing the N-terminal tripeptide, resulting in greatly reduced affinity for IGFBP-1, -3, -4, and -5. Nevertheless, des(1-3)hIGF-I was taken up into CSF. [Leu(24)]hIGF-I and [Leu(60)]hIGF-I have 20- to 85-fold reduced affinity for the type I IGF receptor, yet both were taken up into CSF in amounts similar to hIGF-I. In addition, hIGF-I and des(1-3)hIGF-I were taken up into CSF, although binding to the type II receptor is extremely weak. These data suggest that uptake of circulating IGF-I into CSF is independent of the type I or II IGF receptors as well as IGF sequestration to IGFBP-1, -3, -4, or -5.
Pulford
B E
BE
Departments of Physiology and Biochemistry and Molecular Biology, Colorado State University, Fort Collins, Colorado 80523, USA.
Ishii
D N
DN
D000818:Animals; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D018969:Insulin-Like Growth Factor Binding Proteins / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000031:analogs & derivatives / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D007335:Insulin-Like Growth Factor II / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D007700:Kinetics; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D017527:Receptor, IGF Type 2 / Q000378:metabolism*; D012044:Regression Analysis
D018969:Insulin-Like Growth Factor Binding Proteins; D017527:Receptor, IGF Type 2; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D017526:Receptor, IGF Type 1