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) result s in both uptake of hIGF into the cerebrospinal fluid (CSF) and amelioratio n of brain injury. We tested the hypotheses that IGF uptake into CSF is ind ependent of IGF receptors and IGF-binding proteins (IGFBP). Adult rats were injected sc with various concentrations of hIGF-I or structural analogs, a nd serum and CSF were withdrawn for assay 90 min later. An enzyme-linked im munoassay was used that detected immunoreactive hIGF-I and its analogs, but not rat EGF-I, IGF-II, or insulin. Plasma hIGF-I levels increased linearly (r = 0.97) with hIGF-I dose between 25-300 mug/rat. By contrast, uptake in to CSF reached saturation above 100 mug, 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-f old reduced affinity for the type I IGF receptor, yet both were taken up in to 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 extrem ely weak. These data suggest that uptake of circulating ICF-I into CSF is i ndependent of the type I or II IGF receptors as well as IGF sequestration t o IGFBP-1, -3, -4, or -5.