Uptake of circulating insulin-like growth factor-I into the cerebrospinal fluid of normal and diabetic rats and normalization of IGF-II mRNA content in diabetic rat brain

Abstract

Brain injury has been prevented recently by systemic administration of human insulin-like growth factor-I (hIGF-I). It is widely believed that protein neurotrophic factors do not enter the brain from blood, and the mechanism by which circulating hIGF-I may be neuroprotective is uncertain. This investigation tested the hypothesis that hIGF-I is taken up into cerebrospinal fluid (CSF) from the circulation. (125)I-hIGF-I was injected subcutaneously into rats. The (125)I-IGF-I recovered from CSF and plasma were indistinguishable in size from authentic (125)I-hIGF-I on SDS-PAGE. An ELISA was used that detected immunoreactive hIGF-I, but not rat IGF-I, rat IGF-II, human IGF-II, or insulin. Osmotic minipumps were implanted for constant subcutaneous infusion of various hIGF-I doses. Uptake into CSF reached a plateau at plasma concentrations above approximately 150 ng/ml hIGF-I; the plateau was consistent with carrier-mediated uptake. The plasma, but not CSF, hIGF-I level was significantly reduced in streptozotocin diabetic vs. nondiabetic rats, and uptake of hIGF-I into CSF was nonlinear with respect to plasma hIGF-I concentrations. Nonlinear uptake excluded leakage or transmembrane diffusion of IGF-I from blood into CSF as a dominant route for entry, but the site and mechanism of uptake remain to be established. The IGF-II mRNA content per milligram brain (P < 0.02) as well as per poly(A)(+) RNA (P < 0.05) was significantly increased towards normal in diabetic rats treated by subcutaneous administration of hIGF-I vs. vehicle. This effect of circulating hIGF-I may have been due to regulation of IGF-II gene expression in the choroid plexus and leptomeninges, structures at least in part outside of the blood-central nervous system barrier. These data support the hypothesis that circulating IGF-I supports the brain indirectly through regulation of IGF-II gene expression as well as by uptake into the CSF.