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.

Different modes of GH administration influence gene expression in the male rat brain

“…Circulating IGF1 is believed to mediate some of the effects of GH on the brain (for review, see Å berg et al (2006)). This is possible as IGF1 crosses the BBB via carrier-mediated uptake (Armstrong et al 2000). In addition, both IGF1 (D'Ercole et al 1996, Folli et al 1996 and IGF1R (Yan et al 2011) are expressed in brain.…”

Insulin and Insulin-like Growth Factor 1 (IGF-1) Modulate Cytoplasmic Glucose and Glycogen Levels but Not Glucose Transport across the Membrane in Astrocytes

“…IGF-1 crosses the blood-brain barrier (52), and IGF-1 receptors are expressed by both astrocytes and neurons (53). There is a certain degree of cross-talk between insulin, IGF-1, and their receptors (51).…”

Oral Administration of a GSK3 Inhibitor Increases Brain Insulin-like Growth Factor I Levels

“…A site of entrance of serum IGF-I into the brain is across the choroid plexus (1,8). The blood-CSF barrier provided by choroid plexus epithelial cells is functionally similar to the bloodbrain barrier formed by brain endothelial cells (9).…”