INSULIN-LIKE GROWTH-FACTORS CROSS THE BLOOD-BRAIN-BARRIER

Although evidence exists that insulin may cross the blood-brain barrie r, little is known about the ability of insulin-like growth factors (I GF-I and -II) to cross this barrier. In the present studies, equimolar concentrations of equal specific activity I-125-labeled IGF-I, IGF-II , or insulin were infused into the carotid artery of anesthetized adul t rats. The perfusions were carried out for 3 min in the presence or a bsence of excess unlabeled ligand or insulin, with three or more anima ls in each group. Immediately after the perfusion, brains were frozen and sectioned for autoradiography. All ligands were detected in choroi d plexus, median eminence, and blood vessels, but [I-125]IGF-I and -II were also prominently localized in brain parenchyma. Densitometric an alysis of film autoradiographs (28-day exposure for all ligands) revea led that radiolabeled IGFs, especially IGF-I, were significantly more abundant throughout the forebrain than [I-125]insulin, especially in t he paraventricular nucleus, where [I-125]IGF-I was 10-fold and [I-125] IGF-II was 5-fold more abundant than [I-125]insulin. The difference i n [I-125]IGF-I vs. [I-125]insulin accumulation was confirmed by parall el measurements of radioactivity in anatomically matched brain section s using a gamma-spectrometer. The uptake of radiolabeled IGF-I, IGF-II , and insulin by brain parenchyma and vasculature was completely inhib ited by excess (1,000-fold) unlabeled ligand; however, insulin (10,000 -fold excess) did not completely abolish [I-125]IGF-I and -II accumula tion. Microscopic evaluation of nuclear emulsion-coated brain sections revealed that radioactivity associated with [I-125]IGF-I and -II perf usions was selectively concentrated in capillaries and medium-sized pa renchymal cells in the paraventricular nucleus and, to a lesser extent , the supraoptic nucleus and anterior nucleus of the thalamus, whereas in other brain regions the radioligands were mostly bound to capillar ies. These results suggest that radiolabeled IGF-I and -II bind to bra in capillaries and cross the blood-brain barrier into brain parenchyma more readily than radiolabeled insulin.