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Permeation of Growth Hormone across the Blood-Brain Barrier

Pennington Biomedical Research Center (W.P., Y.Y., C.M.C., A.J.K.), Louisiana State University System, Baton Rouge, Louisiana 70808; Department of Pharmaceutical Biosciences (F.N.), Uppsala University, Uppsala S-75124, Sweden; and Institute Cochin (P.O.C.), Department of Cellular Biology, Paris 75654, France

Address all correspondence and requests for reprints to: Weihong Pan, M.D., Ph.D., Pennington Biomedical Research Center, 6400 Perkins Road, Baton Rouge, Louisiana 70808. E-mail: weihong.pan{at}pbrc.edu.

Exogenous GH can affect central nervous system function when given peripherally to animals and as a supplemental therapy to humans. This study tested whether GH crosses the blood-brain barrier (BBB) by a specific transport system and found that both mice and rats have small but significant uptake of GH into the brain without a species difference. Determined by multiple-time regression analysis, the blood-to-brain influx transfer constants of ¹²⁵I-labeled rat GH in mice (0.23 ± 0.07 µl/g·min) and rats (0.32 ± 0.04 µl/g·min) were comparable to those of some cytokines of similar size, with a half-time disappearance of ¹²⁵I-GH of 3.8–7.6 min in blood. Intact ¹²⁵I-GH was present in both serum and brain homogenate 20 min after iv injection. At this time, about 26.8% of GH in brain entered the parenchyma, whereas 10% was entrapped in endothelial cells. Neither excess GH nor insulin showed acute modulation of the influx, indicating lack of a saturable transport system for GH at the BBB. Binding and cellular uptake studies in cultured cerebral microvessel endothelial cells (RBE4) further ruled out the presence of high-capacity adsorptive endocytosis. The brain influx of GH by simple diffusion adds definitive value to the long-disputed question of whether and how GH crosses the BBB. The central nervous system effects of peripheral GH can be attributed to permeation of the BBB despite the absence of a specific transport system.

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