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Submitted on May 16, 2005
Accepted on July 22, 2005
Pennington Biomedical Research Center, LSU System, Baton Rouge, Louisiana, USA; Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden; Institute Cochin, Department of Cellular Biology, Paris, France
* To whom correspondence should be addressed. E-mail: weihong.pan{at}pbrc.edu.
Exogenous growth hormone (GH) can affect CNS function when given peripherally to animals and as a supplemental therapy to humans. This study tested whether GH crosses the 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 CNS effects of peripheral GH can be attributed to permeation of the BBB despite the absence of a specific transport system.
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