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Entry of exendin-4 into brain is rapid but may be limited at high doses

International Journal of Obesity volume 27, pages 313–318 (2003)Cite this article

Abstract

OBJECTIVE: Peripherally administered exendin-4 is in clinical trials for the treatment of diabetes mellitus and obesity. Since its effects on food intake are mediated centrally, we determined the degree and type of its blood-to-brain penetration of the mouse blood–brain barrier (BBB).

MEASUREMENTS AND RESULTS: High-performance liquid chromatography showed that exendin-4 was stable in blood, with most of the injected peptide reaching the brain intact. Capillary depletion studies with washout showed that the injected exendin-4 reached brain parenchyma rather than being trapped in the endothelial cells composing the BBB. Multiple-time regression analysis showed that exendin-4 crossed the BBB directly at a fast rate. The rapid brain entry of exendin-4, helped by its high lipophilicity as demonstrated by the octanol/buffer partition coefficient, was not dependent upon circumventricular organs and was not affected by food deprivation for 24 h. The simultaneous i.v. injection of high doses of unlabeled exendin-4 resulted in self-inhibition (saturation) that only became statistically significant (P<0.05) when the results of four experiments were combined; this suggests a possible limit to the amount of peripherally administered exendin-4 that can reach the brain after injection of high doses.

CONCLUSION: The results indicate that exendin-4 is well conformed for exerting central effects involved in the control of obesity.

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Acknowledgements

Supported by NIH (DK 54880) and the Department of Veterans Affairs.

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  1. VA Medical Center and Tulane University School of Medicine, New Orleans, 70112-1262, LA, USA

    A J Kastin & V Akerstrom

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Kastin, A., Akerstrom, V. Entry of exendin-4 into brain is rapid but may be limited at high doses. Int J Obes 27, 313–318 (2003). https://doi.org/10.1038/sj.ijo.0802206

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