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 iv 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.