Abstract
We determined the ability of orexin A and orexin B, recently discovered endogenous appetite enhancers, to cross the blood-brain barrier (BBB) of mice. Multiple time-regression analysis showed that an i.v. bolus of125I-orexin A rapidly entered the brain from the blood, with an influx rate (Ki = 2.5 ± 0.3 × 10−4 ml/g·min) many times faster than that of the 99mTc-albumin control. This relatively rapid rate of entry was not reduced by administration of excess orexin A (or leptin) or by fasting for 22 h, even when penetration into only the hypothalamus was measured. Lack of saturability also was shown by perfusion in blood-free buffer. HPLC revealed that most of the injected125I-orexin A reached the brain as intact peptide. Capillary depletion studies showed that the administered peptide did not remain bound to the endothelial cells comprising the BBB but reached the brain parenchyma. Efflux of 125I-orexin A from the brain occurred at the same rate as 99mTc-albumin. The octanol/buffer partition coefficient of 0.232 showed that orexin A was highly lipophilic, whereas the value for orexin B was only 0.030. Orexin B, moreover, was rapidly degraded in blood, so no125I-orexin B could be detected in intact form in brain when injected peripherally. Thus, although orexin B is rapidly metabolized in blood and has low lipophilicity, orexin A rapidly crosses the BBB from blood to reach brain tissue by the process of simple diffusion.
Footnotes
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Send reprint requests to: Dr. Abba J. Kastin, Veterans Affairs Medical Center and Tulane University School of Medicine, 1601 Perdido Street, New Orleans, LA 70112-1262.
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↵1 This work was supported by the Veterans Affairs and National Institutes of Health.
- Abbreviation:
- BBB
- blood-brain barrier
- Received September 11, 1998.
- Accepted November 11, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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