RT Journal Article
SR Electronic
T1 Improved Blood-Brain Barrier Penetration and Enhanced Analgesia of an Opioid Peptide by Glycosylation
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 967
OP 972
VO 299
IS 3
A1 Egleton, R. D.
A1 Mitchell, S. A.
A1 Huber, J. D.
A1 Palian, M. M.
A1 Polt, R.
A1 Davis, T. P.
YR 2001
UL http://jpet.aspetjournals.org/content/299/3/967.abstract
AB Neuropeptide pharmaceuticals have potential for the treatment of neurological disorders, but the blood-brain barrier (BBB) limits entry of peptides to the brain. Several strategies to improve brain delivery are currently under investigation, including glycosylation. In this study we investigated the effect of O-linked glycosylation on Ser6 of a linear opioid peptide amide Tyr-d-Thr-Gly-Phe-Leu-Ser-NH2 on metabolic stability, BBB transport, and analgesia. Peptide stability was studied in brain and serum from both rat and mouse by high-performance liquid chromatography. BBB transport properties were investigated by rat in situ perfusion. Tail-flick analgesia studies were performed on male ICR mice, injected i.v. with 100 μg of peptide ligand. Glycosylation of Ser6 of the peptide led to a significant increase in enzymatic stability in both serum and brain. Glycosylation significantly increased the BBB permeability of the peptide from a value of 1.0 ± 0.2 μl · min−1 · g−1 to 2.2 ± 0.2 μl · min−1 · g−1 (p < 0.05), without significantly altering the initial volume of distribution. Analgesia studies showed that the glycosylated peptide gave a significantly improved analgesia after i.v. administration compared with nonglycosylated peptide. The improved analgesia profile shown by the glycosylated peptide is due in part to an improvement in bioavailability to the central nervous system. The bioavailability is increased by improving stability and transport into the brain. The American Society for Pharmacology and Experimental Therapeutics