The Effect of Glycosylation on the Uptake of an Enkephalin Analogue into the Central Nervous System

In contrast to unglycosylated controls, glycosylated [D-Cys2,5]enkephalin-ser-gly (glycosylated DCDCE-ser-gly) elicits analgesia after intraperitoneal administration. This was postulated to be due to the presence of the glucose moiety allowing the analogue to cross the BBB via the glucose carrier. To test this hypothesis, the present study investigated the biological stability and the CNS uptake ofunglycosylated and glycosylated DCDCE-ser-gly. Interestingly, the metabolic half-lives and ability to cross the in vitro BBB was found to be similar for both analogues. In situ brain perfusion indicated that the brain uptake of glycosylated DCDCE-ser-gly was greater than that for the vascular marker, [14C]sucrose, but similar to the CSF uptake of the peptide. CNS uptake of glycosylated DCDCE-ser-gly was not affected by replacing D- with L- glucose, nor with the addition of 10 µM unlabelled glycosylated DCDCE-ser-gly. In summary, the difference in analgesic response of glycosylated compared to unglycosylated DCDCE-ser-gly, is not related to either differing metabolic profiles, nor the ability of the glycosylated analogue to use the glucose carrier to enter the CNS. However, this study does not eliminate the involvement of a different low affinity, saturable uptake system taking the glycosylated, but not the unglycosylated form.