School of Pharmacy, University of Eastern Finland, Faculty of Health Sciences, P.O. Box 1627, FI-70211 Kuopio, Finland.
Neurosci Lett. 2011 Sep 15;502(2):107-11. doi: 10.1016/j.neulet.2011.07.033. Epub 2011 Jul 29.
Prolyl oligopeptidase (PREP, EC 3.4.21.26) hydrolyzes neuropeptides, such as neurotensin and substance P in vitro, but its importance in the in vivo metabolism of these peptides has not been proved. This is the first report where intracerebral microdialysis combined with highly sensitive radioimmunoassay has been used to investigate the effect of PREP inhibition on the brain extracellular peptide levels in conscious rats. We show that PREP inhibition by KYP-2047 (50μmol/kg=17mg/kg, intraperitoneally, that effectively inhibits PREP in the brain), has no effect on the neurotensin and substance P levels in the striatum extracellular space. This provides a further piece of evidence in support of the proposition that PREP is not significantly responsible for the in vivo cleavage of substance P or neurotensin, and that occasional positive cognitive effects associated with some PREP inhibitors are not mediated through elevated extracellular levels of these peptides. Direct regulation of peptide processing by PREP is not likely because the enzyme is located intracellularly and the peptide substrates are mostly extracellular.
脯氨酰寡肽酶（PREP，EC3.4.21.26）在体外可水解神经肽，如神经降压素和 P 物质，但它在这些肽体内代谢中的重要性尚未得到证实。这是首次报道使用脑室内微透析结合高灵敏度放射免疫分析法来研究 PREP 抑制对清醒大鼠脑外肽水平的影响。我们表明，通过 KYP-2047（50μmol/kg=17mg/kg，腹腔内注射，可有效抑制大脑中的 PREP）抑制 PREP 对纹状体细胞外空间中神经降压素和 P 物质水平没有影响。这进一步证明 PREP 不太可能负责体内 P 物质或神经降压素的切割，并且与一些 PREP 抑制剂偶尔相关的阳性认知效应并非通过这些肽的细胞外水平升高来介导。由于酶位于细胞内，而肽底物主要在细胞外，因此 PREP 直接调节肽加工的可能性不大。
