Canneva Fabio, Golub Yulia, Distler Joerg, Dobner Julia, Meyer Sandra, von Hörsten Stephan
Department of Experimental Therapy, Präklinisches Experimentelles Tierzentrum, Univerisitätsklinikum Erlangen, 91054 Erlangen, Germany.
Department of Child and Adolescent Mental Health, University Clinic of Erlangen, 91054 Erlangen, Germany.
Psychoneuroendocrinology. 2015 Mar;53:195-206. doi: 10.1016/j.psyneuen.2015.01.007. Epub 2015 Jan 19.
Inhibitors of dipeptidyl peptidase 4 (DPP4, CD26) are used for the treatment of type 2 diabetic patients and better glucose tolerance has been confirmed in functionally DPP4-deficient congenic rats (DPP4mut), along with immunological alterations and, interestingly, a stress-resilient phenotype. All these findings are in agreement with the "moonlighting" properties of DPP4, whose proteolytic action is responsible for the inactivation of a number of regulatory peptides including, but not limited to, neuropeptide Y (NPY). Among all candidate substrates, DPP4 displays highest affinity for NPY, an endogenous anxiolytic neurotransmitter that is suggested as a candidate biomarker in post-traumatic stress disorder (PTSD) and depression.
Central and peripheral NPY levels were measured by ELISA in DPP4mut and DAwt rats revealing a significantly higher concentration of the peptide in the CSF of DPP4mut animals. This finding positively correlated with the blunted stress phenotype measured on an analgesia-meter. Additionally, when a classical fear-conditioning paradigm was investigated, short-term fear extinction was significantly potentiated in DPP4mut rats as compared to wt controls.
Our findings indicate a positive correlation between reduced stress-responsiveness and increased central NPY, in DPP4mut rats. Most interestingly, the behavioral phenotype extends to facilitation of fear extinction. These observations raise further interest in DPP4-modulating drugs for the potential effect on NPY metabolism, as a therapeutic tool for psychiatric conditions such as anxiety disorders and PTSD.
二肽基肽酶4（DPP4，CD26）抑制剂用于治疗2型糖尿病患者，并且在功能上缺乏DPP4的同源基因大鼠（DPP4mut）中已证实有更好的糖耐量，同时伴有免疫改变，有趣的是，还有应激弹性表型。所有这些发现都与DPP4的“兼职”特性一致，其蛋白水解作用导致多种调节肽失活，包括但不限于神经肽Y（NPY）。在所有候选底物中，DPP4对NPY的亲和力最高，NPY是一种内源性抗焦虑神经递质，被认为是创伤后应激障碍（PTSD）和抑郁症的候选生物标志物。
通过ELISA测定DPP4mut和DAwt大鼠中枢和外周NPY水平，发现DPP4mut动物脑脊液中该肽的浓度显著更高。这一发现与镇痛仪上测得的钝性应激表型呈正相关。此外，当研究经典恐惧条件反射范式时，与野生型对照相比，DPP4mut大鼠的短期恐惧消退明显增强。
我们的研究结果表明，在DPP4mut大鼠中，应激反应性降低与中枢NPY增加之间存在正相关。最有趣的是，行为表型扩展到促进恐惧消退。这些观察结果进一步引发了对DPP4调节药物的兴趣，因为其对NPY代谢的潜在影响，可作为焦虑症和PTSD等精神疾病的治疗工具。
