抑郁症治疗的新靶点 - α促黑激素的关键水解酶PRCP

Increasing importance has been recognized about the involvement of energy dysfunction in the pathology of depression. Memelanocyte-stimulating hormone(α-MSH）is increased after chronic stress, and its receptor melanocornin 4 receptor(MC4R) is required to mediate the synaptic adaptations for anhedonia. However the underlying molecular mechanism for the elevation of α-MSH has not been extensively studied. It is well documented that α-MSH is inactivated by hydrolysis of prolyl carboxypeptidase(PRCP）, which has been found in the nucleus accubens, the area closely involved in emotional sickness. Our recent work reveals that PRCP expression was decreased in depressive mice exposed to chronic stress. Given the importance of PRCP in the hydrolysis of α-MSH，we hypothesize that PRCP is involved in depression by increasing the level of α-MSH and subsequent activation of MC4R. This project will unravel the role of PRCP in the regulation of depression by electrophysiology, molecular biology, immunocytochemistry, high performance liquid chromatography and behavioral test. We aim to find the clue for novel targets for the treatment of deprssion.

能量代谢异常与抑郁症的发生高度相关。已有研究证明慢性应激引起伏隔核中α-MSH水平显著上升，并激活脑组织中黑皮质素4型受体(Melanocornin 4 receptor, MC4R)参与抑郁症的发生。但抑郁症中α-MSH水平上升的具体机制尚未阐明。α-MSH在体内灭活的关键酶是脯氨酰羧肽酶（prolyl carboxypeptidase，PRCP）, 且PRCP在与抑郁症密切相关的伏隔核有表达。我们的预实验研究发现慢性应激所致抑郁症模型鼠，伏隔核中PRCP的mRNA水平下降。鉴于PRCP对α-MSH强有力的水解作用，我们认为PRCP极有可能通过升高α-MSH水平参与抑郁症的发生。本项目拟结合电生理、分子生物学、免疫细胞化学、高效液相色谱法和行为学实验技术，探讨PRCP在慢性应激诱导抑郁症中的作用及其机制。为抑郁症的药物治疗提供新靶点和实验依据。

已有研究证明慢性应激引起伏隔核中α-MSH水平显著上升，并激活脑组织中黑皮质素4型受体(Melanocornin 4 receptor, MC4R)参与抑郁症的发生。鉴于脯氨酰羧肽酶（prolyl carboxypeptidase，PRCP）是在体内灭活α-MSH的关键酶, 且PRCP在与抑郁症密切相关的伏隔核有表达，抑郁症中α-MSH水平显著上升可能是该酶活性降低所致。但PRCP与抑郁症关系尚不清楚。本项目拟结合电生理、分子生物学、免疫细胞化学、高效液相色谱法和行为学实验技术，探讨PRCP在慢性应激诱导抑郁症中的作用及其机制。结果发现：1） 抑郁症模型伏隔核中PRCP的表达和活性的下降。与对照组相比，PRCP 的mRNA水平显著下降，差异具有统计学意义（control：1.00 ± 0.09，n = 7；susceptible：0.68 ± 0.03，n = 11，P<0.05）。NAc shell脑区PRCP蛋白质表达水平则显著下降（control：1.00 ± 0.07，n = 7；susceptible：0.76 ± 0.06，n = 8，P< 0.05）；且免疫荧光显示NAc shell脑区相较于NAc core脑区PRPC阳性信号较多。2）采用腹腔注射系统给药和NAc脑区给药两种方法，均发现PRCP抑制剂增加小鼠对阈下刺激所致的抑郁样行为的敏感性；3）NAc脑区注射沉默PRCP的AAV病毒，增加了小鼠对阈下刺激所致的抑郁样行为的敏感性；4）相反，NAc脑区注射过表达PRCP的AAV病毒，改善CSDS引起的小鼠抑郁样行为表现为糖水偏好率、社会接触率和社会接触时间增加。5）MC4R阻断剂SHU91619降低PRCP抑制剂对抑郁样行为的影响。因此，我们认为PRCP活性降低所致的α-MSH水平显著上升，激动MC4R参与抑郁症的发生。