Zhang Yuan, Zhu Min-Zhen, Qin Xi-He, Zeng Yuan-Ning, Zhu Xin-Hong
Institute of Mental Health, School of Basic Medical Science, Southern Medical University, Guangzhou, China.
Key Laboratory of Mental Health of the Ministry of Education & Guangdong Province Key Laboratory of Psychiatric Disorders, Guangzhou, China.
Front Neurosci. 2021 Feb 16;15:631424. doi: 10.3389/fnins.2021.631424. eCollection 2021.
Major depressive disorder (MDD) is a debilitating mental illness affecting people worldwide. Although significant progress has been made in the development of therapeutic agents to treat this condition, fewer than half of all patients respond to currently available antidepressants, highlighting the urgent need for the development of new classes of antidepressant drugs. Here, we found that paeoniflorin (PF) produced rapid and sustained antidepressant-like effects in multiple mouse models of depression, including the forced swimming test and exposure to chronic mild stress (CMS). Moreover, PF decreased the bodyweight of mice without affecting food intake and glucose homeostasis, and also reduced the plasma levels of total ghrelin and the expression of ghrelin O-acyltransferase in the stomach; however, the plasma levels of ghrelin and the ghrelin/total ghrelin ratio were unaffected. Furthermore, PF significantly increased the expression of growth hormone secretagogue receptor 1 alpha (GHSR1α, encoded by the gene) in the intestine, whereas the levels of GHSR1α in the brain were only marginally downregulated following subchronic PF treatment. Finally, the genetic deletion of attenuated the antidepressant-like effects of PF in mice exposed to CMS. These results suggested that increased GHSR1α expression in the intestine mediates the antidepressant-like effects of PF. Understanding peripheral ghrelin/GHSR signaling may provide new insights for the screening of antidepressant drugs that produce fast-acting and sustained effects.
重度抑郁症（MDD）是一种使人衰弱的精神疾病，影响着世界各地的人们。尽管在开发治疗这种疾病的治疗药物方面已经取得了重大进展，但在所有患者中，只有不到一半的人对目前可用的抗抑郁药有反应，这突出表明迫切需要开发新型抗抑郁药物。在这里，我们发现芍药苷（PF）在多种抑郁症小鼠模型中产生了快速且持续的抗抑郁样作用，包括强迫游泳试验和暴露于慢性轻度应激（CMS）。此外，PF降低了小鼠的体重，但不影响食物摄入量和葡萄糖稳态，还降低了血浆总胃泌素水平以及胃中胃泌素O-酰基转移酶的表达；然而，胃泌素的血浆水平和胃泌素/总胃泌素比值未受影响。此外，PF显著增加了肠道中生长激素促分泌素受体1α（GHSR1α，由该基因编码）的表达，而在亚慢性PF治疗后，大脑中GHSR1α的水平仅略有下调。最后，该基因的基因缺失减弱了PF对暴露于CMS的小鼠的抗抑郁样作用。这些结果表明，肠道中GHSR1α表达的增加介导了PF的抗抑郁样作用。了解外周胃泌素/GHSR信号通路可能为筛选具有快速起效和持续作用的抗抑郁药物提供新的见解。
