Prenatal stress (PNS) has a prolonged and adverse effect on offspring, leading to a significantly increased vulnerability to developing depression in their later life. Traditional therapies have delayed onset and limited efficacy; thus, it remains an urgent need to find novel medications with fast-onset and high-efficacy potentials. Crocin, with its structure clearly examined, has shown antidepressant-like effects. However, few studies extensively investigated its effect especially in mice exposed to PNS. Using an established PNS model, we tested whether crocin could have a rapid and persistent antidepressant-like effect in PNS mice. Growth hormone secretagogue receptor (GHSR) and phosphoinositide 3-kinase (PI3K) inhibitors were used to test their effects in antidepressant-like effect of crocin. Hippocampal GHSR-PI3K signaling was examined both in PNS mice treated with a single dose of crocin and in combination of GHSR inhibitor. PNS mice showed depression-like behaviors at juvenile and adulthood, and crocin induced an instant and persistent antidepressant-like response in PNS mice in a dose-dependent manner. Moreover, crocin increased the expression of hippocampal synaptic plasticity-associated proteins through the restoration of GHSR-PI3K signaling. Inhibitions of both GHSR and PI3K abolished the effect of crocin in alleviating depressive-like behaviors. More importantly, GHSR inhibitor JMV2959 blocked the enhanced expression of hippocampal plasticity-related proteins induced by crocin. The present study demonstrated that crocin induced a fast-onset and prolonged antidepressant effect in PNS mice and suggested that GHSR-PI3K signaling may play a key role in crocin’s effect at least partially by a restoration of hippocampal synaptic plasticity-associated proteins.

中文翻译：

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在暴露于产前应激的小鼠中，番红花的快速和长期抗抑郁样作用与GHSR介导的海马可塑性相关蛋白有关。

产前压力（PNS）对后代具有长期不利影响，导致其后代发展为抑郁症的脆弱性显着增加。传统疗法延迟了发作，疗效有限。因此，迫切需要找到具有快速起效和高疗效潜能的新型药物。具有清楚检查结构的番红花显示出抗抑郁样作用。但是，很少有研究广泛研究其作用，尤其是在暴露于PNS的小鼠中。使用已建立的PNS模型，我们测试了番红花是否可以在PNS小鼠中具有快速和持久的抗抑郁样作用。生长激素促分泌素受体（GHSR）和磷酸肌醇3激酶（PI3K）抑制剂被用于测试其在番红花抗抑郁样作用中的作用。在用单剂量crocrocin处理的PNS小鼠和GHSR抑制剂的组合中均检查了海马GHSR-PI3K信号传导。PNS小鼠在少年和成年期表现出抑郁样行为，而番红花以剂量依赖的方式在PNS小鼠中引起即时和持续的抗抑郁样反应。此外，番红花通过GHSR-PI3K信号的恢复增加了海马突触可塑性相关蛋白的表达。GHSR和PI3K的抑制作用都取消了番红花在减轻抑郁样行为方面的作用。更重要的是，GHSR抑制剂JMV2959阻断了由番红花诱导的海马可塑性相关蛋白的表达增强。