A novel butyrylcholinesterase inhibitor induces antidepressant, pro-cognitive, and anti-anhedonic effects in Flinders Sensitive Line rats: The role of the ghrelin-dopamine cascade

IF 6.9 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Biomedicine & Pharmacotherapy Pub Date : 2025-05-02 DOI:10.1016/j.biopha.2025.118093

Nadia Olivier , Brian H. Harvey , Stanislav Gobec , Mohammed Shahid , Urban Košak , Simon Žakelj , Christiaan B. Brink

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Abstract

Background and purpose

Major depressive disorder (MDD) is often treatment resistant, particularly in addressing anhedonia and cognitive deficits. Novel pharmacological strategies are needed. While butyrylcholinesterase, ghrelin, and dopamine (DA) have been well studied in the context of stress and MDD, their interaction remains unclear.

Experimental approach

The dose-dependent antidepressant effects of a novel butyrylcholinesterase inhibitor (BChEI) were evaluated in the Flinders Sensitive Line (FSL) rat model of MDD. Behavioural assessments included the forced swim test (despair), sucrose preference test (reward-related), and novel object recognition test (cognition). Brain-derived neurotrophic factor (BDNF), acetylcholine (ACh), and brain monoamines were analysed, as well as serum growth hormone and acyl- and desacyl-ghrelin. To confirm the role of ghrelin, pharmacological exploration was undertaken using the ghrelin receptor antagonist, D-Lys-3-GHRP-6.

Key results

FSL rats had significantly lower ghrelin ratios, BDNF, ACh, DA and growth hormone levels. In FSL rats, both BChEI and escitalopram significantly reduced despair. BChEI significantly outperformed escitalopram in enhancing reward-related and cognitive behaviours. Biochemically, BChEI treatment significantly increased ghrelin ratios and brain DA levels without altering brain 5-HT, ACh or BDNF. D-Lys-3-GHRP-6 significantly reversed the antidepressant-like, rewarding, and pro-cognitive effects of BChEI, accompanied by significant reductions in BDNF and DA.

Conclusions and implications

FSL rats display impaired ghrelin, DA, serotonin, growth hormone, and BDNF signalling, akin to MDD. BChEI exerts antidepressant-like effects across despair, reward, and cognitive domains, most likely via the BChE-ghrelin-DA cascade. Reversal of these effects by ghrelin antagonism underscores the critical role of ghrelin, specifically via growth hormone secretagogue receptor-ghrelin interaction. These findings suggest a potentially novel multimodal neurobiological target for the treatment of MDD.

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一种新型丁酰胆碱酯酶抑制剂在弗林德斯敏感系大鼠中诱导抗抑郁、促进认知和抗快感缺乏作用：胃饥饿素-多巴胺级联的作用

背景和目的重度抑郁症（MDD）通常难以治疗，尤其是在治疗快感缺乏和认知缺陷方面。需要新的药理策略。虽然丁基胆碱酯酶、胃饥饿素和多巴胺（DA）在压力和重度抑郁症中的作用已经得到了很好的研究，但它们之间的相互作用仍不清楚。实验方法采用弗林德斯敏感系（Flinders Sensitive Line， FSL）大鼠模型，评价新型丁酰胆碱酯酶抑制剂（BChEI）的剂量依赖性抗抑郁作用。行为评估包括强迫游泳测试（绝望）、蔗糖偏好测试（奖励相关）和新物体识别测试（认知）。分析脑源性神经营养因子（BDNF）、乙酰胆碱（ACh）和脑单胺，以及血清生长激素和酰基和去酰基胃饥饿素。为了确认ghrelin的作用，我们使用ghrelin受体拮抗剂D-Lys-3-GHRP-6进行了药理学探索。关键结果fsl大鼠胃饥饿素（ghrelin）比值、BDNF、乙酰胆碱（ACh）、DA和生长激素水平显著降低。在FSL大鼠中，BChEI和艾司西酞普兰均能显著减轻绝望情绪。BChEI在增强奖励相关行为和认知行为方面明显优于艾司西酞普兰。生物化学方面，BChEI处理显著提高了ghrelin比率和脑DA水平，但没有改变脑5-HT、ACh或BDNF。D-Lys-3-GHRP-6显著逆转了BChEI的抗抑郁样、奖励和促认知作用，并伴有BDNF和DA的显著减少。结论和意义sfsl大鼠表现出饥饿素、DA、血清素、生长激素和BDNF信号传导受损，类似于重度抑郁症。BChEI在绝望、奖励和认知领域发挥类似抗抑郁的作用，最有可能是通过BChE-ghrelin-DA级联。胃饥饿素拮抗剂逆转这些作用强调了胃饥饿素的关键作用，特别是通过生长激素促分泌素受体与胃饥饿素的相互作用。这些发现提示了治疗重度抑郁症的一个潜在的新的多模式神经生物学靶点。

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来源期刊

Biomedicine & Pharmacotherapy 医学-药学

CiteScore

11.90

自引率

2.70%

发文量

1621

审稿时长

48 days

期刊介绍： Biomedicine & Pharmacotherapy stands as a multidisciplinary journal, presenting a spectrum of original research reports, reviews, and communications in the realms of clinical and basic medicine, as well as pharmacology. The journal spans various fields, including Cancer, Nutriceutics, Neurodegenerative, Cardiac, and Infectious Diseases.