Pitolisant alleviates brain network dysfunction and cognitive deficits in a mouse model of Alzheimer's disease.

IF 5.8 1区医学 Q1 PSYCHIATRY

Translational Psychiatry Pub Date : 2025-04-05 DOI:10.1038/s41398-025-03358-8

Yang Zou, Linhan Yang, Jiahui Zhu, Jihua Fan, Hanrun Zheng, Xiang Liao, Zhiqi Yang, Kuan Zhang, Hongbo Jia, Arthur Konnerth, Yan-Jiang Wang, Chunqing Zhang, Yun Zhang, Sunny C Li, Xiaowei Chen

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引用次数: 0

Abstract

Histamine H₃ receptor (H₃R) antagonists regulate histamine release that modulates neuronal activity and cognitive function. Although H₃R is elevated in Alzheimer's disease (AD) patients, whether H₃R antagonists can rescue AD-associated neural impairments and cognitive deficits remains unknown. Pitolisant is a clinically approved H₃R antagonist/inverse agonist that treats narcolepsy. Here, we find that pitolisant reverses AD-like pathophysiology and cognitive impairments in an AD mouse model. Behavioral assays and in vivo wide-field Ca²⁺ imaging revealed that recognition memory, learning flexibility, and slow-wave impairment were all improved following the 15-day pitolisant treatment. Improved recognition memory was tightly correlated with slow-wave coherence, suggesting slow waves serve as a biomarker for treatment response and for AD drug screening. Furthermore, pitolisant reduced amyloid-β deposition and dystrophic neurites surrounding plaques, and enhanced neuronal lysosomal activity, inhibiting which blocked cognitive and slow-wave restoration. Our findings identify pitolisant as a potential therapeutic agent for AD treatments.

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组胺 H3 受体（H3R）拮抗剂可调节组胺的释放，从而调节神经元活动和认知功能。虽然阿尔茨海默病（AD）患者体内的组胺 H3R 会升高，但 H3R 拮抗剂是否能缓解与 AD 相关的神经损伤和认知障碍仍是未知数。Pitolisant 是一种临床批准的 H3R 拮抗剂/逆激动剂，可治疗嗜睡症。在这里，我们发现 Pitolisant 可以逆转 AD 小鼠模型中类似 AD 的病理生理学和认知障碍。行为测定和体内宽场Ca2+成像显示，经过15天的皮妥利生治疗后，识别记忆、学习灵活性和慢波损伤都得到了改善。识别记忆的改善与慢波连贯性密切相关，这表明慢波可作为治疗反应的生物标志物，并可用于AD药物筛选。此外，匹多莫德还能减少淀粉样蛋白-β沉积和斑块周围的萎缩性神经元，增强神经元溶酶体活性，抑制溶酶体活性会阻碍认知和慢波的恢复。我们的研究结果表明，pitolisant 是一种治疗多发性硬化症的潜在药物。

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来源期刊

Translational Psychiatry PSYCHIATRY-

CiteScore

11.50

自引率

2.90%

发文量

484

审稿时长

23 weeks

期刊介绍： Psychiatry has suffered tremendously by the limited translational pipeline. Nobel laureate Julius Axelrod''s discovery in 1961 of monoamine reuptake by pre-synaptic neurons still forms the basis of contemporary antidepressant treatment. There is a grievous gap between the explosion of knowledge in neuroscience and conceptually novel treatments for our patients. Translational Psychiatry bridges this gap by fostering and highlighting the pathway from discovery to clinical applications, healthcare and global health. We view translation broadly as the full spectrum of work that marks the pathway from discovery to global health, inclusive. The steps of translation that are within the scope of Translational Psychiatry include (i) fundamental discovery, (ii) bench to bedside, (iii) bedside to clinical applications (clinical trials), (iv) translation to policy and health care guidelines, (v) assessment of health policy and usage, and (vi) global health. All areas of medical research, including — but not restricted to — molecular biology, genetics, pharmacology, imaging and epidemiology are welcome as they contribute to enhance the field of translational psychiatry.