Pitolisant alleviates brain network dysfunction and cognitive deficits in a mouse model of Alzheimer’s disease
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 unkno...
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| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-04-01
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| Series: | Translational Psychiatry |
| Online Access: | https://doi.org/10.1038/s41398-025-03358-8 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Yang Zou |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-2a19e58089024101910a66c8d359ad4c |
| institution | OA Journals |
| issn | 2158-3188 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Translational Psychiatry |
| spelling | doaj-art-2a19e58089024101910a66c8d359ad4c2025-08-20T02:08:11ZengNature Publishing GroupTranslational Psychiatry2158-31882025-04-0115111510.1038/s41398-025-03358-8Pitolisant alleviates brain network dysfunction and cognitive deficits in a mouse model of Alzheimer’s diseaseYang Zou0Linhan Yang1Jiahui Zhu2Jihua Fan3Hanrun Zheng4Xiang Liao5Zhiqi Yang6Kuan Zhang7Hongbo Jia8Arthur Konnerth9Yan-jiang Wang10Chunqing Zhang11Yun Zhang12Sunny C. Li13Xiaowei Chen14Guangxi Key Laboratory of Special Biomedicine/Advanced Institute for Brain and Intelligence, School of Medicine, Guangxi UniversityGuangxi Key Laboratory of Special Biomedicine/Advanced Institute for Brain and Intelligence, School of Medicine, Guangxi UniversityGuangxi Key Laboratory of Special Biomedicine/Advanced Institute for Brain and Intelligence, School of Medicine, Guangxi UniversityGuangxi Key Laboratory of Special Biomedicine/Advanced Institute for Brain and Intelligence, School of Medicine, Guangxi UniversityState Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of SciencesCenter for Neurointelligence, School of Medicine, Chongqing UniversityBrain Research Center and State Key Laboratory of Trauma and Chemical Poisoning, Third Military Medical UniversityBrain Research Center and State Key Laboratory of Trauma and Chemical Poisoning, Third Military Medical UniversityGuangxi Key Laboratory of Special Biomedicine/Advanced Institute for Brain and Intelligence, School of Medicine, Guangxi UniversityInstitute of Neuroscience and Munich Cluster for Systems Neurology, Technical University MunichInstitute of Brain and Intelligence, Third Military Medical UniversityInstitute of Brain and Intelligence, Third Military Medical UniversityState Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of SciencesLFC Laboratory and Chongqing Institute for Brain and Intelligence, Guangyang Bay LaboratoryBrain Research Center and State Key Laboratory of Trauma and Chemical Poisoning, Third Military Medical UniversityAbstract 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.https://doi.org/10.1038/s41398-025-03358-8 |
| spellingShingle | 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 Pitolisant alleviates brain network dysfunction and cognitive deficits in a mouse model of Alzheimer’s disease Translational Psychiatry |
| title | Pitolisant alleviates brain network dysfunction and cognitive deficits in a mouse model of Alzheimer’s disease |
| title_full | Pitolisant alleviates brain network dysfunction and cognitive deficits in a mouse model of Alzheimer’s disease |
| title_fullStr | Pitolisant alleviates brain network dysfunction and cognitive deficits in a mouse model of Alzheimer’s disease |
| title_full_unstemmed | Pitolisant alleviates brain network dysfunction and cognitive deficits in a mouse model of Alzheimer’s disease |
| title_short | Pitolisant alleviates brain network dysfunction and cognitive deficits in a mouse model of Alzheimer’s disease |
| title_sort | pitolisant alleviates brain network dysfunction and cognitive deficits in a mouse model of alzheimer s disease |
| url | https://doi.org/10.1038/s41398-025-03358-8 |
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