2. Academic Validation
  3. The ADCY1-mediated cAMP signaling pathway mediates functional effects of montelukast treatment in brain organoids

The ADCY1-mediated cAMP signaling pathway mediates functional effects of montelukast treatment in brain organoids

  • Cell Mol Life Sci. 2025 Jun 5;82(1):224. doi: 10.1007/s00018-025-05764-z.
Zhenhong Xu # 1 2,  Hongye Yan # 1 2,  Bo Wang # 1 2,  Huimin Wang 1 2,  Ye Xia 1 2,  Juan Wan 1 2,  Jiamei Jiang 3 4,  Lin Zeng 5 6,  Beisha Tang 7 8 9,  Qingtuan Meng 10 11 12
Affiliations

Affiliations

  • 1 The First Affiliated Hospital, Multi-Omics Research Center for Brain Disorders, Department of Neurology, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.
  • 2 The First Affiliated Hospital, Clinical Research Center for Immune-Related Encephalopathy of Hunan Province, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.
  • 3 The First Affiliated Hospital, Multi-Omics Research Center for Brain Disorders, Department of Neurology, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China. 645649828@qq.com.
  • 4 The First Affiliated Hospital, Clinical Research Center for Immune-Related Encephalopathy of Hunan Province, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China. 645649828@qq.com.
  • 5 The First Affiliated Hospital, Multi-Omics Research Center for Brain Disorders, Department of Neurology, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China. 2854686580@qq.com.
  • 6 The First Affiliated Hospital, Clinical Research Center for Immune-Related Encephalopathy of Hunan Province, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China. 2854686580@qq.com.
  • 7 The First Affiliated Hospital, Multi-Omics Research Center for Brain Disorders, Department of Neurology, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China. bstang7398@163.com.
  • 8 The First Affiliated Hospital, Clinical Research Center for Immune-Related Encephalopathy of Hunan Province, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China. bstang7398@163.com.
  • 9 Department of Neurology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China. bstang7398@163.com.
  • 10 The First Affiliated Hospital, Multi-Omics Research Center for Brain Disorders, Department of Neurology, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China. mengqingtuan@glmc.edu.cn.
  • 11 The First Affiliated Hospital, Clinical Research Center for Immune-Related Encephalopathy of Hunan Province, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China. mengqingtuan@glmc.edu.cn.
  • 12 MOE Key Lab of Rare Pediatric Diseases & School of Life Sciences, University of South China, Hengyang, 421001, Hunan, China. mengqingtuan@glmc.edu.cn.
  • # Contributed equally.
PMID: 40471331 DOI: 10.1007/s00018-025-05764-z
Abstract

Montelukast (MTK) is a drug widely used for treating allergic rhinitis and asthma. However, severe neuropsychiatric adverse events related to MTK have been reported, with limited understanding of the underlying mechanisms. Here we leveraged human forebrain organoids (hFOs) and showed that MTK exposure in hFOs downregulated the expression of genes associated with multiple neuronal functions and neuropsychiatric disorders. The following integrative analysis highlighted Adenylate Cyclase 1 (ADCY1), a main regulator of the cAMP signaling pathway, as a hub gene mediating the functional effects of MTK exposure. We also showed that MTK exposure resulted in a reduction of cAMP and neuroactivities, and caused neural maturation defects. These cellular phenotypes could be recapitulated by treating hFOs with ST034307, a selective ADCY1 inhibitor, or partially rescued by ADCY1 overexpression in hFOs. Together, this study underscored that MTK exposure caused neuropsychiatric effects through inhibiting the ADCY1-mediated cAMP signaling pathway.

Keywords

ADCY1; CAMP signaling pathway; GPCRs; Human forebrain organoids; Montelukast; Neuropsychiatric effects.

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