Xu Zhenhong, Yan Hongye, Wang Bo, Wang Huimin, Xia Ye, Wan Juan, Jiang Jiamei, Zeng Lin, Tang Beisha, Meng Qingtuan
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.
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.
Cell Mol Life Sci. 2025 Jun 5;82(1):224. doi: 10.1007/s00018-025-05764-z.
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.
孟鲁司特（MTK）是一种广泛用于治疗过敏性鼻炎和哮喘的药物。然而，已有与MTK相关的严重神经精神不良事件的报道，但其潜在机制的了解有限。在此，我们利用人类前脑类器官（hFOs），发现hFOs暴露于MTK会下调与多种神经元功能和神经精神疾病相关的基因表达。接下来的综合分析突出了腺苷酸环化酶1（ADCY1），一种cAMP信号通路的主要调节因子，作为介导MTK暴露功能效应的枢纽基因。我们还表明，MTK暴露导致cAMP和神经活性降低，并引起神经成熟缺陷。用选择性ADCY1抑制剂ST034307处理hFOs可重现这些细胞表型，或者通过在hFOs中过表达ADCY1部分挽救这些表型。总之，本研究强调MTK暴露通过抑制ADCY1介导的cAMP信号通路引起神经精神效应。
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