2. Academic Validation
  3. Notch1-dependent hippocampal apoptosis is associated with monocrotaline-induced anxiety-like behavior

Notch1-dependent hippocampal apoptosis is associated with monocrotaline-induced anxiety-like behavior

  • Toxicology. 2025 Nov 26:520:154357. doi: 10.1016/j.tox.2025.154357.
Lai Baochang 1,  Li Fan 2,  Wang Fei 3,  Yan Xianchun 4,  Wang Zichen 1,  Han Mengzhuan 5,  Zhang Yiman 1,  Kang Mengyang 6,  Liu Bing 1,  Wang Ying 6,  Ma Qiang 6,  Jia Pu 7,  Zheng Xiaohui 7,  Hu Hao 8,  Tian Hongyan 9,  Yin Qian 10
Affiliations

Affiliations

  • 1 Department of Peripheral Vascular, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China; Cardiovascular Research Center, Xi'an Jiaotong University, Xi'an 710061, China.
  • 2 Basic Medicine Experimental Teaching Center, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an 710061, China.
  • 3 Cardiovascular Research Center, Xi'an Jiaotong University, Xi'an 710061, China; The College of Life Sciences, Provincial Center for Research Innovative Drugs, Provincial Key Laboratory of Biomedicine, Northwest University, China.
  • 4 State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, Shaanxi, China.
  • 5 Cardiovascular Research Center, Xi'an Jiaotong University, Xi'an 710061, China.
  • 6 Department of Peripheral Vascular, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
  • 7 The College of Life Sciences, Provincial Center for Research Innovative Drugs, Provincial Key Laboratory of Biomedicine, Northwest University, China.
  • 8 Basic Medicine Experimental Teaching Center, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an 710061, China. Electronic address: [email protected].
  • 9 Department of Peripheral Vascular, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China. Electronic address: [email protected].
  • 10 Department of Peripheral Vascular, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China; Cardiovascular Research Center, Xi'an Jiaotong University, Xi'an 710061, China. Electronic address: [email protected].
PMID: 41314588 DOI: 10.1016/j.tox.2025.154357
Abstract

Monocrotaline (MCT), an alkaloid from the genus Crotalaria, is widely used to establish an animal model of pulmonary hypertension. The toxicity of MCT extends not only to peripheral organs but also to the nervous system. However, the molecular mechanism responsible for the development of anxiety disorders after MCT poisoning remains unclear. MCT (60 mg/kg) administration for 4 weeks was used to induce a rat model of anxiety-like behavior with pulmonary hypertension. Open field and elevated plus maze tests showed MCT increased anxiety-like behavior in rats with pulmonary hypertension. Hematoxylin and eosin staining of the hippocampus and annexin V-FITC/PI staining of the mouse hippocampal cell line HT22 with MCT infusion showed that MCT promoted Apoptosis in hippocampal neurons. The western blot showed MCT increased the Apoptosis effector Caspase-3 expression and activation in vivo and in vitro. Simultaneously, Notch1 and its downstream gene expression were also increased in vivo and in vitro. Furthermore, Notch1 deletion with siRNA can eliminate MCT-induced Apoptosis and Caspase-3 expression and activation. The Notch1 inhibitor DAPT has the same effect in vitro. In addition, DAPT alleviated MCT-induced anxiety-related behavior and attenuated hippocampal Apoptosis in vivo. The present study reveals that the mechanism of MCT-induced neurotoxic effects in hippocampal neurons is mediated by the Notch1/Caspase-3 pathway.

Keywords

Anxiety-like behavior; Caspase-3; Hippocampal apoptosis; Monocrotaline; Notch1.

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