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Puerarin attenuates valproate-induced features of ASD in male mice via regulating Slc7a11-dependent ferroptosis

Neuropsychopharmacology volume 49, pages 497–507 (2024)Cite this article

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Abstract

Autism spectrum disorder (ASD) is a complicated, neurodevelopmental disorder characterized by social deficits and stereotyped behaviors. Accumulating evidence suggests that ferroptosis is involved in the development of ASD, but the underlying mechanism remains elusive. Puerarin has an anti-ferroptosis function. Here, we found that the administration of puerarin from P12 to P15 ameliorated the autism-associated behaviors in the VPA-exposed male mouse model of autism by inhibiting ferroptosis in neural stem cells of the hippocampus. We highlight the role of ferroptosis in the hippocampus neurogenesis and confirm that puerarin treatment inhibited iron overload, lipid peroxidation accumulation, and mitochondrial dysfunction, as well as enhanced the expression of ferroptosis inhibitory proteins, including Nrf2, GPX4, Slc7a11, and FTH1 in the hippocampus of VPA mouse model of autism. In addition, we confirmed that inhibition of xCT/Slc7a11-mediated ferroptosis occurring in the hippocampus is closely related to puerarin-exerted therapeutic effects. In conclusion, our study suggests that puerarin targets core symptoms and hippocampal neurogenesis reduction through ferroptosis inhibition, which might be a potential drug for autism intervention.

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Fig. 1: PU could ameliorate VPA-induced autistic-like behaviors and cognitive impairment in male mice.
Fig. 2: PU treatment improves decreased neurogenesis caused by P14VPA treatment in the DG of the P15 hippocampus.
Fig. 3: The target xCT/Slc7a11 can be a bridge connecting hippocampus neurogenesis and ferroptosis in the effect of PU.
Fig. 4: Characteristics of ferroptosis in the P15 hippocampus of VPA-treated male mice were ameliorated by PU treatment.
Fig. 5: Erastin blocked the improved effect of PU in VPA-induced ASD phenotypes.

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Funding

Funding

This study was supported by the National Nature Science Foundation of China (No. 82071544); National Key R&D Program of China (2021YFA1101203) ; Chongqing Technology Innovation and Application s Development Special key Project (cstc2019jscx-dxwtBX0010); Innovation Team of the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University(2022-CXTD-05); Si chuan Science and Technology Program(grantnumber2019YJ0694) and Student’s Platform for Innovation and Entrepreneurship Training Program (202290031048).

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  1. These authors contributed equally: Peiyan Jiang, Lianyu Zhou.

Authors and Affiliations

  1. Department of Military Cognitive Psychology, School of Psychology, Army Medical University, 400038, Chongqing, China

    Peiyan Jiang, Lianyu Zhou, Linyang Zhao, Xinghang Fei, Zhifei Wang, Tianyao Liu, Yexi Tang, Hong Gong, Yi Luo & Xiaotang Fan

  2. The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, Sichuan, China

    Peiyan Jiang, Song Li, Hui Yang & Huiling Liao

  3. Department of Neurosurgery, Xinqiao Hospital, Army Medical University, 400037, Chongqing, China

    Lianyu Zhou, Xinghang Fei & Yexi Tang

  4. School of Basic Medical Sciences, Southwest Medical University, Luzhou, Sichuan, China

    Dabing Li

  5. Chongqing Institute for Brain and Intelligence, Guangyang Bay Laboratory, Chongqing, China

    Song Li & Hui Yang

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  1. Peiyan Jiang
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Contributions

Conceptualization, PJ, XF, and LZ; methodology, PJ and LZ; validation, XF, PJ, and LZ; formal analysis, LZ, XF, ZW, TL, ZW. HG, YL, and LZ; data curation, YT, XF, and LZ; writing-original draft preparation, PJ and LZ; writing-review and editing, XF, HY, and HL; supervision, XF, SL, and DL; project administration, PJ, XF. All authors have read and agreed to the published version of the paper.

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Correspondence to Huiling Liao or Xiaotang Fan.

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Jiang, P., Zhou, L., Zhao, L. et al. Puerarin attenuates valproate-induced features of ASD in male mice via regulating Slc7a11-dependent ferroptosis. Neuropsychopharmacol. 49, 497–507 (2024). https://doi.org/10.1038/s41386-023-01659-4

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