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Macamide B Pretreatment Attenuates Neonatal Hypoxic-Ischemic Brain Damage of Mice Induced Apoptosis and Regulates Autophagy via the PI3K/AKT Signaling Pathway

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Abstract

Lepidium meyenii (maca) is an annual or biennial herb from South America that is a member of the genus Lepidium L. in the family Cruciferae. This herb possesses antioxidant and antiapoptotic activities, enhances autophagy functions, prevents cell death, and protects neurons from ischemic damage. Macamide B, an effective active ingredient of maca, exerts a neuroprotective effect on neonatal hypoxic-ischemic brain damage (HIBD), but the mechanism underlying its neuroprotective effect is not yet known. The purpose of this study was to explore the effect of macamide B on HIBD-induced autophagy and apoptosis and its potential neuroprotective mechanism. The modified Rice-Vannucci method was used to induce HIBD in 7-day-old (P7) macamide B- and vehicle-pretreated pups. TTC staining was performed to evaluate the cerebral infarct volume in pups, the brain water content was measured to evaluate the neurological function of pups, neurobehavioural testing was conducted to assess functional recovery after HIBD, TUNEL and FJC staining was performed to detect cellular autophagy and apoptosis, and Western blot analysis was used to detect the levels of proteins in the pro-survival phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) signaling pathway and autophagy and apoptosis-related proteins. Macamide B pretreatment significantly decreases brain damage and improves the recovery of neural function after HIBD. At the same time, macamide B pretreatment activates the PI3K/AKT signaling pathway after HIBD, enhances autophagy, and reduces hypoxic-ischemic (HI)-induced apoptosis. In addition, 3-methyladenine (3-MA), an inhibitor of the PI3K/AKT signaling pathway, significantly inhibits the increase in autophagy levels, aggravates HI-induced apoptosis, and reverses the neuroprotective effect of macamide B on HIBD. Our data indicate that a macamide B pretreatment might regulate autophagy through the PI3K/AKT signaling pathway, thereby reducing HIBD-induced apoptosis and exerting neuroprotective effects on neonatal HIBD. Macamide B may become a new drug for the prevention and treatment of HIBD.

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Acknowledgements

The authors acknowledge the technical support from Guangdong Pharmaceutical University.

Funding

This project was financially supported by the National Natural Science Foundation of China for Youth (grant no. 81901524), the Natural Science Foundation of Guangdong Province (2021A1515011525, 2018A030313579), and the Guangdong Medical Science and Technology Research Fund (A2020252).

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  1. Xiaoxia Yang and Mengxia Wang contributed equally.

Authors and Affiliations

  1. School of Biosciences & Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, 510006, Guangdong, People’s Republic of China

    Xiaoxia Yang, Qian Zhou, Yanxian Bai, Jing Liu, Junhua Yang, Lixia Li, Guoying Li & Li Luo

  2. Intensive Care Unit, Guangdong Second Provincial General Hospital, Guangzhou, 510317, Guangdong, People’s Republic of China

    Mengxia Wang

  3. Guangdong Medical Association, Guangzhou, 510180, Guangdong, People’s Republic of China

    Guoying Li & Li Luo

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  1. Xiaoxia Yang
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Contributions

Li Luo and Mengxia Wang established the animal models and providing technical and writing guidance throughout the process; Xiaoxia Yang contributed in experimental operations, statistical analysis, and manuscript writing; Qian Zhou assisted in the completion of Western blot, behavioral tests, immunofluorescence, etc.; Yanxian Bai, Jing Liu, Junhua Yang, and Guoying Li provided technical guidance. All authors read and approved the final manuscript.

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Correspondence to Guoying Li or Li Luo.

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Yang, X., Wang, M., Zhou, Q. et al. Macamide B Pretreatment Attenuates Neonatal Hypoxic-Ischemic Brain Damage of Mice Induced Apoptosis and Regulates Autophagy via the PI3K/AKT Signaling Pathway. Mol Neurobiol 59, 2776–2798 (2022). https://doi.org/10.1007/s12035-022-02751-4

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