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Rutaecarpine Mitigates Cognitive Impairment by Balancing Mitochondrial Function Through Activation of the AMPK/PGC1α Pathway

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Abstract

Mitochondrial dysfunction plays a fundamental role in the pathogenesis of cognitive deficit. Rutaecarpine (Rut) is a natural alkaloid with anti-inflammatory and antioxidant properties. This study explored whether Rut treatment could enhance cognitive function by improving mitochondrial function and examined the potential mechanisms underlying this ameliorative effect. We used the Morris water maze and Y-maze tests to evaluate the behavioral effects of Rut in a mouse model of cognitive impairment induced by subcutaneous injection of D-galactose (D-gal). Furthermore, we assessed the effects of Rut on mitochondrial function using cell viability assays, flow cytometry, western blotting, biochemical analysis, and immunochemical techniques in vivo and in vitro. The results indicated Rut treatment attenuated cognitive deficits and mitochondrial dysfunction in the mouse model. Similarly, it maintained the balance of mitochondrial dynamics in neurocytes and reduced oxidative stress and mitochondrial apoptosis in the HT22 cell model. Moreover, we found that these protective effects were dependent on the activation of the AMP-activated protein kinase/proliferator-activated receptor gamma coactivator 1-alpha (AMPK/PGC1α) signaling pathway. Our data indicate that Rut treatment are sensitive to reversal cognitive deficits and mitochondrial dysfunction induced by D-gal; this suggests that Rut is a promising mitochondria-targeted therapeutic agent for treating cognitive impairment.

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Data Availability

The datasets generated during and/or analyzed during this study are available from the corresponding author upon reasonable request.

Abbreviations

D-gal:

D-galactose

Rut:

Rutaecarpine

AMPK:

Adenosine 5′-monophosphate-activated protein kinase

PGC1α:

Peroxisome proliferator-activated receptor-γ coactivator 1α

Nrf1:

Nuclear respiratory factor 1

TFAM:

Mitochondrial transcription factor A

UCP2:

Uncoupling protein 2

MDA:

Malondialdehyde

SOD:

Superoxide dismutase

GSH:

Reduced glutathione

Drp1:

Dynamic-related protein 1

Mfn-2:

Mitofusin 2

CC3:

cleaved Caspase-3

Cytochrome C:

Cyt-c

MTT:

3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

SDS-PAGE:

Sodium dodecyl sulfate-polyacrylamide gel electrophoresis

ROS:

Reactive oxygen species

TUNEL:

Terminal deoxynucleotidyl transferase-dUTP nick end labeling

MMP:

Mitochondrial membrane potential

WT:

Wild type

MWM:

Morris Water Maze

TEM:

Transmission electron microscopy

qRT-PCR:

Quantitative real-time polymerase chain reaction

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Acknowledgements

We wish to thank Dr. Heng Zhang, Dr. Di-yang Lyv, Dr. Wen-ying Liu, Dr. Xue-chu Wang, Dr. Mengmeng Guo, Dr. Tan Zhao, Dr. Yan Li, and Dr. Yue Zhang for their generous assistant with performing experiments and suggestions on revising the manuscript. We wish to thank Bing-qiu Li, Ling-zhi Xu, Wen-wen Li, Ya-na Pang, and Mei-na Quan for their guidance.

Funding

This study was supported by the Key Project of the National Natural Science Foundation of China (U20A20354), Beijing Brain Initiative from Beijing Municipal Science & Technology Commission (Z201100005520016, Z201100005520017), National major R&D projects of China-Scientific technological innovation 2030 (2021ZD0201802), the National Key Scientific Instrument and Equipment Development Project (31627803), and the Key Project of the National Natural Science Foundation of China (81530036).

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Authors and Affiliations

  1. Innovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Diseases, Changchun Street 45, Xicheng District, Beijing, China

    Min Gong & Jianping Jia

  2. Beijing Key Laboratory of Geriatric Cognitive Disorders, Beijing, China

    Jianping Jia

  3. Clinical Center for Neurodegenerative Disease and Memory Impairment, Capital Medical University, Beijing, China

    Jianping Jia

  4. Center of Alzheimer’s Disease, Beijing Institute of Brain Disorders, Collaborative Innovation Center for Brain Disorders, Capital Medical University, Beijing, China

    Jianping Jia

  5. Key Laboratory of Neurodegenerative Diseases, Ministry of Education, Beijing, 100053, People’s Republic of China

    Jianping Jia

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  1. Min Gong
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Jianping Jia designed the experiments, conceived the study concept, and revised the manuscript. Min Gong designed and performed the experiments, analyzed the data, and wrote the manuscript draft.

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Correspondence to Jianping Jia.

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Gong, M., Jia, J. Rutaecarpine Mitigates Cognitive Impairment by Balancing Mitochondrial Function Through Activation of the AMPK/PGC1α Pathway. Mol Neurobiol 60, 6598–6612 (2023). https://doi.org/10.1007/s12035-023-03505-6

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