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Propolis Promotes Memantine-Dependent Rescue of Cognitive Deficits in APP-KI Mice

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Abstract

Propolis is a complex resinous substance that is relevant as a therapeutic target for Alzheimer’s disease (AD) and other neurodegenerative diseases. In this study, we confirmed that propolis (Brazilian green propolis) further enhances the rescue of cognitive deficits by the novel AD drug memantine in APP-KI mice. In memory-related behavior tasks, administration of a single dose of propolis at 1–100 mg/kg p.o. significantly enhanced the rescue of cognitive deficits by memantine at 1 mg/kg p.o. in APP-KI mice. In in vitro studies, propolis significantly increased intracellular Ca2+ concentration and calcium/calmodulin-dependent protein kinase II (CaMKII) autophosphorylation in Kir6.2-overexpressed N2A cells treated with memantine. Propolis also significantly increased adenosine 5′-triphosphate (ATP) contents and CaMKII autophosphorylation, which was impaired in Aβ-treated Kir6.2-overexpressed N2A cells. Similarly, repeated administration of propolis at 100 mg/kg p.o. for 8 weeks further enhanced the rescue of cognitive deficits by memantine in APP-KI mice. Consistent with the rescued cognitive deficits in APP-KI mice, repeated administration of propolis markedly ameliorated memantine-dependent rescue of injured long-term potentiation (LTP) in APP-KI mice, concomitant with increased CaMKII autophosphorylation and calcium/calmodulin-dependent protein kinase IV (CaMKIV) phosphorylation in the hippocampal CA1 region. Furthermore, repeated administration of both memantine and propolis significantly restored the decreased ATP contents in the CA1 region of APP-KI mice. Finally, we confirmed that repeated administration of memantine at 1 mg/kg p.o. and propolis at 100 mg/kg p.o. for 8 weeks failed to restore the cognitive deficits in Kir6.2−/− mice. Our study demonstrates that propolis increases ATP contents and promotes the amelioration of cognitive deficits rescued by memantine via Kir6.2 channel inhibition in the CA1 region.

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Data Availability

All source data supporting the findings of this manuscript are available from the corresponding authors upon request.

Abbreviations

Aβ:

Amyloid-β

AD:

Alzheimer’s disease

ATP:

Adenosine 5′-triphosphate

BDNF:

Brain-derived neurotrophic factor

CaMKII:

Calcium/calmodulin-dependent protein kinase II

CaMKIV:

Calcium/calmodulin-dependent protein kinase IV

CREB:

CAMP-responsive element binding protein

DMEM:

Dulbecco’s Modified Eagle’s Medium

fEPSPs:

Field excitatory postsynaptic potentials

HFS:

High-frequency stimulation

KATP :

ATP-sensitive potassium

Kir6.2 − / − mice:

Kir6.2 homozygous mice

LTP:

Long-term potentiation

MCU:

Mitochondrial calcium uniporter complex

N2A:

Neuro2A

NMDAR:

N-methyl-D-aspartate receptor

NOR:

Novel object recognition

ROS:

Reactive oxygen species

SUR:

Sulfonylurea receptor

WT:

Wild type

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Acknowledgements

We thank Prof. Susumu Seino for providing the Kir6.2−/− mice used in this study.

Funding

This work was supported in part by grants from the Ministry of Education, Culture, Sports, Science, and Technology, and the Ministry of Health and Welfare of Japan (18K06887 to S.M.), and in part by a grant from the Project of Translational and Clinical Research Core Centers from AMED of Japan (21wm0525031h0001 to S.M.). This research was supported in part by Yamada Research Grant.

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Author notes

  1. Shigeki Moriguchi and Ryo Inagaki contributed equally to this work

Authors and Affiliations

  1. Research Center for Pharmaceutical Development, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Miyagi, 980-8578, Japan

    Shigeki Moriguchi & Ryo Inagaki

  2. Department of Neurocognitive Science, Institute of Brain Science, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan

    Takashi Saito

  3. Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science, Saitama, Japan

    Takaomi C. Saido

  4. Department of CNS Drug Innovation, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan

    Kohji Fukunaga

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  1. Shigeki Moriguchi
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  2. Ryo Inagaki
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  4. Takaomi C. Saido
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  5. Kohji Fukunaga
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Contributions

SM and RI performed the experiments. TS and TCS provided the APP-KI mice. KF provided helpful advice. SM designed the study and wrote the manuscript. All authors reviewed and approved the final manuscript.

Corresponding author

Correspondence to Shigeki Moriguchi.

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Conflict of Interest

TS and TCS serve as the advisor and CEO, respectively, of RIKEN BIO Co. Ltd., which sublicenses animal models, APP knock-in mice, and for-profit organizations; the profits from these enterprises are used for the identification of disease biomarkers. Other authors declare no competing interests.

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Moriguchi, S., Inagaki, R., Saito, T. et al. Propolis Promotes Memantine-Dependent Rescue of Cognitive Deficits in APP-KI Mice. Mol Neurobiol 59, 4630–4646 (2022). https://doi.org/10.1007/s12035-022-02876-6

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