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Comparing the Effects of Melatonin with Caloric Restriction in the Hippocampus of Aging Mice: Involvement of Sirtuin1 and the FOXOs Pathway

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Abstract

It has been suggested that age-related neurodegeneration might be associated with neuropeptide Y (NPY); sirtuin1 (SIRT1) and forkhead box transcription factors O subfamily (FOXOs) pathways. Melatonin, a hormone mainly secreted by the pineal gland, is another anti-aging agent associated with the SIRT1-FOXOs pathway. This study aimed to compare the effects of melatonin (Mel) and caloric restriction (CR) on the expression of Sirt1, FoxO1, FoxO3a and FOXOs target genes in the aging mouse hippocampus. Neuropeptide Y-knockout (NpyKO) and wild-type (WT) male mice aged 19 months were previously treated either with food ad libitum or CR for 16 months. WT old animals were divided into four groups: control, CR, Mel and CR+Mel treated groups. The Mel and CR+Mel were treated with melatonin 10 mg/kg, daily, subcutaneously for 7 consecutive days. Mel treatment upregulated the mRNA expression of Sirt1, FOXOs (FoxO1 and FoxO3a) target genes that regulated the cell cycle [e.g., cyclin-dependent kinase inhibitor 1B (p27)], Wingless and INT-1 (Wnt1) and inducible signaling pathway protein 1 (Wisp1) in the aged mouse hippocampus. CR treatment also showed the similar actions. However, the mRNA expression of Sirt1, FoxO1, FoxO3a, p27 or Wisp1 did not alter in the CR+Mel group when compared with CR or Mel group. Melatonin could not produce any additive effect on the CR treatment group, suggesting that both treatments mimicked the effect, possibly via the same pathway. NPY which mediates physiological adaptations to energy deficits is an essential link between CR and longevity in mice. In order to focus on the role of Npy in mediating the effects of melatonin, the gene expression between NpyKO and WT male mice were compared. Our data showed that, in the absence of Npy, melatonin could not mediate effects on those gene expressions, suggesting that Npy was required for melatonin to mediate the effect, possibly, on life extension.

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Abbreviations

ADAM10:

A disintegrin and metalloprotease domain 10

AgRP:

Agouti-related peptide

AMPK:

Adenosine monophosphate-activated protein kinase

CART:

Cocaine and amphetamine regulated transcript

CBP:

CREB-binding protein

CR:

Caloric restriction

DKK1:

Wnt inhibitor Dickkopf WNT signaling pathway inhibitor 1

FOXOs:

Forkhead box transcription factors and the O subfamily

GAPDH:

Glyceraldehyde 3-phosphate dehydrogenase

IGF-1:

Insulin-like growth factor-1

Mel:

Melatonin

NAD:

Nicotinamide adenine dinucleotide

NAMPT:

Nicotinamide phosphoribosyltransferase

NF-κB:

Nuclear factor-κB

NMNAT:

Nicotinamide/nicotinic acid mononucleotide adenylyltransferase

NPY:

Neuropeptide Y

Nrf2:

Nuclear factor (erythroid-derived 2)-like 2

POMC:

Anorexigenic proopiomelanocortin

p27:

Cyclin-dependent kinase inhibitor 1B

p300:

E1A binding protein p300

p53:

Tumor suppressor protein 53

PGC-1α:

Peroxisome proliferator-activated receptor gamma coactivator 1-alpha

PI3K:

Phosphoinositide-3-kinase

POMC:

Proopiomelanocortin

PPAR-γ:

Peroxisome proliferator-activated receptor gamma

SAMP8:

Senescence-accelerated mouse prone 8

SAMR1:

Senescence-accelerated-resistant mouse

SIRT:

Sirtuin

Wisp1:

Wn1 inducible pathway protein1

WNT:

Wingless-type

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Acknowledgements

This study was supported in part by the Thailand Research Fund (TRF) (DPG5780001), a Mahidol University Research Grant to PG and Goho Life Sciences International Funding to AJ.

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Authors and Affiliations

  1. Research Center for Neuroscience, Institute of Molecular Biosciences, Mahidol University, Salaya, Thailand

    Anorut Jenwitheesuk, Sujira Mukda & Piyarat Govitrapong

  2. Department of Pathology, Nagasaki University School of Medicine and Graduate School of Biomedical Sciences, 1-12-4, Sakamoto, Nagasaki, 852-8523, Japan

    Seongjoon Park & Isao Shimokawa

  3. Center for Research and Innovation, Faculty of Medical Technology, Mahidol University, Salaya, Nakon Pathom, 73170, Thailand

    Prapimpun Wongchitrat

  4. Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand

    Jiraporn Tocharus

  5. Center for Neuroscience and Department of Pharmacology, Faculty of Science, Mahidol University, Salaya, Thailand

    Piyarat Govitrapong

  6. Chulabhorn Graduate Institute, Chulabhorn Royal Academy, Kamphaeng Phet 6 Road, Lak Si, Bangkok, 10210, Thailand

    Piyarat Govitrapong

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  1. Anorut Jenwitheesuk
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  2. Seongjoon Park
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Correspondence to Isao Shimokawa or Piyarat Govitrapong.

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Isao Shimokawa and Piyarat Govitrapong have contributed equally to this work.

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Jenwitheesuk, A., Park, S., Wongchitrat, P. et al. Comparing the Effects of Melatonin with Caloric Restriction in the Hippocampus of Aging Mice: Involvement of Sirtuin1 and the FOXOs Pathway. Neurochem Res 43, 153–161 (2018). https://doi.org/10.1007/s11064-017-2369-7

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