A novel cyclic peptide (Naturido) modulates glia-neuron interactions in vitro and reverses ageing-related deficits in senescence-accelerated mice

Shinichi Ishiguro; Tetsuro Shinada; Zhou Wu; Mayumi Karimazawa; Michimasa Uchidate; Eiji Nishimura; Yoko Yasuno; Makiko Ebata; Piyamas Sillapakong; Hiromi Ishiguro; Nobuyoshi Ebata; Junjun Ni; Muzhou Jiang; Masanobu Goryo; Keishi Otsu; Hidemitsu Harada; Koichi Suzuki

doi:10.1371/journal.pone.0245235

A novel cyclic peptide (Naturido) modulates glia-neuron interactions in vitro and reverses ageing-related deficits in senescence-accelerated mice

PLoS One. 2021 Jan 27;16(1):e0245235. doi: 10.1371/journal.pone.0245235. eCollection 2021.

Authors

Shinichi Ishiguro¹, Tetsuro Shinada², Zhou Wu^{3

4}, Mayumi Karimazawa¹, Michimasa Uchidate⁵, Eiji Nishimura², Yoko Yasuno², Makiko Ebata¹, Piyamas Sillapakong¹, Hiromi Ishiguro¹, Nobuyoshi Ebata¹, Junjun Ni³, Muzhou Jiang³, Masanobu Goryo⁶, Keishi Otsu⁷, Hidemitsu Harada⁷, Koichi Suzuki^{1

6}

Affiliations

¹ Biococoon Laboratories, Inc., Ueda, Morioka, Japan.
² Graduate School of Science, Osaka City University, Sumiyoshi-ku, Osaka, Japan.
³ Faculty of Dental Science, Department of Aging Science and Pharmacology, Kyushu University, Fukuoka, Japan.
⁴ Faculty of Dental Science, OBT Research Center, Kyushu University, Fukuoka, Japan.
⁵ Faculty of Science and Engineering, Iwate University, Ueda, Morioka, Japan.
⁶ Iwate University, Ueda, Morioka, Japan.
⁷ Division of Developmental Biology and Regenerative Medicine, Department of Anatomy, Iwate Medical University, Yahaba, Japan.

Abstract

The use of agents that target both glia and neurons may represent a new strategy for the treatment of ageing disorders. Here, we confirmed the presence of the novel cyclic peptide Naturido that originates from a medicinal fungus (Isaria japonica) grown on domestic silkworm (Bombyx mori). We found that Naturido significantly enhanced astrocyte proliferation and activated the single copy gene encoding the neuropeptide VGF and the neuron-derived NGF gene. The addition of the peptide to the culture medium of primary hippocampal neurons increased dendrite length, dendrite number and axon length. Furthermore, the addition of the peptide to primary microglial cultures shifted CGA-activated microglia towards anti-inflammatory and neuroprotective phenotypes. These findings of in vitro glia-neuron interactions led us to evaluate the effects of oral administration of the peptide on brain function and hair ageing in senescence-accelerated mice (SAMP8). In vivo analyses revealed that spatial learning ability and hair quality were improved in Naturido-treated mice compared with untreated mice, to the same level observed in the normal ageing control (SAMR1). These data suggest that Naturido may be a promising glia-neuron modulator for the treatment of not only senescence, but also Alzheimer's disease and other neurodegenerative diseases.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetylcholinesterase / chemistry
Acetylcholinesterase / metabolism
Aging / drug effects*
Animals
Astrocytes / cytology
Astrocytes / metabolism
Axons / drug effects
Axons / physiology
Cell Proliferation / drug effects
Dendrites / drug effects
Dendrites / physiology
Female
Humans
Hypocreales / metabolism
Male
Maze Learning / drug effects
Mice
Mice, Inbred C57BL
Mice, Inbred ICR
Microglia / cytology
Microglia / drug effects*
Microglia / metabolism
Neurons / cytology
Neurons / drug effects*
Neurons / metabolism
Peptides, Cyclic / administration & dosage
Peptides, Cyclic / chemistry
Peptides, Cyclic / isolation & purification
Peptides, Cyclic / pharmacology*
Transforming Growth Factor beta / genetics
Transforming Growth Factor beta / metabolism
Up-Regulation / drug effects

Substances

Peptides, Cyclic
Transforming Growth Factor beta
Acetylcholinesterase

Supplementary concepts

Isaria japonica

Grants and funding

This study was supported by a grant from the Japan Society for the Promotion of Science to KS. DKS Co., Ltd. (the parent company of Biococoon Laboratories, Inc.) provided support for this study in the form of salaries for KS, SI, MK, ME, PS, HI and NE. The specific roles of these authors are articulated in the ‘author contributions’ section. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.