Research Paper Volume 14, Issue 1 pp 109—142

Kampo formulas alleviate aging-related emotional disturbances and neuroinflammation in male senescence-accelerated mouse prone 8 mice

Naoki Ito1, *, , Akiko Maruko2, *, , Kenshiro Oshima2, , Masaaki Yoshida3, , Kengo Honma4, , Chika Sugiyama5, , Takayuki Nagai1,4,6, , Yoshinori Kobayashi1,5, , Hiroshi Odaguchi1,7, , Norihiro Okada2, ,

  • 1 Oriental Medicine Research Center, Kitasato University, Tokyo 108-8642, Japan
  • 2 Laboratory of Genomics for Health and Longevity, School of Pharmacy, Kitasato University, Sagamihara, Kanagawa 252-0373, Japan
  • 3 Research Laboratory, Kotaro Pharmaceutical Co., Ltd., Hakusan, Ishikawa 920-0201, Japan
  • 4 Graduate School of Infection Control Sciences, Kitasato University, Tokyo 108-8642, Japan
  • 5 Graduate School of Medical Sciences, Kitasato University, Sagamihara, Kanagawa 252-0373, Japan
  • 6 Laboratory of Biochemical Pharmacology for Phytomedicines, Ōmura Satoshi Memorial Institute, Kitasato University, Tokyo 108-8642, Japan
  • 7 Department of Pharmacognosy, School of Pharmacy, Kitasato University, Minato-ku, Tokyo 108-8642, Japan
* Equal contribution

Received: October 13, 2021       Accepted: December 20, 2021       Published: January 3, 2022
How to Cite

Copyright: © 2022 Ito et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Aging-induced neuroinflammation, also known as neuroinflammaging, plays a pivotal role in emotional disturbances, including depression and anxiety, in older individuals, thereby leading to cognitive dysfunction. Although numerous studies have focused on therapeutic strategies for cognitive impairment in older individuals, little research has been performed on treating its preceding emotional disturbances. Here, we examined whether Kampo formulas (kososan [KS], nobiletin-rich kososan [NKS], and hachimijiogan [HJG]) can ameliorate aging-induced emotional disturbances and neuroinflammation in mice. The depression-like behaviors observed in SAMP8 mice, relative to normally aging SAMR1 mice, were significantly prevented by treatment with Kampo formulas for 13 weeks. Western blot analysis revealed that hippocampal neuroinflammation was significantly abrogated by Kampo formulas. KS and NKS also significantly attenuated the hippocampal neuroinflammatory priming induced by lipopolysaccharide (LPS, 0.33 mg/kg, i.p.) challenge in SAMP8 mice. Hippocampal IL-1β, IL-6, and MCP-1 levels were significantly decreased in NKS-treated SAMP8 mice. KS and NKS showed significantly reduced tau accumulation in the brains of SAMP8 mice. RNA-sequencing revealed that each Kampo formula led to unique dynamics of hippocampal gene expression and appeared to abrogate hippocampal inflammatory responses. HJG significantly blocked the LPS-induced increase in serum IL-6 and MCP-1. These results suggest that Kampo formulas would be useful for treating aging-induced depression, in part by regulating neuroinflammatory pathways. This finding may pave the way for the development of therapeutic strategies for aging-related emotional disturbances, which may contribute to the prevention of cognitive dysfunction in older individuals.


Arg1: Arginase1; Cdk5: Cyclin-dependent protein kinase 5; DEGs: differentially expressed genes; Dyrk2: Dual-specificity tyrosine phosphorylated and regulated kinase 2; GO: Gene Ontology; HJG: Hachimijiogan; HRP: Horseradish peroxidase; IL: Interleukin; KEGG: Kyoto Encyclopedia of Genes and Genomes; Klf10: Krüppel-like factor-10; KS: Kososan; LPS: Lipopolysaccharide; MCP-1: Monocyte chemoattractant protein-1; MDD: Major depressive disorder; Nab2: Ngfi-A-binding protein-2; NKS: Nobiletin-rich kososan; NLRP3: Nod-like receptor family, pyrin domain-containing 3; OFT: Open field test; RIN: RNA integrity number; RNA-seq: RNA-sequencing; RT: Room temperature; SAMP8: Senescence-accelerated mouse prone 8; SAMR1: Senescence-accelerated mouse resistant 1; SPT: Sucrose preference test; TLR4: Toll-like receptor 4; TNF-α: Tumor necrosis factor-α; TST: Tail suspension test.