Daily Administration of Agmatine Reduced Anxiety-like Behaviors and Neural Responses in the Brains of Male Mice with Persistent Inflammation in the Craniofacial Region

Iwamoto, Yuya; Piriyaprasath, Kajita; Yusuf, Andi Sitti Hajrah; Hasegawa, Mana; Kakihara, Yoshito; Sato, Tsutomu; Fujii, Noritaka; Yamamura, Kensuke; Okamoto, Keiichiro

doi:10.3390/nu17111848

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Daily Administration of Agmatine Reduced Anxiety-like Behaviors and Neural Responses in the Brains of Male Mice with Persistent Inflammation in the Craniofacial Region

by

Yuya Iwamoto

^1,2

,

Kajita Piriyaprasath

³

,

Andi Sitti Hajrah Yusuf

^1,4,

Mana Hasegawa

^1,5

,

Yoshito Kakihara

^6,7

,

Tsutomu Sato

^7,8,

Noritaka Fujii

^2,5

,

Kensuke Yamamura

¹

and

Keiichiro Okamoto

^1,7,*

¹

Division of Oral Physiology, Faculty of Dentistry, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8514, Japan

²

Division of Dental Clinical Education, Faculty of Dentistry, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8514, Japan

³

Department of Restorative Dentistry, Faculty of Dentistry, Naresuan University, Phitsanulok 650000, Thailand

⁴

Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, Hasanuddin University, Makassar 90245, Indonesia

⁵

Division of General Dentistry and Dental Clinical Education Unit, Niigata University Medical and Dental Hospital, Niigata 951-8514, Japan

⁶

Division of Dental Pharmacology, Faculty of Dentistry, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8514, Japan

⁷

Sakeology Center, Niigata University, Niigata 950-2181, Japan

⁸

Department of Agriculture, Faculty of Agriculture, Graduate School of Science and Technology, Niigata University, Niigata 950-2181, Japan

^*

Author to whom correspondence should be addressed.

Nutrients 2025, 17(11), 1848; https://doi.org/10.3390/nu17111848

Submission received: 25 April 2025 / Revised: 26 May 2025 / Accepted: 27 May 2025 / Published: 28 May 2025

(This article belongs to the Special Issue The Relationship Between Nutrition and Mental Health)

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Abstract

Background/Objectives: Chronic craniofacial inflammation is recognized as a factor in anxiety-like behaviors, yet effective therapeutic options remain limited. Agmatine, a dietary bioactive compound found in fermented foods such as sake lees, exhibits modulatory effects on neural functions, alleviating psychological distress like anxiety associated with local inflammation. Methods: We investigated both the therapeutic and preventive effects of agmatine on anxiety-like behaviors and the related neural basis in a mouse model of persistent craniofacial inflammation induced by complete Freund’s adjuvant (CFA). Results: Comprehensive behavioral assessments, including the elevated plus maze, open field, dark–light box, social interaction, and novel object recognition tests, revealed that therapeutic agmatine administration (1.0 and 30 mg/kg) significantly reduced CFA-induced anxiety-like behaviors, with the higher dose showing more robust and sustained effects across multiple time points. These behavioral improvements were paralleled by reductions in acetylated histone H3, FosB, and c-Fos expression in key anxiety-related brain regions, suggesting a reversal of craniofacial inflammation-associated neural changes. In contrast, preventive agmatine treatment exerted modest and time-dependent behavioral benefits with minimal molecular normalization. Notably, preventive agmatine did not affect general locomotor activity (indicated by total movement distance), indicating that its anxiolytic effects were not confounded by altered locomotor activity. Metabolomic analysis confirmed the presence of agmatine in sake lees (~0.37 mM), supporting the hypothesis that fermented food products might offer dietary routes to emotional resilience. Conclusions: These findings underscore agmatine’s promise as a context-specific epigenetic modulator capable of mitigating anxiety-like behaviors by normalizing inflammation-driven molecular dysregulation in the brain.

Keywords: anxiety; craniofacial tissues; epigenetic change; inflammation

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MDPI and ACS Style

Iwamoto, Y.; Piriyaprasath, K.; Yusuf, A.S.H.; Hasegawa, M.; Kakihara, Y.; Sato, T.; Fujii, N.; Yamamura, K.; Okamoto, K. Daily Administration of Agmatine Reduced Anxiety-like Behaviors and Neural Responses in the Brains of Male Mice with Persistent Inflammation in the Craniofacial Region. Nutrients 2025, 17, 1848. https://doi.org/10.3390/nu17111848

AMA Style

Iwamoto Y, Piriyaprasath K, Yusuf ASH, Hasegawa M, Kakihara Y, Sato T, Fujii N, Yamamura K, Okamoto K. Daily Administration of Agmatine Reduced Anxiety-like Behaviors and Neural Responses in the Brains of Male Mice with Persistent Inflammation in the Craniofacial Region. Nutrients. 2025; 17(11):1848. https://doi.org/10.3390/nu17111848

Chicago/Turabian Style

Iwamoto, Yuya, Kajita Piriyaprasath, Andi Sitti Hajrah Yusuf, Mana Hasegawa, Yoshito Kakihara, Tsutomu Sato, Noritaka Fujii, Kensuke Yamamura, and Keiichiro Okamoto. 2025. "Daily Administration of Agmatine Reduced Anxiety-like Behaviors and Neural Responses in the Brains of Male Mice with Persistent Inflammation in the Craniofacial Region" Nutrients 17, no. 11: 1848. https://doi.org/10.3390/nu17111848

APA Style

Iwamoto, Y., Piriyaprasath, K., Yusuf, A. S. H., Hasegawa, M., Kakihara, Y., Sato, T., Fujii, N., Yamamura, K., & Okamoto, K. (2025). Daily Administration of Agmatine Reduced Anxiety-like Behaviors and Neural Responses in the Brains of Male Mice with Persistent Inflammation in the Craniofacial Region. Nutrients, 17(11), 1848. https://doi.org/10.3390/nu17111848

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Daily Administration of Agmatine Reduced Anxiety-like Behaviors and Neural Responses in the Brains of Male Mice with Persistent Inflammation in the Craniofacial Region

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