Genipin Attenuates Lipopolysaccharide-Induced Persistent Changes of Emotional Behaviors and Neural Activation in the Hypothalamic Paraventricular Nucleus and the central Amygdala Nucleus
Abstract
Sickness behavior is a series of behavioral and psychological changes that develop in inflammatory disease, including infections and cancers. Administration of the bacterial endotoxin lipopolysaccharide (LPS) induces sickness behavior in rodents. Genipin, an aglycon derived from an iridoid glycoside geniposide extracted from the fruit of Gardenia jasminoides, has anti-inflammatory and antidepressant activities. However, the effects of genipin on inflammation-induced changes in emotional behaviors are unknown. In this study, we examined the effects of genipin on LPS-induced inflammation in BV-2 cells and sickness behavior in mice. Pretreatment with genipin inhibited LPS-induced increases in NO production and reduced the mRNA levels of inflammation-related genes (iNOS, COX-2, IL-1β and IL-6) in BV-2 cells. Oral administration of genipin ameliorated LPS-induced depressive-like behavior in the forced swim test and social behavior deficits 24h after LPS administration in mice. LPS-induced expression of mRNAs for inflammation-related genes and the number of c-fos immunopositive cells decreased in the paraventricular nucleus (PVN) of the hypothalamus and the central nucleus of the amygdala (CeA), suggesting that genipin attenuates LPS-induced changes of emotional behaviors through inhibition of neural activation and inflammatory responses in the PVN and CeA. These novel pharmacological effects of genipin may be useful for treatment of patients with sickness behavior.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Genipin inhibits the increase of NO production and iNOS, COX-2, IL-1β, and IL-6 expression in LPS-activated BV2 microglial cells.
“In particular, it has been demonstrated that genipin inhibits the increase of NO production and iNOS, COX-2, IL-1β and IL-6 expression in LPS-activated BV2 microglial cells (Araki et al., 2014).”
From Exploring the Therapeutic Potential of Phytochemicals in Alzheimer’s Disease: Focus on Polyphenols and Monoterpenes (2022) · cites this paper as Araki et al., 2014
Genipin exerts strong anti-inflammatory activity in several models of inflammation by targeting iNOS and NF-κB.
“Genipin has been found to exert a strong anti-inflammatory activity in several models of inflammation by targeting iNOS and NF-κB.”
From Exploring the Therapeutic Potential of Phytochemicals in Alzheimer’s Disease: Focus on Polyphenols and Monoterpenes (2022) · cites this paper as Araki et al., 2014
Cites
From inflammation to sickness and depression: when the immune system subjugates the brain
Dantzer, R., O'Connor, J. C., Freund, G. G., Johnson, R. W., & Kelley, K. W. (2008) · Nature Reviews Neuroscience · doi:10.1038/nrn2297 · Cited by 7,395 · see citing works
The use of c-fos as a metabolic marker in neuronal pathway tracing
Dragunow, M., & Faull, R. (1989) · Journal of Neuroscience Methods · doi:10.1016/0165-0270(89)90150-7 · Cited by 1,416 · see citing works
Cytokines and the Brain: Implications for Clinical Psychiatry
Kronfol, Z., & Remick, D. G. (2000) · American Journal of Psychiatry · doi:10.1176/appi.ajp.157.5.683 · Cited by 784 · see citing works
Innate immunity: the missing link in neuroprotection and neurodegeneration?
Nguyen, M. D., Julien, J., & Rivest, S. (2002) · Nature reviews. Neuroscience · doi:10.1038/nrn752 · Cited by 698 · see citing works
Henry, C. J., Huang, Y., Wynne, A., Hanke, M., Himler, J., Bailey, M. T., Sheridan, J. F., & Godbout, J. P. (2008) · Journal of Neuroinflammation · doi:10.1186/1742-2094-5-15 · Cited by 678 · see citing works
Frenois, F., Moreau, M., O’Connor, J., Lawson, M., Micon, C., Lestage, J., Kelley, K. W., Dantzer, R., & Castanon, N. (2007) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2007.03.005 · Cited by 438 · see citing works
Goehler, L. E., Gaykema, R. P. A., Nguyen, K. T., Lee, J. E., Tilders, F. J. H., Maier, S. F., & Watkins, L. R. (1999) · Journal of Neuroscience · doi:10.1523/jneurosci.19-07-02799.1999 · Cited by 357 · see citing works
Goehler, L. E., Relton, J. K., Dripps, D. J., Kiechle, R., Tartaglia, N. R., Maier, S. F., & Watkins, L. R. (1997) · Brain Research Bulletin · doi:10.1016/s0361-9230(97)00020-8 · Cited by 326 · see citing works
Different receptor mechanisms mediate the pyrogenic and behavioral effects of interleukin 1.
Kent, S., Bluthé, R.-M., Dantzer, R., Hardwick, A. J., KELLEY, K. W., Rothwell, N. J., & Vannice, J. L. (1992) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.89.19.9117 · Cited by 322 · see citing works
Antiinflammatory effects of genipin, an active principle of gardenia
Koo, H.-J., Song, Y. S., Kim, H.-J., Lee, Y.-H., Hong, S.-M., Kim, S., Kim, B.-C., Jin, C., Lim, C., & Park, E. (2004) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2004.05.031 · Cited by 311 · see citing works
Effects of interleukin-1 receptor antagonist on the behavioral effects of lipopolysaccharide in rat
Bluthé, R.-M., Dantzer, R., & Kelley, K. W. (1992) · Brain Research · doi:10.1016/0006-8993(92)90779-9 · Cited by 303 · see citing works
Bluthé, R.-M., Layé, S., Michaud, B., Combe, C., Dantzer, R., & Parnet, P. (2000) · European Journal of Neuroscience · doi:10.1046/j.1460-9568.2000.01348.x · Cited by 283 · see citing works
Role of IL-6 in cytokine-induced sickness behavior: a study with IL-6 deficient mice.
Bluthé, R., Michaud, B., Poli, V., & Dantzer, R. (2000) · Physiology and Behavior · doi:10.1016/s0031-9384(00)00269-9 · Cited by 239 · see citing works
Konsman, J. P., Luheshi, G. N., Bluthé, R., & Dantzer, R. (2000) · European Journal of Neuroscience · doi:10.1046/j.0953-816x.2000.01319.x · Cited by 234 · see citing works
Central injection of IL-10 antagonizes the behavioural effects of lipopolysaccharide in rats
Bluthé, R.-M., Castanon, N., Pousset, F., Bristow, A., Ball, C., Lestage, J., Michaud, B., KELLEY, K. W., & Dantzer, R. (1999) · Psychoneuroendocrinology · doi:10.1016/s0306-4530(98)00077-8 · Cited by 179 · see citing works
A critical review of human endotoxin administration as an experimental paradigm of depression.
DellaGioia, N., & Hannestad, J. (2010) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2009.07.014 · Cited by 175 · see citing works
Effects of interleukin-1 and endotoxin in the forced swim and tail suspension tests in mice
DUNN, A., & Swiergiel, A. H. (2005) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2005.04.019 · Cited by 169 · see citing works
Marvel, F. A., Chen, C.-C., Badr, N. A., Gaykema, R. P. A., & Goehler, L. E. (2003) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2003.09.004 · Cited by 163 · see citing works
Swiergiel, A. H., Smagin, G. N., Johnson, L. J., & Dunn, A. J. (1997) · Brain Research · doi:10.1016/s0006-8993(97)01009-3 · Cited by 130 · see citing works
Genipin inhibits the inflammatory response of rat brain microglial cells
Nam, K. N., Choi, Y.-S., Jung, H.-J., Park, G. H., Park, J., Moon, S., Cho, K., Kang, C., Kang, I., Oh, M. S., et al. (2010) · International Immunopharmacology · doi:10.1016/j.intimp.2010.01.011 · Cited by 121 · see citing works
Haba, R., Shintani, N., Onaka, Y., Wang, H., Takenaga, R., Hayata, A., Baba, A., & Hashimoto, H. (2011) · Behavioural Brain Research · doi:10.1016/j.bbr.2011.12.027 · Cited by 120 · see citing works
Prostaglandins mediate depressive-like behaviour induced by endotoxin in mice
de Paiva, V. N., Lima, S. N. P., Fernandes, M. M., Soncini, R., Andrade, C. A. F., & Giusti-Paiva, A. (2010) · Behavioural Brain Research · doi:10.1016/j.bbr.2010.07.015 · Cited by 104 · see citing works
Naturally Occurring Oxygen Heterocyclics. IX.1 Isolation and Characterization of Genipin2
Djerassi, C., GRAY, J. D., & Kincl, F. A. (1960) · The Journal of Organic Chemistry · doi:10.1021/jo01082a022 · Cited by 100 · see citing works
Terpenoids. XLVII.1 The Structure of Genipin2
Djerassi, C., Nakano, T., James, A., Zalkow, L. H., Eisenbraun, E. J., & Shoolery, J. Ν. (1961) · The Journal of Organic Chemistry · doi:10.1021/jo01063a052 · Cited by 95 · see citing works
Gibb, J., Hayley, S. P., Poulter, M. O., & Anisman, H. (2010) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2010.11.008 · Cited by 94 · see citing works
Antidepressant-like effect of genipin in mice
Tian, J., Cui, Y., Hu, L., Gao, S., Chi, W., Dong, T.-J., & Liu, L.-P. (2010) · Neuroscience Letters · doi:10.1016/j.neulet.2010.05.069 · Cited by 65 · see citing works
Yirmiya, R., Tio, D. L., & Taylor, A. N. (1996) · Brain Behavior and Immunity · doi:10.1006/brbi.1996.0019 · Cited by 48 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Potential role of genipin in cancer therapy
Shanmugam, M. K., Shen, H., Tang, F. R., Arfuso, F., Rajesh, M., Wang, L., Kumar, A. P., Bian, J., Goh, B. C., Bishayee, A., et al. (2018) · Pharmacological Research · doi:10.1016/j.phrs.2018.05.007 · Cited by 138 · see citing works
Hu, P., Lü, Y., Pan, B., & Zhang, W. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms231911076 · Cited by 134 · see citing works
Ding, Y., Zheng, Y., Huang, J., Peng, W., Chen, X., Kang, X., & Zeng, Q. (2019) · International Immunopharmacology · doi:10.1016/j.intimp.2019.03.043 · Cited by 82 · see citing works
Piccialli, I., Tedeschi, V., Caputo, L., D’Errico, S., Ciccone, R., De Feo, V., Secondo, A., & Pannaccione, A. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.876614 · Cited by 73 · see citing works
Zheng, M., Li, K., Chen, T., Liu, S., & He, L. (2021) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2021.02.008 · Cited by 60 · see citing works
Mitochondrial uncoupling protein 2 and pancreatic cancer: A new potential target therapy
Donadelli, M., Dando, I., Pozza, E. D., & Palmieri, M. (2015) · World Journal of Gastroenterology · doi:10.3748/wjg.v21.i11.3232 · Cited by 45 · see citing works
Phatak, R. S. (2015) · Pharmacognosy Journal · doi:10.5530/pj.2015.5.1 · Cited by 44 · see citing works
Genipin Inhibits LPS-Induced Inflammatory Response in BV2 Microglial Cells
Wang, J., Chen, L., Liang, Z., Li, Y., Yuan, F., Liu, J., Tian, Y., Hao, Z., Zhou, F., Liu, X., et al. (2017) · Neurochemical Research · doi:10.1007/s11064-017-2289-6 · Cited by 44 · see citing works
Therapeutic Potential of Genipin in Central Neurodegenerative Diseases
Li, Y., Li, L., & Hölscher, C. (2016) · CNS Drugs · doi:10.1007/s40263-016-0369-9 · Cited by 43 · see citing works
Spermine protects from LPS-induced memory deficit via BDNF and TrkB activation
Frühauf-Perez, P. K., Temp, F. R., Pillat, M. M., Signor, C., Wendel, A. L., Ulrich, H., Mello, C. F., & Rubin, M. A. (2018) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2018.02.012 · Cited by 43 · see citing works
Fodor, A., Kovács, K., Balázsfi, D., Klausz, B., Pintér, O., Demeter, K., Daviu, N., Rabasa, C., Rotllant, D., Nadal, R. A., et al. (2016) · Physiology & Behavior · doi:10.1016/j.physbeh.2016.02.041 · Cited by 38 · see citing works
Genipin alleviates LPS-induced acute lung injury by inhibiting NF-κB and NLRP3 signaling pathways
Zhang, A., Wang, S., Zhang, J., & Wu, H. M. (2016) · International Immunopharmacology · doi:10.1016/j.intimp.2016.05.011 · Cited by 32 · see citing works
Chen, J., Shi, B., Xiang, H., Hou, W.-J., Qin, X., Tian, J., & Du, G. (2015) · Journal of Pharmaceutical and Biomedical Analysis · doi:10.1016/j.jpba.2015.07.002 · Cited by 32 · see citing works
Liu, D., Wang, Q., Li, Y., Yuan, Z., Liu, Z., Guo, J., Li, X., Zhang, W., Tao, Y., & Mei, J. (2023) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2023.1167312 · Cited by 30 · see citing works
Wang, Q., Wang, J., Hu, M., Yu, Y. W., Guo, L., Xu, J., Lei, C., Jiao, Y., & Xu, J. (2016) · Mediators of Inflammation · doi:10.1155/2016/9154230 · Cited by 26 · see citing works
Araki, R., Hiraki, Y., Nishida, S., Inatomi, Y., & Yabe, T. (2016) · Journal of Pharmacological Sciences · doi:10.1016/j.jphs.2016.09.004 · Cited by 25 · see citing works
Jaafar, A., Zulkipli, M. A., Hatta, F. H. M., Jahidin, A. H., Nasir, N. A. A., & Hasan, M. H. (2023) · Saudi Pharmaceutical Journal · doi:10.1016/j.jsps.2023.101876 · Cited by 24 · see citing works
Genipin inhibits allergic responses in ovalbumin-induced asthmatic mice
Ko, J., Shin, N., Park, S.-H., Cho, Y.-K., Kim, J.-C., Seo, C., & Shin, I. (2017) · International Immunopharmacology · doi:10.1016/j.intimp.2017.10.010 · Cited by 24 · see citing works
Rosado-Ramos, R., Poças, G. M., Marques, D., Foito, A., Sevillano, D. M., Lopes‐da‐Silva, M., Gonçalves, L. G., Menezes, R., Ottens, M., Stewart, D., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-37561-2 · Cited by 23 · see citing works
Morland, R., Novejarque, A., Spicer, C., Pheby, T., & Rice, A. S. C. (2016) · European Journal of Pain · doi:10.1002/ejp.839 · Cited by 19 · see citing works
Zuo, T., Xu, W., Li, H., Song, H., & Zhu, M. (2017) · Medicinal Chemistry Research · doi:10.1007/s00044-016-1765-x · Cited by 18 · see citing works
Yu, X., Wang, Y., Tao, S., & Sun, S. (2019) · Experimental and Molecular Pathology · doi:10.1016/j.yexmp.2019.104349 · Cited by 16 · see citing works
RetractedFinger release sequence for fastball and curveball pitches.
Stevenson, J. M. (1985) · PubMed · Cited by 16 · see citing works
Araki, R., Nishida, S., Hiraki, Y., Li, F., Matsumoto, K., & Yabe, T. (2016) · Biological and Pharmaceutical Bulletin · doi:10.1248/bpb.b15-00707 · Cited by 13 · see citing works
Nishida, S., Araki, R., Baba, A., Asari, S., Tachibana, S., Nakajima, Y., Iwakumo, A., & Yabe, T. (2020) · Journal of Pharmacological Sciences · doi:10.1016/j.jphs.2020.02.007 · Cited by 11 · see citing works
Wu, Z., Yin, Y., Liu, R., Li, X., Wang, Z., Wu, C., Tan, J., Fu, Z., Song, C., Wong, N. L., et al. (2024) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2024.119031 · Cited by 8 · see citing works
A scientific data-driven review of natural product genipin for disease therapy
Xu, D. W., Qiao, T., Gao, K., Zhao, M., Zhang, W., Tao, X., & Wang, J. (2025) · Phytochemistry Reviews · doi:10.1007/s11101-024-10041-1 · Cited by 5 · see citing works
Araki, R., Fujiwara, H., Matsumoto, K., Toume, K., & Yabe, T. (2018) · Traditional & Kampo Medicine · doi:10.1002/tkm2.1198 · Cited by 5 · see citing works
Wu, X., Wu, W., Teng, Y., Yang, D., & Yang, H. (2026) · British Journal of Pharmacology · doi:10.1111/bph.70341 · Cited by 4 · see citing works
RetractedGenipin Activates Autophagy and Promotes Myoblast Differentiation by Activating AMPK Pathway
Li, J., Xie, L., Dou, Z., Zhou, Y., Mo, J., & Chen, W. (2024) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.3c06638 · Cited by 1 · see citing works
Dai, P., Chen, Y., Wei, Y., Yin, W., & Chen, C. (2024) · Research Square · doi:10.21203/rs.3.rs-3942015/v1
Wang, S., Zhao, Y. P., Pan, J., Zhang, D., Wang, A., & Ma, K. (2025) · Psychopharmacology · doi:10.1007/s00213-025-06978-6
- Authors
- Araki, R., Hiraki, Y., & Yabe, T.
- Affiliations
- Setsunan University (JP)
- Corresponding author
- Araki, Ryota
- Yabe, Takeshi
- Venue
- European Journal of Pharmacology
- Publisher
- Elsevier BV
- Published
- 2014-10
- Volume
- 741
- Pages
- 1-7
- ISSN
- 0014-2999 (ISSN-L)
- OpenAlex
- W1993187317
- Cited by
- 32
- References
- 27
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 3 · 2023: 3 · 2022: 2 · 2021: 1 · 2020: 1 · 2019: 2 · 2018: 3 · 2017: 3 · 2016: 7 · 2015: 3
- FWCI
- 1.33
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- European Journal of Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- genipin, lipopolysaccharide, sickness behavior, inflammation, depression-like behavior, social behavior deficits, hypothalamic paraventricular nucleus, central amygdala, neuroinflammation, inducible nitric oxide synthase, cyclooxygenase-2, IL-1β, interleukin-6, c-fos, BV-2 cells, Gardenia jasminoides, iridoid glycosides
- MeSH terms
- Animals, Cell Line, Cell Survival, Emotions, Lipopolysaccharides, Male, Paraventricular Hypothalamic Nucleus, Rubiaceae, Iridoids, Mice, Illness Behavior, Central Amygdaloid Nucleus
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
