Intravenous administration of sodium propionate induces antidepressant or prodepressant effect in a dose dependent manner
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Propionate has been reported to exert antidepressant effects, but high-dose propionate may induce autism-like symptoms in experimental animals through induction of dysbiosis of neurotransmitters. The bi-directional effects of propionate seem to be dose-dependent. However, due to the pathological discrepancies between depression and autism, conclusions drawn from autism may not be simply transferable to depression. The effect and underlying action mechanisms of high-dose propionate on depression remains undetermined. To investigate the effects of propionate on depression, propionate dose gradients were intravenously administrated to rats exposed to chronic unpredictable mild stress (CUMS) for 1 week. Results of these behavioral tests demonstrate that low-dose propionate (2 mg/kg body weight/day) induces antidepressant effect through bodyweight recovery, elevated reward-seeking behaviors, and reduced depression-like behaviors, while high-dose propionate (200 mg/kg body weight/day) induces prodepressant effects opposite of those of low-dose propionate. A comprehensive profiling of neurotransmitters in the hippocampus demonstrated that CUMS induces reduction of NE (Norepinephrine), DA (Dopamine). GABA (γ-aminobutyric acid) was recovered by low-dose propionate, while high-dose propionate exerted more complicated effects on neurotransmitters, including reduction of NE, DA, 5-Hydroxytryptamine and Tryptophan, and increase of GABA, Kynurenine, Homovanillic acid, 3-hydroxyanthranilic acid, 3-hydroxykynurenine, 3,4-dihydroxyphenylacetic acid, and 3-methoxytyramine. The neurotransmitters disturbed by high-dose propionate suggest metabolic disorders in the hippocampus, which were confirmed by the clear group separation in PCA of metabolomic profiling. The results of this study demonstrate the double-edged dose-dependent effects of propionate on depression and suggest potential cumulative toxicity of propionate as a food additive to mood disorders.
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Propionic acid promotes neuroregeneration through mechanisms involving free fatty acid receptor signaling and inhibition of class I/II histone deacetylase activity.
“Priopionic acid (PA) has been shown to promote neuroregeneration through mechanisms involving free fatty acid receptor signaling and the inhibition of class I/II histone deacetylase (HDAC) activity [54].”
From The Gut–Brain–Microbiota Connection and Its Role in Autism Spectrum Disorders (2025) · cites this paper as [54]
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McGuinness, A. J., Davis, J. A., Dawson, S. L., Loughman, A., Collier, F., O’Hely, M., Simpson, C. A., Green, J., Marx, W., Hair, C., et al. (2022) · Molecular Psychiatry · doi:10.1038/s41380-022-01456-3 · Cited by 502 · see citing works
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- Authors
- Hao, C., Gao, Z., Liu, X., Rong, Z., Jia, J., Kang, K., Guo, W., & Li, J.
- Affiliations
- Taiyuan University of Science and Technology (CN)
- Shanxi University (CN)
- Corresponding author
- Li, Jianguo
- Venue
- Scientific Reports
- Published
- 2020-11-16
- Volume
- 10
- Issue
- 1
- Pages
- 19917-19917
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC7670463
- OpenAlex
- W3098529305
- Cited by
- 43
- References
- 43
- Citations by year
- 2026: 5 · 2025: 12 · 2024: 11 · 2023: 11 · 2022: 4
- FWCI
- 2.25
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- the Shanxi Soft Science Research Program (2018041031-2)
- the Educational Reform Project of Taiyuan University of Science and Technology (ZL2019002)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- sodium propionate, antidepressant effects, dose-dependent effects, chronic unpredictable mild stress, depression, kynurenine pathway, food additive toxicity, autism-like symptoms, reward-seeking behavior
- MeSH terms
- Animals, Antidepressive Agents, Behavior, Animal, Depression, Disease Models, Animal, Dose-Response Relationship, Drug, Male, Propionates, Stress, Psychological, Rats, Sprague-Dawley, Rats, Administration, Intravenous
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