Sodium Butyrate and Mood Stabilizers Block Ouabain-Induced Hyperlocomotion and Increase BDNF, NGF and GDNF Levels in Brain of Wistar Rats
Abstract
Bipolar Disorder (BD) is one of the most severe psychiatric disorders. Despite adequate treatment, patients continue to have recurrent mood episodes, residual symptoms, and functional impairment. Some preclinical studies have shown that histone deacetylase inhibitors may act on manic-like behaviors. Neurotrophins have been considered important mediators in the pathophysiology of BD. The present study aims to investigate the effects of lithium (Li), valproate (VPA), and sodium butyrate (SB), an HDAC inhibitor, on BDNF, NGF and GDNF in the brain of rats subjected to an animal model of mania induced by ouabain. Wistar rats received a single ICV injection of ouabain or artificial cerebrospinal fluid. From the day following ICV injection, the rats were treated for 6 days with intraperitoneal injections of saline, Li, VPA or SB twice a day. In the 7th day after ouabain injection, locomotor activity was measured using the open-field test. The BDNF, NGF and GDNF levels were measured in the hippocampus and frontal cortex by sandwich-ELISA. Li, VPA or SB treatments reversed ouabain-related manic-like behavior. Ouabain decreased BDNF, NGF and GDNF levels in hippocampus and frontal cortex of rats. The treatment with Li, VPA or SB reversed these impairment induced by ouabain. In addition, Li, VPA and SB per se increased NGF and GDNF levels in hippocampus of rats. Our data support the notion that neurotrophic factors play a role in BD and in the mechanisms of the action of Li, VPA and SB.
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SCFAs modulate neurotrophic factors such as NGF, GDNF, and BDNF, which regulate the growth, survival and differentiation of neurons and synapses in the CNS and play important parts in learning and memory and in a range of brain disorders.
“Neurotrophic factors, such as nerve growth factor (NGF), glial cell line-derived neurotrophic factor (GDNF), and BDNF that regulate the growth, survival and differentiation of neurons and synapses in the CNS also play important parts in learning and memory and in a range of brain disorders have been also shown to be modulated by SCFAs (120–123).”
From The Role of Short-Chain Fatty Acids From Gut Microbiota in Gut-Brain Communication (2020) · cites this paper as [121]
SCFAs influence neuroplasticity and neurogenesis by modulating neurotrophic factors including BDNF, NGF, and GDNF.
“SCFAs additionally influence neuroplasticity and neurogenesis by modulating neurotrophic factors, including brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and glial cell line-derived neurotrophic factor (GDNF) [149,150].”
From Unraveling the Connections: Eating Issues, Microbiome, and Gastrointestinal Symptoms in Autism Spectrum Disorder (2025) · cites this paper as [149]
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Dalile, B., Van Oudenhove, L., Vervliet, B., & Verbeke, K. (2019) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-019-0157-3 · Cited by 3,357 · see citing works
The Role of Short-Chain Fatty Acids From Gut Microbiota in Gut-Brain Communication
Silva, Y. P., Bernardi, A., & Frozza, R. L. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.00025 · Cited by 3,043 · see citing works
Butyrate, neuroepigenetics and the gut microbiome: Can a high fiber diet improve brain health?
Bourassa, M. W., Alim, I., Bultman, S. J., & Ratan, R. R. (2016) · Neuroscience Letters · doi:10.1016/j.neulet.2016.02.009 · Cited by 636 · see citing works
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The Role of Gut Bacterial Metabolites in Brain Development, Aging and Disease
Tran, S. M.-S., & Mohajeri, M. H. (2021) · Nutrients · doi:10.3390/nu13030732 · Cited by 207 · see citing works
Chidambaram, S. B., Essa, M. M., Rathipriya, A. G., Bishir, M., Ray, B., Mahalakshmi, A. M., Tousif, A. H., Sakharkar, M. K., Kashyap, R. S., Friedland, R. P., et al. (2022) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2021.107988 · Cited by 204 · see citing works
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Gut microbiome, cognitive function and brain structure: a multi-omics integration analysis
Liang, X., Fu, Y., Cao, W., Wang, Z., Zhang, K., Jiang, Z., Jia, X., Liu, C., Lin, H.-R., Zhong, H., et al. (2022) · Translational Neurodegeneration · doi:10.1186/s40035-022-00323-z · Cited by 188 · see citing works
Bojović, K., Ignjatović, Đ., Bajić, S. S., Milutinović, D. V., Tomić, M., Golić, N., & Tolinački, M. (2020) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2020.00223 · Cited by 169 · see citing works
Li, H., Sun, J., Wang, F., Ding, G., Chen, W., Fang, R., Yao, Y., Pang, M., Lu, Z.-Q., & Liu, J. (2016) · Brain Research · doi:10.1016/j.brainres.2016.03.031 · Cited by 152 · see citing works
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Li, N., Tan, S., Wang, Y., Deng, J., Wang, N., Zhu, S., Tian, W., Xu, J., & Wang, Q. (2023) · Gut Microbes · doi:10.1080/19490976.2023.2252764 · Cited by 117 · see citing works
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Multiple roles of short-chain fatty acids in Alzheimer disease
Chen, H., Meng, L., & Shen, L. (2021) · Nutrition · doi:10.1016/j.nut.2021.111499 · Cited by 107 · see citing works
Jaworska, J., Zalewska, T., Sypecka, J., & Ziemka‐Nałęcz, M. (2019) · Molecular Neurobiology · doi:10.1007/s12035-019-1518-1 · Cited by 94 · see citing works
Gut-brain axis: Focus on gut metabolites short-chain fatty acids
Guo, C., Huo, Y., Li, Y., Han, Y., & Zhou, D. (2022) · World Journal of Clinical Cases · doi:10.12998/wjcc.v10.i6.1754 · Cited by 95 · see citing works
Brain modulation by the gut microbiota: From disease to therapy
Mitra, S., Dash, R., Nishan, A. A., Habiba, S. U., & Moon, I. S. (2023) · Journal of Advanced Research · doi:10.1016/j.jare.2022.12.001 · Cited by 87 · see citing works
The microbiota-gut-brain axis: Focus on the fundamental communication pathways
Bistoletti, M., Bosi, A., Banfi, D., Giaroni, C., & Baj, A. (2020) · Progress in molecular biology and translational science · doi:10.1016/bs.pmbts.2020.08.012 · Cited by 88 · see citing works
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Messengers From the Gut: Gut Microbiota-Derived Metabolites on Host Regulation
Li, C., Liang, Y., & Qiao, Y. (2022) · Frontiers in Microbiology · doi:10.3389/fmicb.2022.863407 · Cited by 86 · see citing works
Duan, W.-X., Wang, F., Liu, J., & Liu, C. (2023) · Neuroscience Bulletin · doi:10.1007/s12264-023-01123-9 · Cited by 78 · see citing works
The Role of the Human Microbiome in the Pathogenesis of Pain
Ustianowska, K., Ustianowski, Ł., Machaj, F., Gorący, A., Rosik, J., Szostak, B., Szostak, J., & Pawlik, A. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232113267 · Cited by 75 · see citing works
Na+, K+-ATPase Signaling and Bipolar Disorder
Lichtstein, D., Ilani, A., Rosen, H., Horesh, N., Singh, S. V., Buzaglo, N., & Hodes, A. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19082314 · Cited by 68 · see citing works
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Gut microbiota and neuropsychiatric disorders: Implications for neuroendocrine-immune regulation
Ge, T., Yao, X., Zhao, H., Yang, W., Zou, X., Peng, F., Li, B., & Cui, R. (2021) · Pharmacological Research · doi:10.1016/j.phrs.2021.105909 · Cited by 62 · see citing works
Major Depressive Disorder and Gut Microbiota: Role of Physical Exercise
de Souza, P. B., Borba, L. A., de Jesus, L. C., Valverde, A. P., Gil‐Mohapel, J., & Rodrigues, A. L. S. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms242316870 · Cited by 65 · see citing works
Exploring the microbiota-gut-brain axis: impact on brain structure and function
Yassin, L. K., Nakhal, M. M., Alderei, A., Almehairbi, A., Mydeen, A. B., Akour, A. A., & Hamad, M. I. K. (2025) · Frontiers in Neuroanatomy · doi:10.3389/fnana.2025.1504065 · Cited by 60 · see citing works
Gut microbiota-derived short chain fatty acids act as mediators of the gut-liver-brain axis
Li, C., Yao, J., Yang, C., Yu, S., Yang, Z., Wang, L., Li, S., & He, N. (2025) · Metabolic Brain Disease · doi:10.1007/s11011-025-01554-5 · Cited by 56 · see citing works
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Tsybko, A. S., Ilchibaeva, T. V., & Popova, N. K. (2017) · Reviews in the Neurosciences · doi:10.1515/revneuro-2016-0063 · Cited by 46 · see citing works
Microbiota and Pain: Save Your Gut Feeling
Morreale, C., Bresesti, I., Bosi, A., Baj, A., Giaroni, C., Agosti, M. A., & Salvatore, S. (2022) · Cells · doi:10.3390/cells11060971 · Cited by 44 · see citing works
Zhang, Q., Zhao, W., Hou, Y., Song, X., Yu, H., Tan, J., Zhou, Y., & Zhang, H. (2023) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.14132 · Cited by 40 · see citing works
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Garcez, M. L., de Carvalho, C. A., Mina, F., Bellettini-Santos, T., Schiavo, G. L., da Silva, S., Campos, A. C. B. F., Varela, R. B., Valvassori, S. S., Damiani, A. P., et al. (2018) · Experimental Gerontology · doi:10.1016/j.exger.2018.10.005 · Cited by 41 · see citing works
Abbasi, N., Mirabzadeh, Y., Khesali, G., Ebrahimkhani, Z., Karimi, H., & Vaseghi, S. (2024) · Psychopharmacology · doi:10.1007/s00213-024-06566-0 · Cited by 41 · see citing works
Gut-brain axis: gut dysbiosis and psychiatric disorders in Alzheimer’s and Parkinson’s disease
Denman, C. R., Park, S. M., & Jo, J. (2023) · Frontiers in Neuroscience · doi:10.3389/fnins.2023.1268419 · Cited by 43 · see citing works
Martínez-Levy, G. A., Rocha, L., Rodríguez-Pineda, F., Alonso-Vanegas, M. A., Nani, A., Buentello-García, R. M., Briones-Velasco, M., San-Juan, D., Cienfuegos, J., & Cruz-Fuentes, C. S. (2017) · Molecular Neurobiology · doi:10.1007/s12035-017-0597-0 · Cited by 37 · see citing works
Lan, Z., Tang, X., Lu, M., Hu, Z., & Tang, Z. (2024) · Heliyon · doi:10.1016/j.heliyon.2024.e26377 · Cited by 39 · see citing works
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Epigenetic Mechanisms in Psychiatric Diseases and Epigenetic Therapy
Karslı-Çeppioğlu, S. (2016) · Drug Development Research · doi:10.1002/ddr.21340 · Cited by 30 · see citing works
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Kucharczyk, M. W., Kurek, A., Detka, J., Ślusarczyk, J., Papp, M., Tota-Glowczyk, K., Basta‐Kaim, A., Kubera, M., Lasoń, W., & Budziszewska, B. (2015) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2015.12.019 · Cited by 29 · see citing works
Cognition and gut microbiota in schizophrenia spectrum and mood disorders: A systematic review
Frileux, S., Boltri, M., Dore, J. M., Leboyer, M., & Roux, P. (2024) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2024.105722 · Cited by 27 · see citing works
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Tomaszek, N., Urbaniak, A. D., Bałdyga, D., Chwesiuk, K., Modzelewski, S., & Waszkiewicz, N. (2025) · Nutrients · doi:10.3390/nu17030486 · Cited by 30 · see citing works
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Potential Therapeutic Effects of Short-Chain Fatty Acids on Chronic Pain
Tang, Y., Du, J., Wu, H., Wang, M., Liu, S., & Tao, F. (2022) · Current Neuropharmacology · doi:10.2174/1570159x20666220927092016 · Cited by 26 · see citing works
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Possible Roles of Cyclic Meditation in Regulation of the Gut-Brain Axis
Ningthoujam, D. S., Singh, N., & Mukherjee, S. (2021) · Frontiers in Psychology · doi:10.3389/fpsyg.2021.768031 · Cited by 24 · see citing works
Inhibition of GSK-3β on Behavioral Changes and Oxidative Stress in an Animal Model of Mania
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Probiotics for Preventing Cognitive Impairment in Alzheimer’s Disease
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Butyrate: a key mediator of gut-brain communication in Alzheimer’s disease
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Preventing epigenetic traces of caregiver maltreatment: A role for HDAC inhibition
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Role of short chain fatty acids on astrocytes and microglia in Alzheimer's disease brain
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Probiotics in Postoperative Pain Management
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Implications of Gut-Brain axis in the pathogenesis of Psychiatric disorders
Taniguchi, K., Ikeda, Y., Nagase, N., Tsuji, A., Kitagishi, Y., & Matsuda, S. (2021) · AIMS bioengineering · doi:10.3934/bioeng.2021021 · Cited by 12 · see citing works
Genomics as a Clinical Decision Support Tool: Successful Proof of Concept for Improved ASD Outcomes
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Role of gut microbiota in the GBR12909 model of mania-like behavior in mice
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Therapeutic Potential of Sodium Butyrate in Neurological and Psychiatric Disorders
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Epigenetic Drugs for Mood Disorders
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Na,K-ATPase mediated and cardiotonic induced signaling in health and disease
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Animal Models of Mania: Essential Tools to Better Understand Bipolar Disorder
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Docosahexaenoic acid supplementation and infant brain development: role of gut microbiome
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Consequences of the Lack of TNFR1 in Ouabain Response in the Hippocampus of C57BL/6J Mice
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Epigenetics and Gut Microbiota in the Pathogenesis and Treatment of Bipolar Disorder (BD)
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Role of the Intestinal Microbiota in the Molecular Pathogenesis of Atypical Parkinsonian Syndromes
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Barros, H. D. D. F. Q., Casagrande, B. P., Araújo, D. D., Mutran, T. A. J., Telles, M. M., Estadella, D., & Pisani, L. P. (2026) · Reviews in Endocrine and Metabolic Disorders · doi:10.1007/s11154-026-10038-5 · Cited by 2 · see citing works
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The Gut Microbiota and NDG: What Is the Interplay
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PREBIOTICS FOR ACUTE ISCHEMIC STROKE
Renamastika, S. N., Wahyuningrum, D. R., PUTRI, V. A., & Aisy, R. (2021) · International Journal of Pharmacy and Pharmaceutical Sciences · doi:10.22159/ijpps.2021v13i5.41110 · Cited by 1 · see citing works
- Authors
- Varela, R. B., Valvassori, S. S., Lopes-Borges, J., Mariot, E., Dal-Pont, G. C., Amboni, R. T., Bianchini, G., & Quevedo, J.
- Affiliations
- Universidade do Extremo Sul Catarinense (BR)
- Venue
- Journal of Psychiatric Research
- Publisher
- Elsevier BV
- Published
- 2015-02
- Volume
- 61
- Pages
- 114-121
- ISSN
- 0022-3956 (ISSN-L)
- OpenAlex
- W2068078801
- Cited by
- 115
- References
- 90
- Citations by year
- 2026: 7 · 2025: 16 · 2024: 12 · 2023: 12 · 2022: 12 · 2021: 13 · 2020: 9 · 2019: 9 · 2018: 8 · 2017: 6 · 2016: 8 · 2015: 3
- FWCI
- 4.33
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Psychiatric Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Fundação de Amparo à Pesquisa e Inovação do Estado de Santa Catarina
- Conselho Nacional de Desenvolvimento Científico e Tecnológico
- Universidade do Extremo Sul Catarinense
- Instituto Mente e Cérebro - Neurociência
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Bipolar Disorder and Treatment
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Keywords
- sodium butyrate, histone deacetylase inhibitors, bipolar disorder, mania, ouabain, hyperlocomotion, lithium, valproic acid, brain-derived neurotrophic factor, nerve growth factor, glial cell line-derived neurotrophic factor, neurotrophic factors, hippocampus, frontal cortex, mood stabilizers
- MeSH terms
- Affect, Animals, Bipolar Disorder, Disease Models, Animal, Hippocampus, Histamine Antagonists, Locomotion, Male, Motor Activity, Ouabain, Valproic Acid, Treatment Outcome, Rats, Wistar, Prefrontal Cortex, Lithium Compounds, Antimanic Agents, Brain-Derived Neurotrophic Factor, Butyric Acid, Nerve Growth Factor, Glial Cell Line-Derived Neurotrophic Factor, Rats
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