Depression is a common disease that afflicts one in 6 people. Numerous hypotheses have been raised in the past decades, but the exact mechanism for depression onset remains obscure. Recently, the neuroinflammatory response and oxidative stress are being attracted more and more attention due to their roles in depression pathogenesis. The inhibition of neuroinflammatory response and oxidative stress is now considered a potential strategy for depression prevention and/or therapy. Sodium butyrate (SB) is a sodium form of the endogenous butyrate. It can inhibit proinflammatory responses and oxidative stress in different models of disease. In the present study, we investigated the effect of SB on lipopolysaccharide (LPS)-induced depression-like behaviors, neuroinflammatory response, and oxido-nitrosative stress in the hippocampus and prefrontal cortex in C57BL6/J mice. Our results showed that 10 days of SB pretreatment at the dose of 300 but not 100 mg/kg markedly ameliorated LPS (0.83 mg/kg)-induced depression-like behaviors in the tail suspension test, forced swimming test, and sucrose preference test. Further analysis showed that 10 days of SB pretreatment not only prevented LPS-induced increases in proinflammatory cytokines, such as interleukin (IL)-1β, IL-6, and tumor necrosis factor-α, in the hippocampus and prefrontal cortex but also prevented LPS-induced enhancement of oxido-nitrosative stress. Taken together, these results demonstrate that SB is such an agent that could be used to prevent depression onset and/or progression, and inhibition of neuroinflammatory response and oxido-nitrosative stress may be a potential mechanism for its antidepressant actions.

Keywords:
Sodium butyrate, Depression, Neuroinflammation, Oxidative stress, Lipopolysaccharide
1.
Malinow R. Depression: ketamine steps out of the darkness.
Nature
. 2016 May;533(7604):477–8.
2.
Heim C, Binder EB. Current research trends in early life stress and depression: review of human studies on sensitive periods, gene-environment interactions, and epigenetics.
Exp Neurol
. 2012 Jan;233(1):102–11.
3.
Davis L, Uezato A, Newell JM, Frazier E. Major depression and comorbid substance use disorders.
Curr Opin Psychiatry
. 2008 Jan;21(1):14–8.
4.
Trevizan FB, Miyazaki MC, Silva YL, Roque CM. Quality of life, depression, anxiety and coping strategies after heart transplantation.
Rev Bras Cir Cardiovasc
. 2017 May-Jun;32(3):162–70.
5.
Zhang MW, Zhang SF, Li ZH, Han F. 7,8-Dihydroxyflavone reverses the depressive symptoms in mouse chronic mild stress.
Neurosci Lett
. 2016 Dec;635:33–8.
6.
Liu F, Wu J, Gong Y, Wang P, Zhu L, Tong L, et al. Harmine produces antidepressant-like effects via restoration of astrocytic functions.
Prog Neuropsychopharmacol Biol Psychiatry
. 2017 Oct;79 Pt B:258–67.
7.
Clevenger SS, Malhotra D, Dang J, Vanle B, IsHak WW. The role of selective serotonin reuptake inhibitors in preventing relapse of major depressive disorder.
Ther Adv Psychopharmacol
. 2018 Jan;8(1):49–58.
8.
Gibiino S, Serretti A. Paroxetine for the treatment of depression: a critical update.
Expert Opin Pharmacother
. 2012 Feb;13(3):421–31.
9.
Fabbri, C, Marsano A, Balestri M, De Ronchi D, Serretti A. Clinical features and drug induced side effects in early versus late antidepressant responders.
J Psychiatr Res
. 2013 Oct;47(10):1309–18.
10.
Chen Z, Huang C, He H, Ding W. 2, 3, 5, 4′-Tetrahydroxystilbene-2-O-β-D-glucoside prevention of lipopolysaccharide-induced depressive-like behaviors in mice involves neuroinflammation and oxido-nitrosative stress inhibition.
Behav Pharmacol
. 2017 Aug;28(5):365–74.
11.
Yang R, Wang P, Chen Z, Hu W, Gong Y, Zhang W, et al. WY-14643, a selective agonist of peroxisome proliferator-activated receptor-α, ameliorates lipopolysaccharide-induced depressive-like behaviors by preventing neuroinflammation and oxido-nitrosative stress in mice.
Pharmacol Biochem Behav
. 2017 Feb;153:97–104.
12.
Huang C, Wang P, Xu X, Zhang Y, Gong Y, Hu W, et al. The ketone body metabolite β-hydroxybutyrate induces an antidepression-associated ramification of microglia via HDACs inhibition-triggered Akt-small RhoGTPase activation.
Glia
. 2018 Feb;66(2):256–78.
13.
Kopschina Feltes P, Doorduin J, Klein HC, Juárez-Orozco LE, Dierckx RA, Moriguchi-Jeckel CM, et al. Anti-inflammatory treatment for major depressive disorder: implications for patients with an elevated immune profile and non-responders to standard antidepressant therapy.
J Psychopharmacol
. 2017 Sep;31(9):1149–65.
14.
Kaufmann FN, Costa AP, Ghisleni G, Diaz AP, Rodrigues AL, Peluffo H, et al. NLRP3 inflammasome-driven pathways in depression: clinical and preclinical findings.
Brain Behav Immun
. 2017 Aug;64:367–83.
15.
Kv A, Madhana RM, Js IC, Lahkar M, Sinha S, Naidu VG. Antidepressant activity of vorinostat is associated with amelioration of oxidative stress and inflammation in a corticosterone-induced chronic stress model in mice.
Behav Brain Res
. 2018 May;344:73–84.
16.
Lu X, Yang RR, Zhang JL, Wang P, Gong Y, Hu WF, et al. Tauroursodeoxycholic acid produces antidepressant-like effects in a chronic unpredictable stress model of depression via attenuation of neuroinflammation, oxido-nitrosative stress, and endoplasmic reticulum stress.
Fundam Clin Pharmacol
. 2018 Aug;32(4):363–77.
17.
Valvassori SS, Bavaresco DV, Feier G, Cechinel-Recco K, Steckert AV, Varela RB, et al. Increased oxidative stress in the mitochondria isolated from lymphocytes of bipolar disorder patients during depressive episodes.
Psychiatry Res
. 2018 Jun;264:192–201.
18.
van Velzen LS, Wijdeveld M, Black CN, van Tol MJ, van der Wee NJ, Veltman DJ, et al. Oxidative stress and brain morphology in individuals with depression, anxiety and healthy controls.
Prog Neuropsychopharmacol Biol Psychiatry
. 2017 Jun;76:140–4.
19.
Hepgul N, Cattaneo A, Agarwal K, Baraldi S, Borsini A, Bufalino C, et al. Transcriptomics in interferon-α-treated patients identifies inflammation-, neuroplasticity- and oxidative stress-related signatures as predictors and correlates of depression.
Neuropsychopharmacology
. 2016 Sep;41(10):2502–11.
20.
Canbeyli R. Sensorimotor modulation of mood and depression: an integrative review.
Behav Brain Res
. 2010 Mar;207(2):249–64.
21.
Lucassen PJ, Pruessner J, Sousa N, Almeida OF, Van Dam AM, Rajkowska G, et al. Neuropathology of stress.
Acta Neuropathol
. 2014 Jan;127(1):109–35.
22.
Cheng L, Huang C, Chen Z. Tauroursodeoxycholic acid ameliorates lipopolysaccharide-induced depression like behavior in Mice via the inhibition of neuroinflammation and oxido-nitrosative stress.
Pharmacology
. 2019;103(1-2):93–100.
23.
Bourassa MW, Alim I, Bultman SJ, Ratan RR. Butyrate, neuroepigenetics and the gut microbiome: can a high fiber diet improve brain health?
Neurosci Lett
. 2016 Jun;625:56–63.
24.
Minamiyama M, Katsuno M, Adachi H, Waza M, Sang C, Kobayashi Y, et al. Sodium butyrate ameliorates phenotypic expression in a transgenic mouse model of spinal and bulbar muscular atrophy.
Hum Mol Genet
. 2004 Jun;13(11):1183–92.
25.
Lim S, Chesser AS, Grima JC, Rappold PM, Blum D, Przedborski S, et al. D-β-hydroxybutyrate is protective in mouse models of Huntington’s disease.
PLoS One
. 2011;6(9):e24620.
26.
Jaworska J, Ziemka-Nalecz M, Sypecka J, Zalewska T. The potential neuroprotective role of a histone deacetylase inhibitor, sodium butyrate, after neonatal hypoxia-ischemia.
J Neuroinflammation
. 2017 Feb;14(1):34.
27.
Park MJ, Sohrabji F. The histone deacetylase inhibitor, sodium butyrate, exhibits neuroprotective effects for ischemic stroke in middle-aged female rats.
J Neuroinflammation
. 2016 Dec;13(1):300.
28.
Patnala R, Arumugam TV, Gupta N, Dheen ST. HDAC Inhibitor sodium butyrate-mediated epigenetic regulation enhances neuroprotective function of microglia during ischemic stroke.
Mol Neurobiol
. 2017 Oct;54(8):6391–411.
29.
Valvassori SS, Dal-Pont GC, Steckert AV, Varela RB, Lopes-Borges J, Mariot E, et al. Sodium butyrate has an antimanic effect and protects the brain against oxidative stress in an animal model of mania induced by ouabain.
Psychiatry Res
. 2016 Jan;235:154–9.
30.
Yamawaki Y, Yoshioka N, Nozaki K, Ito H, Oda K, Harada K, et al. Sodium butyrate abolishes lipopolysaccharide-induced depression-like behaviors and hippocampal microglial activation in mice.
Brain Res
. 2018 Feb;1680:13–38.
31.
Wang P, Zhang Y, Gong Y, Yang R, Chen Z, Hu W, et al. Sodium butyrate triggers a functional elongation of microglial process via Akt-small RhoGTPase activation and HDACs inhibition.
Neurobiol Dis
. 2018 Mar;111:12–25.
32.
Liu FG, Hu WF, Wang JL, Wang P, Gong Y, Tong LJ, et al. Z-Guggulsterone produces antidepressant-like effects in mice through activation of the BDNF signaling pathway.
Int J Neuropsychopharmacol
. 2017 Jun;20(6):485–97.
33.
Jangra A, Datusalia AK, Khandwe S, Sharma SS. Amelioration of diabetes-induced neurobehavioral and neurochemical changes by melatonin and nicotinamide: implication of oxidative stress-PARP pathway.
Pharmacol Biochem Behav
. 2013 Dec;114-115:43–51.
34.
Sun J, Wang F, Hong G, Pang M, Xu H, Li H, et al. Antidepressant-like effects of sodium butyrate and its possible mechanisms of action in mice exposed to chronic unpredictable mild stress.
Neurosci Lett
. 2016 Apr;618:159–66.
35.
Maes M, Kubera M, Leunis JC. The gut-brain barrier in major depression: intestinal mucosal dysfunction with an increased translocation of LPS from gram negative enterobacteria (leaky gut) plays a role in the inflammatory pathophysiology of depression.
Neuro Endocrinol Lett
. 2008 Feb;29(1):117–24.
36.
Kelly JR, Borre Y, O’ Brien C, Patterson E, El Aidy S, Deane J, et al. Transferring the blues: depression-associated gut microbiota induces neurobehavioural changes in the rat.
J Psychiatr Res
. 2016 Nov;82:109–18.
37.
Draper A, Koch RM, van der Meer JW, Aj Apps M, Pickkers P, Husain M, et al. Effort but not reward sensitivity is altered by acute sickness induced by experimental endotoxemia in humans.
Neuropsychopharmacology
. 2018 Apr;43(5):1107–18.
38.
Sandiego CM, Gallezot JD, Pittman B, Nabulsi N, Lim K, Lin SF, et al. Imaging robust microglial activation after lipopolysaccharide administration in humans with PET.
Proc Natl Acad Sci USA
. 2015 Oct;112(40):12468–73.
39.
Singh V, Bhatia HS, Kumar A, de Oliveira AC, Fiebich BL. Histone deacetylase inhibitors valproic acid and sodium butyrate enhance prostaglandins release in lipopolysaccharide-activated primary microglia.
Neuroscience
. 2014 Apr;265:147–57.
40.
Kannan V, Brouwer N, Hanisch UK, Regen T, Eggen BJ, Boddeke HW. Histone deacetylase inhibitors suppress immune activation in primary mouse microglia.
J Neurosci Res
. 2013 Sep;91(9):1133–42.
41.
Steliou K, Boosalis MS, Perrine SP, Sangerman J, Faller DV. Butyrate histone deacetylase inhibitors.
Biores Open Access
. 2012 Aug;1(4):192–8.
42.
Monneret C. Histone deacetylase inhibitors.
Eur J Med Chem
. 2005 Jan;40(1):1–13.
43.
Kaisar MM, Pelgrom LR, van der Ham AJ, Yazdanbakhsh M, Everts B. Butyrate conditions human dendritic cells to prime type 1 regulatory T cells via both histone deacetylase inhibition and G protein-coupled receptor 109A signaling.
Front Immunol
. 2017 Oct;8:1429.
44.
Mokhtari-Zaer A, Hosseini M, Boskabady MH. The effects of exercise on depressive- and anxiety-like behaviors as well as lung and hippocampus oxidative stress in ovalbumin-sensitized juvenile rats.
Respir Physiol Neurobiol
. 2018 Jan;248:55–62.
45.
Zeni AL, Camargo A, Dalmagro AP. Ferulic acid reverses depression-like behavior and oxidative stress induced by chronic corticosterone treatment in mice.
Steroids
. 2017 Sep;125:131–6.
46.
Diniz BS, Mendes-Silva AP, Silva LB, Bertola L, Vieira MC, Ferreira JD, et al. Oxidative stress markers imbalance in late-life depression.
J Psychiatr Res
. 2018 Jul;102:29–33.
47.
Mouzaoui S, Rahim I, Djerdjouri B. Aminoguanidine and curcumin attenuated tumor necrosis factor (TNF)-α-induced oxidative stress, colitis and hepatotoxicity in mice.
Int Immunopharmacol
. 2012 Jan;12(1):302–11.
48.
Shimazu T, Hirschey MD, Newman J, He W, Shirakawa K, Le Moan N, et al. Suppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylase inhibitor.
Science
. 2013 Jan;339(6116):211–4.
49.
Dong W, Jia Y, Liu X, Zhang H, Li T, Huang W, et al. Sodium butyrate activates NRF2 to ameliorate diabetic nephropathy possibly via inhibition of HDAC.
J Endocrinol
. 2017 Jan;232(1):71–83.
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