Skip to main content

Sodium Butyrate Prevents Memory Impairment by Re-establishing BDNF and GDNF Expression in Experimental Pneumococcal Meningitis


Pneumococcal meningitis is a serious infection of the central nervous system (CNS) with high fatality rates that causes reduced psychomotor performance, slight mental slowness, impairments in attention executive functions and learning and memory deficiencies. Previously, we demonstrated a correlation between memory impairment and decreased levels of brain-derived neurotropic factor (BDNF) in the hippocampi of rats subjected to pneumococcal meningitis. Emerging evidence demonstrates that histone acetylation regulates neurotrophins; therefore, a potential molecular intervention against cognitive impairment in bacterial meningitis may be the histone deacetylase (HDAC) inhibitor, sodium butyrate, which stimulates the acetylation of histones and increases BDNF expression. In this study, animals received either artificial cerebrospinal fluid as a placebo or a Streptococcus pneumoniae suspension at a concentration of 5 × 109 colony-forming units (CFU/mL). The animals received antibiotic treatment as usual and received saline or sodium butyrate as an adjuvant treatment. Ten days after, meningitis was induced; the animals were subjected to open-field habituation and the step-down inhibitory avoidance task. Immediately after these behavioural tasks, the animals were killed, and their hippocampi were removed to evaluate the expression of BDNF, nerve growth factor (NGF) and glial cell line-derived neurotrophic factor (GDNF). In the meningitis group that received saline, the animals presented memory impairment in both behavioural tasks, and hippocampal BDNF and GDNF expression was decreased. Sodium butyrate was able to prevent memory impairment and re-establish hippocampal neurotrophin expression in experimental pneumococcal meningitis.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3


  1. Hoogman M, van de Beek D, Weisfelt M, de Gans J, Schmand B (2007) Cognitive outcome in adults after bacterial meningitis. J Neurol Neurosurg Psychiatry 78(10):1092–1096

    Article  PubMed  PubMed Central  Google Scholar 

  2. Merkelbach S, Sittinger H, Schweizer I, Muller M (2000) Cognitive outcome after bacterial meningitis. Acta Neurol Scand 102(2):118–123

    CAS  Article  PubMed  Google Scholar 

  3. Schmidt H, Heimann B, Djukic M, Mazurek C, Fels C, Wallesch CW, Nau R (2006) Neuropsychological sequelae of bacterial and viral meningitis. Brain 129(2):333–345

    CAS  Article  PubMed  Google Scholar 

  4. Barichello T, Silva GZ, Generoso JS, Savi GD, Michelon CM, Feier G, Comim CM, Quevedo J (2010) Time-dependent behavioral recovery after pneumococcal meningitis in rats. J Neural Transm 117(7):819–826

    Article  PubMed  Google Scholar 

  5. Barichello T, Generoso JS, Milioli G, Elias SG, Teixeira AL (2013) Pathophysiology of bacterial infection of the central nervous system and its putative role in the pathogenesis of behavioral changes. Rev Bras Psiquiatr 35(1):81–87

    Article  PubMed  Google Scholar 

  6. Barichello T, Belarmino E Jr, Comim CM, Cipriano AL, Generoso JS, Savi GD, Stertz L, Kapczinski F, Quevedo J (2010) Correlation between behavioral deficits and decreased brain-derived neurotrophic [correction of neurotrofic] factor in neonatal meningitis. J Neuroimmunol 223(1–2):73–76

    CAS  Article  PubMed  Google Scholar 

  7. Li L, Shui QX, Liang K, Ren H (2007) Brain-derived neurotrophic factor rescues neurons from bacterial meningitis. Pediatr Neurol 36(5):324–329

    Article  PubMed  Google Scholar 

  8. Cunha C, Brambilla R, Thomas KL (2010) A simple role for BDNF in learning and memory? Front Mol Neurosci 3(1)

  9. Martinez-Levy GA, Cruz-Fuentes CS (2014) Genetic and epigenetic regulation of the brain-derived neurotrophic factor in the central nervous system. The Yale journal of biology and medicine 87(2):173–186

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Intlekofer KA, Berchtold NC, Malvaez M, Carlos AJ, McQuown SC, Cunningham MJ, Wood MA, Cotman CW (2013) Exercise and sodium butyrate transform a subthreshold learning event into long-term memory via a brain-derived neurotrophic factor-dependent mechanism. Neuropsychopharmacology 38(10):2027–2034

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. Calfa G, Chapleau CA, Campbell S, Inoue T, Morse SJ, Lubin FD, Pozzo-Miller L (2012) HDAC activity is required for BDNF to increase quantal neurotransmitter release and dendritic spine density in CA1 pyramidal neurons. Hippocampus 22(7):1493–1500

    CAS  Article  PubMed  Google Scholar 

  12. Wu X, Chen PS, Dallas S, Wilson B, Block ML, Wang CC, Kinyamu H, Lu N, Gao X, Leng Y, Chuang DM, Zhang W, Lu RB, Hong JS (2008) Histone deacetylase inhibitors up-regulate astrocyte GDNF and BDNF gene transcription and protect dopaminergic neurons. Int J Neuropsychopharmacol 11(8):1123–1134

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. Kim HJ, Chuang DM (2014) HDAC inhibitors mitigate ischemia-induced oligodendrocyte damage: potential roles of oligodendrogenesis, VEGF, and anti-inflammation. Am J Transl Res 6(3):206–223

    PubMed  PubMed Central  Google Scholar 

  14. 14. Yoo DY, Kim DW, Kim MJ, Choi JH, Jung HY, Nam SM, Kim JW, Yoon YS, Choi SY, Hwang IK (2014) Sodium butyrate, a histone deacetylase Inhibitor, ameliorates SIRT2-induced memory impairment, reduction of cell proliferation, and neuroblast differentiation in the dentate gyrus. Neurol Res. Epub ahead of print

  15. Barichello T, Generoso JS, Simoes LR, Elias SG, Tashiro MH, Dominguini D, Comim CM, Vilela MC, Teixeira AL, Quevedo J (2013) Inhibition of indoleamine 2,3-dioxygenase prevented cognitive impairment in adult Wistar rats subjected to pneumococcal meningitis. Transl Res 162(6):390–397

    CAS  Article  PubMed  Google Scholar 

  16. Barichello T, Simoes LR, Generoso JS, Sangiogo G, Danielski LG, Florentino D, Dominguini D, Comim CM, Petronilho F, Quevedo J (2013) Erythropoietin prevents cognitive impairment and oxidative parameters in Wistar rats subjected to pneumococcal meningitis. Transl Res 163(5):503–513

    Article  PubMed  Google Scholar 

  17. Arent CO, Valvassori SS, Fries GR, Stertz L, Ferreira CL, Lopes-Borges J, Mariot E, Varela RB, Ornell F, Kapczinski F, Andersen ML, Quevedo J (2011) Neuroanatomical profile of antimaniac effects of histone deacetylases inhibitors. Mol Neurobiol 43(3):207–214

    CAS  Article  PubMed  Google Scholar 

  18. Barichello T, Goncalves JC, Generoso JS, Milioli GL, Silvestre C, Costa CS, Coelho Jda R, Comim CM, Quevedo J (2013) Attenuation of cognitive impairment by the nonbacteriolytic antibiotic daptomycin in Wistar rats submitted to pneumococcal meningitis. BMC Neurosci 14(42):1471–2202

    Google Scholar 

  19. Vianna MR, Alonso M, Viola H, Quevedo J, de Paris F, Furman M, de Stein ML, Medina JH, Izquierdo I (2000) Role of hippocampal signaling pathways in long-term memory formation of a nonassociative learning task in the rat. Learn Mem 7(5):333–340

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. Quevedo J, Vianna M, Zanatta MS, Roesler R, Izquierdo I, Jerusalinsky D, Quillfeldt JA (1997) Involvement of mechanisms dependent on NMDA receptors, nitric oxide and protein kinase A in the hippocampus but not in the caudate nucleus in memory. Behav Pharmacol 8(8):713–717

    CAS  Article  PubMed  Google Scholar 

  21. Roesler R, Schroder N, Vianna MR, Quevedo J, Bromberg E, Kapczinski F, Ferreira MB (2003) Differential involvement of hippocampal and amygdalar NMDA receptors in contextual and aversive aspects of inhibitory avoidance memory in rats. Brain Res 975(1–2):207–213

    CAS  Article  PubMed  Google Scholar 

  22. Bevilaqua LR, Kerr DS, Medina JH, Izquierdo I, Cammarota M (2003) Inhibition of hippocampal Jun N-terminal kinase enhances short-term memory but blocks long-term memory formation and retrieval of an inhibitory avoidance task. Eur J Neurosci 17(4):897–902

    Article  PubMed  Google Scholar 

  23. Izquierdo I, Barros DM, e Souza MT, de Souza MM, Izquierdo IZ, Medina JH (1998) Mechanisms for memory types differ. Nature 393(6686):635–636

    CAS  Article  PubMed  Google Scholar 

  24. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193(1):265–275

    CAS  PubMed  Google Scholar 

  25. Frey BN, Andreazza AC, Cereser KM, Martins MR, Valvassori SS, Reus GZ, Quevedo J, Kapczinski F (2006) Effects of mood stabilizers on hippocampus BDNF levels in an animal model of mania. Life Sci 79(3):281–286

    CAS  Article  PubMed  Google Scholar 

  26. Allen SJ, Watson JJ, Shoemark DK, Barua NU, Patel NK (2013) GDNF, NGF and BDNF as therapeutic options for neurodegeneration. Pharmacol Ther 138(2):155–175

    CAS  Article  PubMed  Google Scholar 

  27. 27. Song X, Lian D, He D, Sun J, Zhu M, Li L (2014) The responsiveness of TrkB to exogenous BDNF in frontal cortex during antibiotic treatment of Streptococcus pneumoniae meningitis. Neurol Sci. Epub ahead of print

  28. Duarte EP, Curcio M, Canzoniero LM, Duarte CB (2012) Neuroprotection by GDNF in the ischemic brain. Growth Factors 30(4):242–257

    CAS  Article  PubMed  Google Scholar 

  29. Katsuragi S, Ikeda T, Ikenoue T (2011) A strategy to treat neonatal hypoxic encephalopathy using glial cell line-derived neurotrophic factor. No to hattatsu Brain and development 43(4):265–272

    PubMed  Google Scholar 

  30. Kim HJ, Leeds P, Chuang DM (2009) The HDAC inhibitor, sodium butyrate, stimulates neurogenesis in the ischemic brain. J Neurochem 110(4):1226–1240

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. Kim HJ, Rowe M, Ren M, Hong JS, Chen PS, Chuang DM (2007) Histone deacetylase inhibitors exhibit anti-inflammatory and neuroprotective effects in a rat permanent ischemic model of stroke: multiple mechanisms of action. J Pharmacol Exp Ther 321(3):892–901

    CAS  Article  PubMed  Google Scholar 

  32. Reolon GK, Maurmann N, Werenicz A, Garcia VA, Schroder N, Wood MA, Roesler R (2011) Posttraining systemic administration of the histone deacetylase inhibitor sodium butyrate ameliorates aging-related memory decline in rats. Behav Brain Res 221(1):329–332

    CAS  Article  PubMed  PubMed Central  Google Scholar 

Download references


The Laboratory of Experimental Microbiology and Laboratory of Neurosciences (Brazil) are centres of the National Institute for Translational Medicine (INCT-TM) and members of the Center of Excellence in Applied Neurosciences of Santa Catarina (NENASC). This research was supported by grants from CNPq (JQ and TB), FAPESC (JQ and TB), Instituto Cérebro e Mente (JQ and TB) and UNESC (JQ and TB). JQ and TB are CNPq Research Fellows. JSG and LRS are holders of a CAPES studentship.

Conflict of Interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Tatiana Barichello.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Barichello, T., Generoso, J.S., Simões, L.R. et al. Sodium Butyrate Prevents Memory Impairment by Re-establishing BDNF and GDNF Expression in Experimental Pneumococcal Meningitis. Mol Neurobiol 52, 734–740 (2015).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:


  • Pneumococcal meningitis
  • Sodium butyrate
  • BDNF
  • GDNF
  • NGF
  • Memory