Neurochemical Research

, Volume 40, Issue 11, pp 2333–2347 | Cite as

Sodium Benzoate, a Metabolite of Cinnamon and a Food Additive, Upregulates Ciliary Neurotrophic Factor in Astrocytes and Oligodendrocytes

  • Khushbu K. Modi
  • Malabendu Jana
  • Susanta Mondal
  • Kalipada PahanEmail author
Original Paper


Ciliary neurotrophic factor (CNTF) is a promyelinating trophic factor that plays an important role in multiple sclerosis (MS). However, mechanisms by which CNTF expression could be increased in the brain are poorly understood. Recently we have discovered anti-inflammatory and immunomodulatory activities of sodium benzoate (NaB), a metabolite of cinnamon and a widely-used food additive. Here, we delineate that NaB is also capable of increasing the mRNA and protein expression of CNTF in primary mouse astrocytes and oligodendrocytes and primary human astrocytes. Accordingly, oral administration of NaB and cinnamon led to the upregulation of astroglial and oligodendroglial CNTF in vivo in mouse brain. Induction of experimental allergic encephalomyelitis, an animal model of MS, reduced the level of CNTF in the brain, which was restored by oral administration of cinnamon. While investigating underlying mechanisms, we observed that NaB induced the activation of protein kinase A (PKA) and H-89, an inhibitor of PKA, abrogated NaB-induced expression of CNTF. The activation of cAMP response element binding (CREB) protein by NaB, the recruitment of CREB and CREB-binding protein to the CNTF promoter by NaB and the abrogation of NaB-induced expression of CNTF in astrocytes by siRNA knockdown of CREB suggest that NaB increases the expression of CNTF via the activation of CREB. These results highlight a novel myelinogenic property of NaB and cinnamon, which may be of benefit for MS and other demyelinating disorders.


Sodium benzoate CNTF Astrocytes Oligodendrocytes PKA CREB 



This study was supported by National Institutes of Health Grant (AT6681) and Veteran Affairs Merit Award (I01BX002174).


  1. 1.
    Varon S, Manthorpe M, Adler R (1979) Cholinergic neuronotrophic factors: I. Survival, neurite outgrowth and choline acetyltransferase activity in monolayer cultures from chick embryo ciliary ganglia. Brain Res 173:29–45CrossRefPubMedGoogle Scholar
  2. 2.
    Stankoff B, Aigrot MS, Noel F, Wattilliaux A, Zalc B, Lubetzki C (2002) Ciliary neurotrophic factor (CNTF) enhances myelin formation: a novel role for CNTF and CNTF-related molecules. J Neurosci 22:9221–9227PubMedGoogle Scholar
  3. 3.
    Louis JC, Magal E, Takayama S, Varon S (1993) CNTF protection of oligodendrocytes against natural and tumor necrosis factor-induced death. Science 259:689–692CrossRefPubMedGoogle Scholar
  4. 4.
    Barres BA, Schmid R, Sendnter M, Raff MC (1993) Multiple extracellular signals are required for long-term oligodendrocyte survival. Development 118:283–295PubMedGoogle Scholar
  5. 5.
    Hafler DA, Weiner HL (1989) MS: a CNS and systemic autoimmune disease. Immunol Today 10:104–107CrossRefPubMedGoogle Scholar
  6. 6.
    Martin R, McFarland HF, McFarlin DE (1992) Immunological aspects of demyelinating diseases. Annu Rev Immunol 10:153–187CrossRefPubMedGoogle Scholar
  7. 7.
    Steinman L (1996) Multiple sclerosis: a coordinated immunological attack against myelin in the central nervous system. Cell 85:299–302CrossRefPubMedGoogle Scholar
  8. 8.
    Pahan K (2010) Neuroimmune pharmacological control of EAE. J Neuroimmune Pharmacol 5:165–167CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Kuhlmann T, Remington L, Cognet I, Bourbonniere L, Zehntner S, Guilhot F, Herman A, Guay-Giroux A, Antel JP, Owens T, Gauchat JF (2006) Continued administration of ciliary neurotrophic factor protects mice from inflammatory pathology in experimental autoimmune encephalomyelitis. Am J Pathol 169:584–598CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Lu Z, Hu X, Zhu C, Wang D, Zheng X, Liu Q (2009) Overexpression of CNTF in Mesenchymal Stem Cells reduces demyelination and induces clinical recovery in experimental autoimmune encephalomyelitis mice. J Neuroimmunol 206:58–69CrossRefPubMedGoogle Scholar
  11. 11.
    Linker RA, Maurer M, Gaupp S, Martini R, Holtmann B, Giess R, Rieckmann P, Lassmann H, Toyka KV, Sendtner M, Gold R (2002) CNTF is a major protective factor in demyelinating CNS disease: a neurotrophic cytokine as modulator in neuroinflammation. Nat Med 8:620–624CrossRefPubMedGoogle Scholar
  12. 12.
    Linker RA, Brechlin P, Jesse S, Steinacker P, Lee DH, Asif AR, Jahn O, Tumani H, Gold R, Otto M (2009) Proteome profiling in murine models of multiple sclerosis: identification of stage specific markers and culprits for tissue damage. PLoS One 4:e7624CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Giess R, Maurer M, Linker R, Gold R, Warmuth-Metz M, Toyka KV, Sendtner M, Rieckmann P (2002) Association of a null mutation in the CNTF gene with early onset of multiple sclerosis. Arch Neurol 59:407–409CrossRefPubMedGoogle Scholar
  14. 14.
    Emerich DF, Thanos CG (2006) Intracompartmental delivery of CNTF as therapy for Huntington’s disease and retinitis pigmentosa. Curr Gene Ther 6:147–159CrossRefPubMedGoogle Scholar
  15. 15.
    Aebischer P, Schluep M, Deglon N, Joseph JM, Hirt L, Heyd B, Goddard M, Hammang JP, Zurn AD, Kato AC, Regli F, Baetge EE (1996) Intrathecal delivery of CNTF using encapsulated genetically modified xenogeneic cells in amyotrophic lateral sclerosis patients. Nat Med 2:696–699CrossRefPubMedGoogle Scholar
  16. 16.
    Gropman AL, Summar M, Leonard JV (2007) Neurological implications of urea cycle disorders. J Inherit Metab Dis 30:865–879CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Scaglia F, Carter S, O’Brien WE, Lee B (2004) Effect of alternative pathway therapy on branched chain amino acid metabolism in urea cycle disorder patients. Mol Genet Metab 81(Suppl 1):S79–S85CrossRefPubMedGoogle Scholar
  18. 18.
    Bridges JW, French MR, Smith RL, Williams RT (1970) The fate of benzoic acid in various species. Biochem J 118:47–51CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Kubota K, Ishizaki T (1991) Dose-dependent pharmacokinetics of benzoic acid following oral administration of sodium benzoate to humans. Eur J Clin Pharmacol 41:363–368CrossRefPubMedGoogle Scholar
  20. 20.
    Toth B (1984) Lack of tumorigenicity of sodium benzoate in mice. Fundam Appl Toxicol 4:494–496CrossRefPubMedGoogle Scholar
  21. 21.
    Brahmachari S, Pahan K (2007) Sodium benzoate, a food additive and a metabolite of cinnamon, modifies T cells at multiple steps and inhibits adoptive transfer of experimental allergic encephalomyelitis. J Immunol 179:275–283CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Mondal S, Pahan K (2015) Cinnamon ameliorates experimental allergic encephalomyelitis in mice via regulatory T cells: implications for multiple sclerosis therapy. PLoS One 10:e0116566CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Jana A, Modi KK, Roy A, Anderson JA, van Breemen RB, Pahan K (2013) Up-regulation of neurotrophic factors by cinnamon and its metabolite sodium benzoate: therapeutic implications for neurodegenerative disorders. J Neuroimmune Pharmacol 8:739–755CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Modi KK, Roy A, Brahmachari S, Rangasamy SB, Pahan K (2015) Cinnamon and its metabolite sodium benzoate attenuate the activation of p21rac and protect memory and learning in an animal model of alzheimer’s disease. PLoS One 10:e0130398CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Jana M, Pahan K (2013) Down-regulation of myelin gene expression in human oligodendrocytes by nitric oxide: implications for demyelination in multiple sclerosis. J Clin Cell Immunol 4Google Scholar
  26. 26.
    Ghosh A, Pahan K (2012) Gemfibrozil, a lipid-lowering drug, induces suppressor of cytokine signaling 3 in glial cells: implications for neurodegenerative disorders. J Biol Chem 287:27189–27203CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Khasnavis S, Jana A, Roy A, Mazumder M, Bhushan B, Wood T, Ghosh S, Watson R, Pahan K (2012) Suppression of nuclear factor-kappaB activation and inflammation in microglia by physically modified saline. J Biol Chem 287:29529–29542CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Brahmachari S, Fung YK, Pahan K (2006) Induction of glial fibrillary acidic protein expression in astrocytes by nitric oxide. J Neurosci 26:4930–4939CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Jana M, Jana A, Pal U, Pahan K (2007) A simplified method for isolating highly purified neurons, oligodendrocytes, astrocytes, and microglia from the same human fetal brain tissue. Neurochem Res 32:2015–2022CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Jana M, Mondal S, Gonzalez FJ, Pahan K (2012) Gemfibrozil, a lipid-lowering drug, increases myelin genes in human oligodendrocytes via peroxisome proliferator-activated receptor-beta. J Biol Chem 287:34134–34148CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Brahmachari S, Jana A, Pahan K (2009) Sodium benzoate, a metabolite of cinnamon and a food additive, reduces microglial and astroglial inflammatory responses. J Immunol 183:5917–5927CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Jana A, Pahan K (2010) Fibrillar amyloid-beta-activated human astroglia kill primary human neurons via neutral sphingomyelinase: implications for Alzheimer’s disease. J Neurosci 30:12676–12689CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Khasnavis S, Pahan K (2012) Sodium benzoate, a metabolite of cinnamon and a food additive, upregulates neuroprotective Parkinson disease protein DJ-1 in astrocytes and neurons. J Neuroimmune Pharmacol 7:424–435CrossRefPubMedGoogle Scholar
  34. 34.
    Roy A, Pahan K (2013) Myelin basic protein-primed T helper 2 cells suppress microglial activation via AlphaVBeta3 integrin: implications for multiple sclerosis. J Clin Cell Immunol 7:158PubMedPubMedCentralGoogle Scholar
  35. 35.
    Corbett GT, Roy A, Pahan K (2012) Gemfibrozil, a lipid-lowering drug, upregulates IL-1 receptor antagonist in mouse cortical neurons: implications for neuronal self-defense. J Immunol 189:1002–1013CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Ghosh A, Corbett GT, Gonzalez FJ, Pahan K (2012) Gemfibrozil and fenofibrate, FDA-approved lipid-lowering drugs, upregulate tripeptidyl-peptidase 1 in brain cells via peroxisome proliferator-activated receptor-a: implications for late infantile neuronal ceroid lipofuscinosis therapy. J Biol Chem 287:38922–38935CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Modi KK, Sendtner M, Pahan K (2013) Up-regulation of ciliary neurotrophic factor in astrocytes by aspirin: implications for remyelination in multiple sclerosis. J Biol Chem 288:18533–18545CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Ito Y, Wiese S, Funk N, Chittka A, Rossoll W, Bommel H, Watabe K, Wegner M, Sendtner M (2006) Sox10 regulates ciliary neurotrophic factor gene expression in Schwann cells. Proc Natl Acad Sci USA 103:7871–7876CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Taylor SS, Kim C, Cheng CY, Brown SH, Wu J, Kannan N (2008) Signaling through cAMP and cAMP-dependent protein kinase: diverse strategies for drug design. Biochim Biophys Acta 1784:16–26CrossRefPubMedGoogle Scholar
  40. 40.
    Kandel ER (2012) The molecular biology of memory: cAMP, PKA, CRE, CREB-1, CREB-2, and CPEB. Mol Brain 5:14CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Waltereit R, Weller M (2003) Signaling from cAMP/PKA to MAPK and synaptic plasticity. Mol Neurobiol 27:99–106CrossRefPubMedGoogle Scholar
  42. 42.
    Iwasaki Y, Ikeda K, Shiojima T, Kinoshita M (1992) Increased plasma concentrations of aspartate, glutamate and glycine in Parkinson’s disease. Neurosci Lett 145:175–177CrossRefPubMedGoogle Scholar
  43. 43.
    Mitch WE, Brusilow S (1982) Benzoate-induced changes in glycine and urea metabolism in patients with chronic renal failure. J Pharmacol Exp Ther 222:572–575PubMedGoogle Scholar
  44. 44.
    Barkhatova VP, Zavalishin IA, Askarova L, Shavratskii V, Demina EG (1998) Changes in neurotransmitters in multiple sclerosis. Neurosci Behav Physiol 28:341–344CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Khushbu K. Modi
    • 1
  • Malabendu Jana
    • 1
  • Susanta Mondal
    • 1
  • Kalipada Pahan
    • 1
    • 2
    Email author
  1. 1.Department of Neurological SciencesRush University Medical CenterChicagoUSA
  2. 2.Division of Research and DevelopmentJesse Brown Veterans Affairs Medical CenterChicagoUSA

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