Journal of Neuroimmune Pharmacology

, Volume 11, Issue 4, pp 693–707 | Cite as

Cinnamon Converts Poor Learning Mice to Good Learners: Implications for Memory Improvement

  • Khushbu K. Modi
  • Suresh B. Rangasamy
  • Sridevi Dasarathi
  • Avik Roy
  • Kalipada PahanEmail author


This study underlines the importance of cinnamon, a commonly used natural spice and flavoring material, and its metabolite sodium benzoate (NaB) in converting poor learning mice to good learning ones. NaB, but not sodium formate, was found to upregulate plasticity-related molecules, stimulate NMDA- and AMPA-sensitive calcium influx and increase of spine density in cultured hippocampal neurons. NaB induced the activation of CREB in hippocampal neurons via protein kinase A (PKA), which was responsible for the upregulation of plasticity-related molecules. Finally, spatial memory consolidation-induced activation of CREB and expression of different plasticity-related molecules were less in the hippocampus of poor learning mice as compared to good learning ones. However, oral treatment of cinnamon and NaB increased spatial memory consolidation-induced activation of CREB and expression of plasticity-related molecules in the hippocampus of poor-learning mice and converted poor learners into good learners. These results describe a novel property of cinnamon in switching poor learners to good learners via stimulating hippocampal plasticity.


Cinnamon Sodium benzoate Poor learners CREB Memory and learning 



This study was supported by grants from National Institutes of Health (AT6681) and Alzheimer’s Association (IIRG-12-241179) and Veterans Affairs Merit Award (1I01BX003033).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.


  1. Abd El-Mawla AM, Schmidt W, Beerhues L (2001) Cinnamic acid is a precursor of benzoic acids in cell cultures of Hypericum androsaemum L. But not in cell cultures of Centaurium erythraea RAFN. Planta 212:288–293CrossRefPubMedGoogle Scholar
  2. Atack JR (2010) Preclinical and clinical pharmacology of the GABAA receptor alpha5 subtype-selective inverse agonist alpha5IA. Pharmacol Ther 125:11–26CrossRefPubMedGoogle Scholar
  3. Bell KF, Zheng L, Fahrenholz F, Cuello AC (2008) ADAM-10 over-expression increases cortical synaptogenesis. Neurobiol Aging 29:554–565CrossRefPubMedGoogle Scholar
  4. 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
  5. 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
  6. Bridges JW, French MR, Smith RL, Williams RT (1970) The fate of benzoic acid in various species. Biochem J 118:47–51CrossRefPubMedPubMedCentralGoogle Scholar
  7. Clayton DA, Mesches MH, Alvarez E, Bickford PC, Browning MD (2002) A hippocampal NR2B deficit can mimic age-related changes in long-term potentiation and spatial learning in the Fischer 344 rat. J Neurosci 22:3628–3637PubMedGoogle Scholar
  8. Colangelo V, Schurr J, Ball MJ, Pelaez RP, Bazan NG, Lukiw WJ (2002) Gene expression profiling of 12633 genes in Alzheimer hippocampal CA1: transcription and neurotrophic factor down-regulation and up-regulation of apoptotic and pro-inflammatory signaling. J Neurosci Res 70:462–473CrossRefPubMedGoogle Scholar
  9. Collingridge GL, Peineau S, Howland JG, Wang YT (2010) Long-term depression in the CNS. Nat Rev Neurosci 11:459–473CrossRefPubMedGoogle Scholar
  10. Corbett GT, Roy A, Pahan K (2012a) 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
  11. Corbett GT, Roy A, Pahan K (2012b) 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
  12. Corbett GT, Roy A, Pahan K (2013) Sodium phenylbutyrate enhances astrocytic neurotrophin synthesis via protein kinase C (PKC)-mediated activation of cAMP-response element-binding protein (CREB): implications for Alzheimer disease therapy. J Biol Chem 288:8299–8312CrossRefPubMedPubMedCentralGoogle Scholar
  13. Desjardins S, Mayo W, Vallee M, Hancock D, Le Moal M, Simon H, Abrous DN (1997) Effect of aging on the basal expression of c-fos, c-Jun, and Egr-1 proteins in the hippocampus. Neurobiol Aging 18:37–44CrossRefPubMedGoogle Scholar
  14. 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
  15. Ghosh A, Roy A, Liu X, Kordower JH, Mufson EJ, Hartley DM, Ghosh S, Mosley RL, Gendelman HE, Pahan K (2007) Selective inhibition of NF-kappaB activation prevents dopaminergic neuronal loss in a mouse model of Parkinson’s disease. Proc Natl Acad Sci U S A 104:18754–18759CrossRefPubMedPubMedCentralGoogle Scholar
  16. Impey S, Goodman RH (2001) CREB signaling--timing is everything. Sci STKE 2001:pe1PubMedGoogle Scholar
  17. Isaac J (2001) Protein phosphatase 1 and LTD: synapses are the architects of depression. Neuron 32:963–966CrossRefPubMedGoogle Scholar
  18. Jacob CP, Koutsilieri E, Bartl J, Neuen-Jacob E, Arzberger T, Zander N, Ravid R, Roggendorf W, Riederer P, Grunblatt E (2007) Alterations in expression of glutamatergic transporters and receptors in sporadic Alzheimer’s disease. J Alzheimers Dis 11:97–116PubMedGoogle Scholar
  19. 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
  20. 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
  21. 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
  22. Khasnavis S, Pahan K (2014) Cinnamon treatment upregulates neuroprotective proteins Parkin and DJ-1 and protects dopaminergic neurons in a mouse model of Parkinson’s disease. J NeuroImmune Pharmacol 9:569–581CrossRefPubMedPubMedCentralGoogle Scholar
  23. 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
  24. 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
  25. Leonard JV, Morris AA (2002) Urea cycle disorders. Semin Neonatol 7:27–35CrossRefPubMedGoogle Scholar
  26. Malenka RC, Bear MF (2004) LTP and LTD: an embarrassment of riches. Neuron 44:5–21CrossRefPubMedGoogle Scholar
  27. Mishizen-Eberz AJ, Rissman RA, Carter TL, Ikonomovic MD, Wolfe BB, Armstrong DM (2004) Biochemical and molecular studies of NMDA receptor subunits NR1/2 A/2B in hippocampal subregions throughout progression of Alzheimer’s disease pathology. Neurobiol Dis 15:80–92CrossRefPubMedGoogle Scholar
  28. 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
  29. Modi KK, Jana A, Ghosh S, Watson R, Pahan K (2014) A physically-modified saline suppresses neuronal apoptosis, attenuates tau phosphorylation and protects memory in an animal model of Alzheimer’s disease. PLoS One 9:e103606CrossRefPubMedPubMedCentralGoogle Scholar
  30. 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
  31. Mondal S, Pahan K (2014) Cinnamon ameliorates experimental allergic encephalomyelitis in mice via regulatory T cells: implications for multiple sclerosis therapy. PLoS One 10:e0116566CrossRefGoogle Scholar
  32. 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
  33. Mondal S, Roy A, Jana A, Ghosh S, Kordower JH, Pahan K (2012) Testing NF-kappaB-based therapy in hemiparkinsonian monkeys. J Neuroimmune Pharmacol 7:544–556CrossRefPubMedPubMedCentralGoogle Scholar
  34. Morris RG, Anderson E, Lynch GS, Baudry M (1986) Selective impairment of learning and blockade of long-term potentiation by an N-methyl-D-aspartate receptor antagonist, AP5. Nature 319:774–776CrossRefPubMedGoogle Scholar
  35. Myers SJ, Dingledine R, Borges K (1999) Genetic regulation of glutamate receptor ion channels. Annu Rev Pharmacol Toxicol 39:221–241CrossRefPubMedGoogle Scholar
  36. Nair B (2001) Final report on the safety assessment of benzyl alcohol, benzoic acid, and sodium benzoate. Int J Toxicol 20(Suppl 3):23–50PubMedGoogle Scholar
  37. Olney JW, Wozniak DF, Farber NB (1998) Glumate receptor dysfunction and Alzheimer’s disease. Restor Neurol Neurosci 13:75–83PubMedGoogle Scholar
  38. Pahan K (2015) Prospects of cinnamon in multiple sclerosis. J Mult Scler (Foster City) 2:1000149CrossRefGoogle Scholar
  39. Proctor DT, Coulson EJ, Dodd PR (2010) Reduction in post-synaptic scaffolding PSD-95 and SAP-102 protein levels in the Alzheimer inferior temporal cortex is correlated with disease pathology. J Alzheimers Dis 21:795–811PubMedGoogle Scholar
  40. Prut L, Abramowski D, Krucker T, Levy CL, Roberts AJ, Staufenbiel M, Wiessner C (2007) Aged APP23 mice show a delay in switching to the use of a strategy in the Barnes maze. Behav Brain Res 179:107–110CrossRefPubMedGoogle Scholar
  41. Reddy PH, Mani G, Park BS, Jacques J, Murdoch G, Whetsell W Jr, Kaye J, Manczak M (2005) Differential loss of synaptic proteins in Alzheimer’s disease: implications for synaptic dysfunction. J Alzheimers Dis 7:103–117 discussion 173-180PubMedGoogle Scholar
  42. Roy A, Pahan K (2015) PPARalpha signaling in the hippocampus: crosstalk between fat and memory. J NeuroImmune Pharmacol 10:30–34CrossRefPubMedPubMedCentralGoogle Scholar
  43. Roy A, Jana A, Yatish K, Freidt MB, Fung YK, Martinson JA, Pahan K (2008) Reactive oxygen species up-regulate CD11b in microglia via nitric oxide: implications for neurodegenerative diseases. Free Radic Biol Med 45:686–699CrossRefPubMedPubMedCentralGoogle Scholar
  44. Roy A, Jana M, Corbett GT, Ramaswamy S, Kordower JH, Gonzalez FJ, Pahan K (2013) Regulation of cyclic AMP response element binding and hippocampal plasticity-related genes by peroxisome proliferator-activated receptor alpha. Cell Rep 4:724–737CrossRefPubMedPubMedCentralGoogle Scholar
  45. Roy A, Modi KK, Khasnavis S, Ghosh S, Watson R, Pahan K (2014) Enhancement of morphological plasticity in hippocampal neurons by a physically modified saline via phosphatidylinositol-3 kinase. PLoS One 9:e101883CrossRefPubMedPubMedCentralGoogle Scholar
  46. Saha RN, Ghosh A, Palencia CA, Fung YK, Dudek SM, Pahan K (2009) TNF-alpha preconditioning protects neurons via neuron-specific up-regulation of CREB-binding protein. J Immunol 183:2068–2078CrossRefPubMedPubMedCentralGoogle Scholar
  47. 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
  48. Selkoe DJ (2002) Alzheimer’s disease is a synaptic failure. Science 298:789–791CrossRefPubMedGoogle Scholar
  49. Shim KS, Lubec G (2002) Drebrin, a dendritic spine protein, is manifold decreased in brains of patients with Alzheimer’s disease and down syndrome. Neurosci Lett 324:209–212CrossRefPubMedGoogle Scholar
  50. Waltereit R, Weller M (2003) Signaling from cAMP/PKA to MAPK and synaptic plasticity. Mol Neurobiol 27:99–106CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Khushbu K. Modi
    • 1
  • Suresh B. Rangasamy
    • 1
  • Sridevi Dasarathi
    • 1
  • Avik Roy
    • 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

Personalised recommendations