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

Abstract

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.

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References

  • 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 212:288–293

    CAS  Article  PubMed  Google Scholar 

  • Atack JR (2010) Preclinical and clinical pharmacology of the GABAA receptor alpha5 subtype-selective inverse agonist alpha5IA. Pharmacol Ther 125:11–26

    CAS  Article  PubMed  Google Scholar 

  • Bell KF, Zheng L, Fahrenholz F, Cuello AC (2008) ADAM-10 over-expression increases cortical synaptogenesis. Neurobiol Aging 29:554–565

    CAS  Article  PubMed  Google Scholar 

  • 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 179:275–283

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • 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 183:5917–5927

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Bridges JW, French MR, Smith RL, Williams RT (1970) The fate of benzoic acid in various species. Biochem J 118:47–51

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • 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 22:3628–3637

    CAS  PubMed  Google Scholar 

  • 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 70:462–473

    CAS  Article  PubMed  Google Scholar 

  • Collingridge GL, Peineau S, Howland JG, Wang YT (2010) Long-term depression in the CNS. Nat Rev Neurosci 11:459–473

    CAS  Article  PubMed  Google Scholar 

  • 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 189:1002–1013

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • 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 189:1002–1013

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • 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 288:8299–8312

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • 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 18:37–44

    CAS  Article  PubMed  Google Scholar 

  • 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 287:27189–27203

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • 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 104:18754–18759

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Impey S, Goodman RH (2001) CREB signaling--timing is everything. Sci STKE 2001:pe1

    CAS  PubMed  Google Scholar 

  • Isaac J (2001) Protein phosphatase 1 and LTD: synapses are the architects of depression. Neuron 32:963–966

    CAS  Article  PubMed  Google Scholar 

  • 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 11:97–116

    CAS  PubMed  Google Scholar 

  • 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 32:2015–2022

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • 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 8:739–755

    Article  PubMed  PubMed Central  Google Scholar 

  • 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 7:424–435

    Article  PubMed  Google Scholar 

  • 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 9:569–581

    Article  PubMed  PubMed Central  Google Scholar 

  • 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 287:29529–29542

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Kubota K, Ishizaki T (1991) Dose-dependent pharmacokinetics of benzoic acid following oral administration of sodium benzoate to humans. Eur J Clin Pharmacol 41:363–368

    CAS  Article  PubMed  Google Scholar 

  • Leonard JV, Morris AA (2002) Urea cycle disorders. Semin Neonatol 7:27–35

    CAS  Article  PubMed  Google Scholar 

  • Malenka RC, Bear MF (2004) LTP and LTD: an embarrassment of riches. Neuron 44:5–21

    CAS  Article  PubMed  Google Scholar 

  • 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 15:80–92

    CAS  Article  PubMed  Google Scholar 

  • 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 288:18533–18545

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • 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:e103606

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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:e0130398

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mondal S, Pahan K (2014) Cinnamon ameliorates experimental allergic encephalomyelitis in mice via regulatory T cells: implications for multiple sclerosis therapy. PLoS One 10:e0116566

    Article  Google Scholar 

  • Mondal S, Pahan K (2015) Cinnamon ameliorates experimental allergic encephalomyelitis in mice via regulatory T cells: implications for multiple sclerosis therapy. PLoS One 10:e0116566

    Article  PubMed  PubMed Central  Google Scholar 

  • Mondal S, Roy A, Jana A, Ghosh S, Kordower JH, Pahan K (2012) Testing NF-kappaB-based therapy in hemiparkinsonian monkeys. J Neuroimmune Pharmacol 7:544–556

    Article  PubMed  PubMed Central  Google Scholar 

  • 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 319:774–776

    CAS  Article  PubMed  Google Scholar 

  • Myers SJ, Dingledine R, Borges K (1999) Genetic regulation of glutamate receptor ion channels. Annu Rev Pharmacol Toxicol 39:221–241

    CAS  Article  PubMed  Google Scholar 

  • Nair B (2001) Final report on the safety assessment of benzyl alcohol, benzoic acid, and sodium benzoate. Int J Toxicol 20(Suppl 3):23–50

    PubMed  Google Scholar 

  • Olney JW, Wozniak DF, Farber NB (1998) Glumate receptor dysfunction and Alzheimer’s disease. Restor Neurol Neurosci 13:75–83

    CAS  PubMed  Google Scholar 

  • Pahan K (2015) Prospects of cinnamon in multiple sclerosis. J Mult Scler (Foster City) 2:1000149

    Article  Google Scholar 

  • 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 21:795–811

    CAS  PubMed  Google Scholar 

  • 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 179:107–110

    CAS  Article  PubMed  Google Scholar 

  • 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 173-180

    CAS  PubMed  Google Scholar 

  • Roy A, Pahan K (2015) PPARalpha signaling in the hippocampus: crosstalk between fat and memory. J NeuroImmune Pharmacol 10:30–34

    Article  PubMed  PubMed Central  Google Scholar 

  • 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 45:686–699

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • 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 4:724–737

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • 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:e101883

    Article  PubMed  PubMed Central  Google Scholar 

  • 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 183:2068–2078

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • 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–S85

    CAS  Article  PubMed  Google Scholar 

  • Selkoe DJ (2002) Alzheimer’s disease is a synaptic failure. Science 298:789–791

    CAS  Article  PubMed  Google Scholar 

  • 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 324:209–212

    CAS  Article  PubMed  Google Scholar 

  • Waltereit R, Weller M (2003) Signaling from cAMP/PKA to MAPK and synaptic plasticity. Mol Neurobiol 27:99–106

    CAS  Article  PubMed  Google Scholar 

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Acknowledgments

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).

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Correspondence to Kalipada Pahan.

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Modi, K.K., Rangasamy, S.B., Dasarathi, S. et al. Cinnamon Converts Poor Learning Mice to Good Learners: Implications for Memory Improvement. J Neuroimmune Pharmacol 11, 693–707 (2016). https://doi.org/10.1007/s11481-016-9693-6

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  • DOI: https://doi.org/10.1007/s11481-016-9693-6

Keywords

  • Cinnamon
  • Sodium benzoate
  • Poor learners
  • CREB
  • Memory and learning