Skip to main content

Advertisement

SpringerLink
Log in

Cinnamon and its Metabolite Protect the Nigrostriatum in a Mouse Model of Parkinson’s Disease Via Astrocytic GDNF

  • ORIGINAL ARTICLE
  • Published:
Journal of Neuroimmune Pharmacology Aims and scope Submit manuscript

Abstract

Glial cell line-derived neurotrophic factor (GDNF) has potent neurotrophic effects and is known to promote the dopaminergic (DA) neuronal survival in cellular and animal models of Parkinson’s disease (PD). However, long-term ectopic GDNF delivery is associated with long lasting adverse side effects in PD patients. Therefore, finding safer and effective ways to elevate endogenous GDNF levels is an active area of research. This study underlines the importance of sodium benzoate (NaB), a metabolite of commonly-used spice cinnamon, a food-additive and an FDA-approved drug against hyperammonemia, in stimulating GDNF in primary mouse and human astrocytes. Presence of cAMP response element (CRE) in the Gdnf gene promoter, recruitment of CREB to the Gdnf promoter by NaB and abrogation of NaB-mediated GDNF expression by siRNA knockdown of CREB suggest that NaB induces the transcription of Gdnf via CREB. Finally, oral administration of NaB and cinnamon itself increased the level of GDNF in vivo in the substantia nigra pars compacta (SNpc) of normal as well as MPTP-intoxicated mice. Accordingly, cinnamon and NaB treatment protected tyrosine hydroxylase positive neurons in the SNpc and fibers in the striatum, normalized striatal neurotransmitters, and improved locomotor activities in MPTP-intoxicated Gfapcre mice, but not GdnfΔastro mice lacking GDNF in astrocytes. These findings highlight the importance of astroglial GDNF in cinnamon- and NaB-mediated protection of the nigrostriatum in MPTP mouse model of PD and suggest possible therapeutic potential of cinnamon and NaB in PD patients.

Cinnamon metabolite sodium benzoate (NaB) activates cAMP-response element-binding (CREB) via protein kinase A (PKA) in astrocytes. Activated CREB then binds to cAMP-response element (CRE) present in GDNF gene promoter to stimulate the transcription of GDNF in astrocytes. This astrocytic GDNF leads to nigral trophism and protects dopaminergic neurons from MPTP insult.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Aloe L, Rocco ML, Bianchi P, Manni L (2012) Nerve growth factor: from the early discoveries to the potential clinical use. J Transl Med 10:239

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Andereggen L, Meyer M, Guzman R, Ducray AD, Widmer HR (2009) Effects of GDNF pretreatment on function and survival of transplanted fetal ventral mesencephalic cells in the 6-OHDA rat model of Parkinson's disease. Brain Res 1276:39–49

    Article  CAS  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

    Article  CAS  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cartharius K, Frech K, Grote K, Klocke B, Haltmeier M, Klingenhoff A, Frisch M, Bayerlein M, Werner T (2005) MatInspector and beyond: promoter analysis based on transcription factor binding sites. Bioinformatics 21:2933–2942

    Article  CAS  PubMed  Google Scholar 

  • Chandra G, Roy A, Rangasamy SB, Pahan K (2017) Induction of adaptive immunity leads to Nigrostriatal disease progression in MPTP mouse model of Parkinson's disease. J Immunol 198:4312–4326

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 189:1002–1013

    Article  CAS  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Corbett GT, Gonzalez FJ, Pahan K (2015) Activation of peroxisome proliferator-activated receptor alpha stimulates ADAM10-mediated proteolysis of APP. Proc Natl Acad Sci U S A 112:8445–8450

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • De Deurwaerdere P, Di Giovanni G, Millan MJ (2017) Expanding the repertoire of L-DOPA's actions: a comprehensive review of its functional neurochemistry. Prog Neurobiol 151:57–100

    Article  CAS  PubMed  Google Scholar 

  • Ellis JM, Fell MJ (2017) Current approaches to the treatment of Parkinson's disease. Bioorg Med Chem Lett 27:4247–4255

    Article  CAS  Google Scholar 

  • Emamzadeh FN, Surguchov A (2018) Parkinson's disease: biomarkers, treatment, and risk factors. Front Neurosci 12:612

    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

    Article  PubMed  PubMed Central  Google Scholar 

  • Ghosh A, Roy A, Matras J, Brahmachari S, Gendelman HE, Pahan K (2009) Simvastatin inhibits the activation of p21ras and prevents the loss of dopaminergic neurons in a mouse model of Parkinson's disease. J Neurosci 29:13543–13556

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Goodman RH, Smolik S (2000) CBP/p300 in cell growth, transformation, and development. Genes Dev 14:1553–1577

    CAS  PubMed  Google Scholar 

  • Hariri M, Ghiasvand R (2016) Cinnamon and chronic diseases. Adv Exp Med Biol 929:1–24

    Article  CAS  PubMed  Google Scholar 

  • Hirtz D, Thurman DJ, Gwinn-Hardy K, Mohamed M, Chaudhuri AR, Zalutsky R (2007) How common are the "common" neurologic disorders? Neurology 68:326–337

    Article  CAS  PubMed  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 

  • Jankovic J (2008) Parkinson's disease: clinical features and diagnosis. J Neurol Neurosurg Psychiatry 79:368–376

    Article  CAS  PubMed  Google Scholar 

  • Kalia LV, Lang AE (2015) Parkinson's disease. Lancet 386:896–912

    Article  CAS  Google Scholar 

  • Kang H, Park SH, Yun JM, Nam TG, Kim YE, Kim DO, Kim YJ (2014) Effect of cinnamon water extract on monocyte-to-macrophage differentiation and scavenger receptor activity. BMC Complement Altern Med 14:90

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kearns CM, Gash DM (1995) GDNF protects nigral dopamine neurons against 6-hydroxydopamine in vivo. Brain Res 672:104–111

    Article  CAS  PubMed  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, Roy A, Ghosh S, Watson R, Pahan K (2013) Protection of dopaminergic neurons in a mouse model of Parkinson's disease by a physically-modified saline containing charge-stabilized nanobubbles. J NeuroImmune Pharmacol 9:218–232

    Article  Google Scholar 

  • Kirik D, Rosenblad C, Bjorklund A, Mandel RJ (2000) Long-term rAAV-mediated gene transfer of GDNF in the rat Parkinson's model: intrastriatal but not intranigral transduction promotes functional regeneration in the lesioned nigrostriatal system. J Neurosci 20:4686–4700

    Article  CAS  PubMed  Google Scholar 

  • Kong XY, Cai Z, Pan L, Zhang L, Shu J, Dong YL, Yang N, Li Q, Huang XJ, Zuo PP (2008) Transplantation of human amniotic cells exerts neuroprotection in MPTP-induced Parkinson disease mice. Brain Res 1205:108–115

    Article  CAS  PubMed  Google Scholar 

  • Koyama Y (2002) Functional alterations of astroglia on brain pathologies and their intracellular mechanisms. Nihon Yakurigaku Zasshi 119:135–143

    Article  CAS  PubMed  Google Scholar 

  • Lang AE, Lozano AM (1998) Parkinson's disease. First of two parts. N Engl J Med 339:1044–1053

    Article  CAS  PubMed  Google Scholar 

  • Lang AE, Gill S, Patel NK, Lozano A, Nutt JG, Penn R, Brooks DJ, Hotton G, Moro E, Heywood P, Brodsky MA, Burchiel K, Kelly P, Dalvi A, Scott B, Stacy M, Turner D, Wooten VGF, Elias WJ, Laws ER, Dhawan V, Stoessl AJ, Matcham J, Coffey RJ, Traub M (2006) Randomized controlled trial of intraputamenal glial cell line-derived neurotrophic factor infusion in Parkinson disease. Ann Neurol 59:459–466

    Article  CAS  PubMed  Google Scholar 

  • Lin LF, Doherty DH, Lile JD, Bektesh S, Collins F (1993) GDNF: a glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons. Science 260:1130–1132

    Article  CAS  Google Scholar 

  • Meredith GE, Rademacher DJ (2011) MPTP mouse models of Parkinson's disease: an update. J Park Dis 1:19–33

    CAS  Google Scholar 

  • Mirfeizi M, Mehdizadeh Tourzani Z, Mirfeizi SZ, Asghari Jafarabadi M, Rezvani HR, Afzali M (2016) Controlling type 2 diabetes mellitus with herbal medicines: a triple-blind randomized clinical trial of efficacy and safety. J Diabetes 8:647–656

    Article  CAS  PubMed  Google Scholar 

  • Modi KK, Jana M, Mondal S, Pahan K (2015a) Sodium benzoate, a metabolite of cinnamon and a food additive, Upregulates Ciliary Neurotrophic factor in astrocytes and Oligodendrocytes. Neurochem Res 40:2333–2347

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Modi KK, Roy A, Brahmachari S, Rangasamy SB, Pahan K (2015b) 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 

  • Modi KK, Rangasamy SB, Dasarathi S, Roy A, Pahan K (2016) Cinnamon converts poor learning mice to good learners: implications for memory improvement. J NeuroImmune Pharmacol 11:693–707

    Article  PubMed  PubMed Central  Google Scholar 

  • Morrison PF, Lonser RR, Oldfield EH (2007) Convective delivery of glial cell line-derived neurotrophic factor in the human putamen. J Neurosurg 107:74–83

    Article  PubMed  Google Scholar 

  • Nayak IN, Chinta R, Jetti R (2017) Anti-atherosclerotic potential of aqueous extract of Cinnamomum Zeylanicum bark against glucocorticoid induced atherosclerosis in Wistar rats. J Clin Diagn Res 11:FC19–FC23

    CAS  PubMed  PubMed Central  Google Scholar 

  • Neuberger JM, Schweitzer S, Rolland MO, Burghard R (2000) Effect of sodium benzoate in the treatment of atypical nonketotic hyperglycinaemia. J Inherit Metab Dis 23:22–26

    Article  CAS  PubMed  Google Scholar 

  • Nutt JG, Burchiel KJ, Comella CL, Jankovic J, Lang AE, Laws ER, Jr., Lozano AM, Penn RD, Simpson RK, Jr., Stacy M, Wooten GF, factor IGSGIiGcl-dn (2003) Randomized, double-blind trial of glial cell line-derived neurotrophic factor (GDNF) in PD. Neurology 60:69–73

  • Patel NK, Gill SS (2007) GDNF delivery for Parkinson's disease. Acta Neurochir Suppl 97:135–154

    Article  CAS  PubMed  Google Scholar 

  • Patel D, Roy A, Kundu M, Jana M, Luan CH, Gonzalez FJ, Pahan K (2018) Aspirin binds to PPARalpha to stimulate hippocampal plasticity and protect memory. Proc Natl Acad Sci U S A 115:E7408–E7417

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rascol O, Payoux P, Ory F, Ferreira JJ, Brefel-Courbon C, Montastruc JL (2003) Limitations of current Parkinson's disease therapy. Ann Neurol 53(Suppl 3):S3–S12 discussion S12-15

  • Rathi B, Bodhankar S, Mohan V, Thakurdesai P (2013) Ameliorative effects of a Polyphenolic fraction of Cinnamomum zeylanicum L. bark in animal models of inflammation and arthritis. Sci Pharm 81:567–589

    Article  CAS  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Roy A, Jana M, Kundu M, Corbett GT, Rangaswamy SB, Mishra RK, Luan CH, Gonzalez FJ, Pahan K (2015) HMG-CoA Reductase inhibitors bind to PPARalpha to Upregulate Neurotrophin expression in the brain and improve memory in mice. Cell Metab 22:253–265

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Saavedra A, Baltazar G, Duarte EP (2008) Driving GDNF expression: the green and the red traffic lights. Prog Neurobiol 86:186–215

    Article  CAS  PubMed  Google Scholar 

  • Santos HO, da Silva GAR (2018) To what extent does cinnamon administration improve the glycemic and lipid profiles? Clin Nutr ESPEN 27:1–9

    Article  PubMed  Google Scholar 

  • Sauer H, Rosenblad C, Bjorklund A (1995) Glial cell line-derived neurotrophic factor but not transforming growth factor beta 3 prevents delayed degeneration of nigral dopaminergic neurons following striatal 6-hydroxydopamine lesion. Proc Natl Acad Sci U S A 92:8935–8939

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Seifert G, Schilling K, Steinhauser C (2006) Astrocyte dysfunction in neurological disorders: a molecular perspective. Nat Rev Neurosci 7:194–206

    Article  CAS  PubMed  Google Scholar 

  • Shishehbor F, Rezaeyan Safar M, Rajaei E, Haghighizadeh MH (2018) Cinnamon consumption improves clinical symptoms and inflammatory markers in women with rheumatoid arthritis. J Am Coll Nutr:1–6

  • Slevin JT, Gash DM, Smith CD, Gerhardt GA, Kryscio R, Chebrolu H, Walton A, Wagner R, Young AB (2007) Unilateral intraputamenal glial cell line-derived neurotrophic factor in patients with Parkinson disease: response to 1 year of treatment and 1 year of withdrawal. J Neurosurg 106:614–620

    Article  CAS  PubMed  Google Scholar 

  • Villadiego J, Mendez-Ferrer S, Valdes-Sanchez T, Silos-Santiago I, Farinas I, Lopez-Barneo J, Toledo-Aral JJ (2005) Selective glial cell line-derived neurotrophic factor production in adult dopaminergic carotid body cells in situ and after intrastriatal transplantation. J Neurosci 25:4091–4098

    Article  CAS  PubMed  Google Scholar 

  • Villar-Pique A, Lopes da Fonseca T, Outeiro TF (2016) Structure, function and toxicity of alpha-synuclein: the Bermuda triangle in synucleinopathies. J Neurochem 139(Suppl 1):240–255

    Article  CAS  PubMed  Google Scholar 

  • Wakabayashi K, Tanji K, Mori F, Takahashi H (2007) The Lewy body in Parkinson's disease: molecules implicated in the formation and degradation of alpha-synuclein aggregates. Neuropathology 27:494–506

    Article  Google Scholar 

  • Weissmiller AM, Wu C (2012) Current advances in using neurotrophic factors to treat neurodegenerative disorders. Transl Neurodegener 1:14

    Article  PubMed  PubMed Central  Google Scholar 

  • Winkler C, Sauer H, Lee CS, Bjorklund A (1996) Short-term GDNF treatment provides long-term rescue of lesioned nigral dopaminergic neurons in a rat model of Parkinson's disease. J Neurosci 16:7206–7215

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This study was supported by a merit award from Veteran Affairs (I01BX003033) and a grant (NS083054) from NIH.

Author information

Author notes

  1. Arundhati Jana

    Present address: Department of Medicine, University of Illinois, Chicago, IL, 60612, USA

Authors and Affiliations

  1. Department of Neurological Sciences, Rush University Medical Center, 1735 West Harrison St, Suite Cohn 310, Chicago, IL, 60612, USA

    Dhruv Patel, Arundhati Jana, Avik Roy & Kalipada Pahan

  2. Division of Research and Development, Jesse Brown Veterans Affairs Medical Center, Chicago, IL, USA

    Avik Roy & Kalipada Pahan

Authors
  1. Dhruv Patel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Arundhati Jana
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Avik Roy
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kalipada Pahan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kalipada Pahan.

Ethics declarations

Conflict of Interests

None.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

ESM 1

(PDF 212 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Patel, D., Jana, A., Roy, A. et al. Cinnamon and its Metabolite Protect the Nigrostriatum in a Mouse Model of Parkinson’s Disease Via Astrocytic GDNF. J Neuroimmune Pharmacol 14, 503–518 (2019). https://doi.org/10.1007/s11481-019-09855-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11481-019-09855-0

Keywords

Search

Navigation