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

J Neuroimmune Pharmacol. 2019 Sep;14(3):503-518. doi: 10.1007/s11481-019-09855-0. Epub 2019 May 22.

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. Graphical abstract 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.

Keywords: Astrocytes; Cinnamon; Dopamine; GDNF; Parkinson’s disease; Sodium benzoate.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antiparkinson Agents / pharmacology
  • Antiparkinson Agents / therapeutic use*
  • Astrocytes / metabolism*
  • Biotransformation
  • Cinnamomum zeylanicum / metabolism*
  • Corpus Striatum / drug effects*
  • Corpus Striatum / metabolism
  • Corpus Striatum / pathology
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Drug Evaluation, Preclinical
  • Exploratory Behavior
  • Gene Expression Regulation / drug effects
  • Glial Cell Line-Derived Neurotrophic Factor / biosynthesis
  • Glial Cell Line-Derived Neurotrophic Factor / genetics
  • Glial Cell Line-Derived Neurotrophic Factor / physiology*
  • Humans
  • MPTP Poisoning / drug therapy
  • MPTP Poisoning / pathology
  • Mice
  • Mice, Inbred C57BL
  • Parkinsonian Disorders / drug therapy*
  • Parkinsonian Disorders / pathology
  • Pars Compacta / drug effects
  • Pars Compacta / metabolism
  • Pars Compacta / pathology
  • Plant Bark
  • Promoter Regions, Genetic / genetics
  • Rotarod Performance Test
  • Sodium Benzoate / pharmacology*
  • Substantia Nigra / drug effects*
  • Substantia Nigra / metabolism
  • Substantia Nigra / pathology
  • Transcription Factors / metabolism
  • Up-Regulation / drug effects

Substances

  • Antiparkinson Agents
  • Creb1 protein, mouse
  • Cyclic AMP Response Element-Binding Protein
  • GDNF protein, human
  • Gdnf protein, mouse
  • Glial Cell Line-Derived Neurotrophic Factor
  • Transcription Factors
  • Sodium Benzoate