A-Type Cinnamon Procyanidin Oligomers Protect Against 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Induced Neurotoxicity in Mice Through Inhibiting the P38 Mitogen-Activated Protein Kinase/P53/BCL-2 Associated X Protein Signaling Pathway

J Nutr. 2020 Jul 1;150(7):1731-1737. doi: 10.1093/jn/nxaa128.

Abstract

Background: Parkinson's disease (PD) is a common neurodegenerative disorder. Cinnamon procyanidin oligomers (CPOs) are flavonoids with many claimed health benefits.

Objective: This study aimed to elucidate the neuroprotection of A-type CPOs (CPO-A) and the underlying mechanisms in cultured cell and animal models of PD.

Methods: Thirty male mice (C57BL/6, 9-wk old) were assigned to 3 groups (n = 10), and were given daily gavage of saline [control and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) groups] or CPO-A (150 mg/kg, CPO-A group) during days 1-15 and daily intraperitoneal injections of saline (control group) or MPTP (20 mg/kg; MPTP and MPTP + CPO-A groups) during days 11-15. After the motor behavior test, all mice were killed on day 16 to collect the substantia nigra (SN) for assaying the neuroprotective effects of CPO-A. SH-SY5Y cells were treated with 12.5 μM CPO-A for 2 h or 3 activators of stress-related kinases (5-25 μM) for 12-48 h followed by 1 mM 1-methyl-4-phenylpyridinium (MPP+) for assays of viability, morphology, and stress status.

Results: Compared with the control, the MPTP treatment decreased (P < 0.05) locomotor activity by 21%, and tyrosine hydroxylase (TH) positive neurons by 55% and Th mRNA concentration by 51% in the SN. The CPO-A treatment attenuated or restored (P < 0.05) these changes and inhibited (P < 0.05) the MPTP-induced activation of P38 mitogen-activated protein kinase (P38MAPK) and P53, along with the downstream expression of BCL-2 associated X protein (BAX) in the SN. In SH-SY5Y cells, the CPO-A treatment blocked (P < 0.01) the MPP+-induced accumulation of intracellular reactive oxygen species and neurotoxicity. However, this protection was abolished (P < 0.05) by activators of the P38MAPK/P53/BAX pathway.

Conclusion: CPO-A protected against MPP+-induced cytotoxicity in SH-SY5Y cells and MPTP-induced neurotoxicity in mice by regulating the P38MAPK/P53/BAX signaling. Our findings reveal a novel role and mechanism of a food flavonoid CPO-A in preventing neurodegeneration.

Keywords: Parkinson's disease; animal model; cinnamon procyanidin oligomers; flavonoids; neuroprotection.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biflavonoids / chemistry*
  • Catechin / chemistry*
  • Cell Line, Tumor
  • Cell Survival
  • Cinnamomum zeylanicum / chemistry*
  • Gene Expression Regulation / drug effects
  • Locomotion
  • MPTP Poisoning*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Morpholinos / chemistry*
  • Morpholinos / pharmacology*
  • Proanthocyanidins / chemistry*
  • Reactive Oxygen Species
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism
  • bcl-2-Associated X Protein / genetics
  • bcl-2-Associated X Protein / metabolism
  • p38 Mitogen-Activated Protein Kinases / genetics
  • p38 Mitogen-Activated Protein Kinases / metabolism*

Substances

  • Bax protein, mouse
  • Biflavonoids
  • Morpholinos
  • Proanthocyanidins
  • Reactive Oxygen Species
  • Tumor Suppressor Protein p53
  • bcl-2-Associated X Protein
  • procyanidin
  • Catechin
  • p38 Mitogen-Activated Protein Kinases