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. 2022 Aug 6;27(15):5007.
doi: 10.3390/molecules27155007.

The Relationship between Procyanidin Structure and Their Protective Effect in a Parkinson's Disease Model

Juan Chen  1 , Yixuan Chen  1 , Yangfan Zheng  1 , Jiawen Zhao  1 , Huilin Yu  1 , Jiajin Zhu  1
Affiliations

The Relationship between Procyanidin Structure and Their Protective Effect in a Parkinson's Disease Model

Juan Chen et al. Molecules. .

Abstract

This study evaluated the effect of grape seed-derived monomer, dimeric, and trimeric procyanidins on rat pheochromocytoma cell line (PC12) cells and in a zebrafish Parkinson's disease (PD) model. PC12 cells were cultured with grape seed-derived procyanidins or deprenyl for 24 h and then exposed to 1.5 mm 1-methyl-4-phenylpyridinium (MPP+) for 24 h. Zebrafish larvae (AB strain) 3 days post-fertilization were incubated with deprenyl or grape seed-derived procyanidins in 400 µM 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) for 4 days. The results showed that the procyanidin dimers procyanidin B1 (B1), procyanidin B2 (B2), procyanidin B3 (B3), procyanidin B4 (B4), procyanidin B1-3-O-gallate (B1-G), procyanidin B2-3-O-gallate (B2-G), and the procyanidin trimer procyanidin C1 (C1) had a protective effect on PC12 cells, decreasing the damaged dopaminergic neurons and motor impairment in zebrafish. In PC12 cells and the zebrafish PD model, procyanidin (B1, B2, B3, B4, B1-G, B2-G, C1) treatment decreased the content of reactive oxygen species (ROS) and malondialdehyde (MDA), increased the activity of antioxidant enzymes glutathione peroxidase (GSH-Px), catalase (CAT), and superoxide dismutase (SOD), and upregulated the expression of nuclear factor-erythroid 2-related factor (Nrf2), NAD(P)H: quinone oxidoreductase 1 (NQO1), and heme oxygenase-1 (HO-1). These results suggest that in PC12 cells and the zebrafish PD model, the neuroprotective effects of the procyanidins were positively correlated with their degree of polymerization.

Keywords: Nrf2/ARE pathway; PC12 cells; Parkinson’s disease; procyanidins; zebrafish.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
PCs structure: (a) (+)-Catechin (C). (b) (-)-Epicatechin (EC). (c) (-)-Epicatechin gallate (ECG). (d) Procyanidin B1 (B1). (e) Procyanidin B2 (B2). (f) Procyanidin B3 (B3). (g) Procyanidin B4 (B4). (h) Procyanidin B1-3-O-gallate (B1-G). (i) Procyanidin B2-3-O-gallate (B2-G). (j) Procyanidin C1 (C1).
Figure 2
Figure 2
Effect of different structural procyanidins on MPP+-induced PC12 cell damage. (a) Effect of 2.5 μM procyanidins with different structures on the survival of MPP+-injured PC12 cells. (b) Effect of 5 μM procyanidins with different structures on the survival of MPP+-injured PC12 cells. (c) Effect of 2.5 μM procyanidins with different structures on MPP+-induced LDH release. (d) Effect of 5 μM procyanidins with different structures on MPP+-induced LDH release. Control, Blank control group; Model, MPP+ (1.5 mM); Positive control, Deprenyl (30 μM) + MPP+ (1.5 mM). Data are expressed as the mean ± SD. All experiments were conducted six times. Different letters (a–d) on the bar represent significant differences, while the same letters represent no significant differences (p < 0.05, one-way ANOVA).
Figure 3
Figure 3
Effects of different structural procyanidins on the expression of Bax and Bcl-2 proteins in the PC12 cell PD model. (a) Protein levels of Bax and Bcl-2, as determined by Western blotting. (b) Bcl-2/Bax protein relative expression (ratio to control). Control, Blank control group; Model, MPP+ (1.5 mM); Positive control, Deprenyl (30 μM) + MPP+ (1.5 mM); C: C (5 μM) + MPP+ (1.5 mM); EC: EC (5 μM) + MPP+ (1.5 mM); ECG: ECG (5 μM) + MPP+ (1.5 mM); B1: B1 (5 μM) + MPP+ (1.5 mM); B2: B2 (5 μM) + MPP+ (1.5 mM); B3: B3 (5 μM) + MPP+ (1.5 mM); B4: B4 (5 μM) + MPP+ (1.5 mM); B1-G: B1-G (5 μM) + MPP+ (1.5 mM); B2-G: B2-G (5 μM) + MPP+ (1.5 mM); C1: C1(5 μM) + MPP+ (1.5 mM). Data are expressed as the mean ± SD. All experiments were conducted six times. Different letters (a–e) on the bar represent significant differences, while the same letters represent no significant differences (p < 0.05, one-way ANOVA).
Figure 4
Figure 4
Effects of different structural procyanidins on oxidative stress in the PC12 cell PD model. (a) Representative fluorescence photomicrographs of PC12 cells. (b) ROS level. (c) MDA level. (d,e) CAT activity. (f) SOD activity. Control, Blank control group; Model, MPP+ (1.5 mM); Positive control, Deprenyl (30 μM) + MPP+ (1.5 mM); C: C (5 μM) + MPP+ (1.5 mM); EC: EC (5 μM) + MPP+ (1.5 mM); ECG: ECG (5 μM) + MPP+ (1.5 mM); B1: B1 (5 μM) + MPP+ (1.5 mM); B2: B2 (5 μM) + MPP+ (1.5 mM); B3: B3 (5 μM) + MPP+ (1.5 mM); B4: B4 (5 μM) + MPP+ (1.5 mM); B1-G: B1-G (5 μM) + MPP+ (1.5 mM); B2-G: B2-G (5 μM) + MPP+ (1.5 mM); C1: C1(5 μM) + MPP+ (1.5 mM). Data are expressed as the mean ± SD. All experiments were conducted three times. Different letters (a–f) on the bar represent significant differences, while the same letters represent no significant differences (p < 0.05, one-way ANOVA).
Figure 4
Figure 4
Effects of different structural procyanidins on oxidative stress in the PC12 cell PD model. (a) Representative fluorescence photomicrographs of PC12 cells. (b) ROS level. (c) MDA level. (d,e) CAT activity. (f) SOD activity. Control, Blank control group; Model, MPP+ (1.5 mM); Positive control, Deprenyl (30 μM) + MPP+ (1.5 mM); C: C (5 μM) + MPP+ (1.5 mM); EC: EC (5 μM) + MPP+ (1.5 mM); ECG: ECG (5 μM) + MPP+ (1.5 mM); B1: B1 (5 μM) + MPP+ (1.5 mM); B2: B2 (5 μM) + MPP+ (1.5 mM); B3: B3 (5 μM) + MPP+ (1.5 mM); B4: B4 (5 μM) + MPP+ (1.5 mM); B1-G: B1-G (5 μM) + MPP+ (1.5 mM); B2-G: B2-G (5 μM) + MPP+ (1.5 mM); C1: C1(5 μM) + MPP+ (1.5 mM). Data are expressed as the mean ± SD. All experiments were conducted three times. Different letters (a–f) on the bar represent significant differences, while the same letters represent no significant differences (p < 0.05, one-way ANOVA).
Figure 5
Figure 5
Effects of different structural procyanidins on the nuclear factor-erythroid 2-related factor 2 (Nrf2)/ARE Pathway in the PC12 cell PD model. (a) Protein levels of Nrf2, as determined by Western blotting. (b) Nrf2/GAPDH protein relative expression (ratio to control). (c) Protein expression levels of nuclear Nrf2 and cytoplasmic Nrf2, as determined by Western blotting. (d) Nuclear Nrf2/LaminB protein relative expression (ratio to control). (e) Cytoplasmic Nrf2/GAPDH protein relative expression (ratio to control). (f) Protein levels of HO-1 and NQO1, as determined by Western blotting; (g) HO-1/GAPDH protein relative expression (ratio to control). (h) NQO1/GAPDH protein relative expression (ratio to control). Control, Blank control group; Model, MPP+ (1.5 mM); Positive control, Deprenyl (30 μM) + MPP+ (1.5 mM); C: C (5 μM) + MPP+ (1.5 mM); EC: EC (5 μM) + MPP+ (1.5 mM); ECG: ECG (5 μM) + MPP+ (1.5 mM); B1: B1 (5 μM) + MPP+ (1.5 mM); B2: B2 (5 μM) + MPP+ (1.5 mM); B3: B3 (5 μM) + MPP+ (1.5 mM); B4: B4 (5 μM) + MPP+ (1.5 mM); B1-G: B1-G (5 μM) + MPP+ (1.5 mM); B2-G: B2-G (5 μM) + MPP+ (1.5 mM); C1: C1(5 μM) + MPP+ (1.5 mM). Data are expressed as the mean ± SD. All experiments were conducted three times. Different letters (a–g) on the bar represent significant differences, while the same letters represent no significant differences (p < 0.05, one-way ANOVA).
Figure 5
Figure 5
Effects of different structural procyanidins on the nuclear factor-erythroid 2-related factor 2 (Nrf2)/ARE Pathway in the PC12 cell PD model. (a) Protein levels of Nrf2, as determined by Western blotting. (b) Nrf2/GAPDH protein relative expression (ratio to control). (c) Protein expression levels of nuclear Nrf2 and cytoplasmic Nrf2, as determined by Western blotting. (d) Nuclear Nrf2/LaminB protein relative expression (ratio to control). (e) Cytoplasmic Nrf2/GAPDH protein relative expression (ratio to control). (f) Protein levels of HO-1 and NQO1, as determined by Western blotting; (g) HO-1/GAPDH protein relative expression (ratio to control). (h) NQO1/GAPDH protein relative expression (ratio to control). Control, Blank control group; Model, MPP+ (1.5 mM); Positive control, Deprenyl (30 μM) + MPP+ (1.5 mM); C: C (5 μM) + MPP+ (1.5 mM); EC: EC (5 μM) + MPP+ (1.5 mM); ECG: ECG (5 μM) + MPP+ (1.5 mM); B1: B1 (5 μM) + MPP+ (1.5 mM); B2: B2 (5 μM) + MPP+ (1.5 mM); B3: B3 (5 μM) + MPP+ (1.5 mM); B4: B4 (5 μM) + MPP+ (1.5 mM); B1-G: B1-G (5 μM) + MPP+ (1.5 mM); B2-G: B2-G (5 μM) + MPP+ (1.5 mM); C1: C1(5 μM) + MPP+ (1.5 mM). Data are expressed as the mean ± SD. All experiments were conducted three times. Different letters (a–g) on the bar represent significant differences, while the same letters represent no significant differences (p < 0.05, one-way ANOVA).
Figure 6
Figure 6
Verification of the effect of Nrf2 on the protective effect of different structural procyanidins in the PC12 cell PD model. (a) Knockout efficiency was detected by determination of Nrf2 protein expression using Western blotting. (b) Nrf2/GAPDH protein relative expression (ratio to control). (c) Cell viability. Data are shown as the mean ± SD. All experiments were conducted three times. Different letters (a–e) on the bar represent significant differences, while the same letters represent no significant differences (p < 0.05, one-way ANOVA).
Figure 7
Figure 7
Effects of different structural procyanidins on exercise capacity in the zebrafish PD model. (a) Swimming traces of zebrafish in each group. (b) Average total distance of zebrafish in each group. Control, Blank control group; Model, MPTP (400 μM); Positive control, Deprenyl (40 μM) + MPTP (400 μM); C: C (25 μM) + MPTP (400 μM); EC: EC (25 μM) + MPTP (400 μM); ECG: ECG (25 μM) + MPTP (400 μM); B1: B1 (25 μM) + MPTP (400 μM); B2: B2 (25 μM) + MPTP (400 μM); B3: B3 (25 μM) + MPTP (400 μM); B4: B4 (25 μM) + MPTP (400 μM); B1-G: B1-G (25 μM) + MPTP (400 μM); B2-G: B2-G (25 μM) + MPTP (400 μM); C1: C1 (25 μM) + MPTP (400 μM). Data are expressed as the mean ± SD. All experiments were conducted three times. Different letters (a–d) on the bar represent significant differences, while the same letters represent no significant differences (p < 0.05, one-way ANOVA).
Figure 8
Figure 8
Effects of different structural procyanidins on dopaminergic neuron injury in the zebrafish PD model. (a) Representative pictures of the dopaminergic neurons in the brains of zebrafish. (b) Quantitative analysis of the tyrosine hydroxylase (TH) density. Control, Blank control group; Model, MPTP (400 μM); Positive control, Deprenyl (40 μM) + MPTP (400 μM); C: C (25 μM) + MPTP (400 μM); EC: EC (25 μM) + MPTP (400 μM); ECG: ECG (25 μM) + MPTP (400 μM); B1: B1 (25 μM) + MPTP (400 μM); B2: B2 (25 μM) + MPTP (400 μM); B3: B3 (25 μM) + MPTP (400 μM); B4: B4 (25 μM) + MPTP (400 μM); B1-G: B1-G (25 μM) + MPTP (400 μM); B2-G: B2-G (25 μM) + MPTP (400 μM); C1: C1 (25 μM) + MPTP (400 μM). Data are expressed as the mean ± SD. All experiments were conducted three times. Different letters (a–e) on the bar represent significant differences, while the same letters represent no significant differences (p < 0.05, one-way ANOVA).
Figure 9
Figure 9
Effects of different structural procyanidins on oxidative stress in the zebrafish PD model. (a) MDA levels. (b) GSH-Px activity. (c) CAT activity. (d) SOD activity. Control, Blank control group; Model, MPTP (400 μM); Positive control, Deprenyl (40 μM) + MPTP (400 μM); C: C (25 μM) + MPTP (400 μM); EC: EC (25 μM) + MPTP (400 μM); ECG: ECG (25 μM) + MPTP (400 μM); B1: B1 (25 μM) + MPTP (400 μM); B2: B2 (25 μM) + MPTP (400 μM); B3: B3 (25 μM) + MPTP (400 μM); B4: B4 (25 μM) + MPTP (400 μM); B1-G: B1-G (25 μM) + MPTP (400 μM); B2-G: B2-G (25 μM) + MPTP (400 μM); C1: C1 (25 μM) + MPTP (400 μM). Data are expressed as the mean ± SD. All experiments were conducted three times. Different letters (a–f) on the bar represent significant differences, while the same letters represent no significant differences (p < 0.05, one-way ANOVA).
Figure 10
Figure 10
Effects of different structural procyanidins on the Nrf2/ARE pathway in the zebrafish PD model. (a) Nrf2 levels. (b) NQO1 levels. (c) HO-1 levels. Control, Blank control group; Model, MPTP (400 μM); Positive control, Deprenyl (40 μM) + MPTP (400 μM); C: C (25 μM) + MPTP (400 μM); EC: EC (25 μM) + MPTP (400 μM); ECG: ECG (25 μM) + MPTP (400 μM); B1: B1 (25 μM) + MPTP (400 μM); B2: B2 (25 μM) + MPTP (400 μM); B3: B3 (25 μM) + MPTP (400 μM); B4: B4 (25 μM) + MPTP (400 μM); B1-G: B1-G (25 μM) + MPTP (400 μM); B2-G: B2-G (25 μM) + MPTP (400 μM); C1: C1 (25 μM) + MPTP (400 μM). Data are expressed as the mean ± SD. All experiments were conducted three times. Different letters (a–g) on the bar represent significant differences, while the same letters represent no significant differences (p < 0.05, one-way ANOVA).
Figure 11
Figure 11
Schematic diagram of the protective effects of procyanidins in PD models.
See this image and copyright information in PMC

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