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. 2024 Oct 24;25(21):11414.
doi: 10.3390/ijms252111414.

Ginsenoside Rg3 Improved Age-Related Macular Degeneration Through Inhibiting ROS-Mediated Mitochondrion-Dependent Apoptosis In Vivo and In Vitro

Rui-Yi Hu  1 , Si-Min Qi  1 , Ya-Jun Wang  1   2 , Wen-Lin Li  1 , Wan-Chen Zou  1   2 , Zi Wang  1 , Shen Ren  1 , Wei Li  1   2
Affiliations

Ginsenoside Rg3 Improved Age-Related Macular Degeneration Through Inhibiting ROS-Mediated Mitochondrion-Dependent Apoptosis In Vivo and In Vitro

Rui-Yi Hu et al. Int J Mol Sci. .

Abstract

Age-related macular degeneration (AMD) is marked by a progressive loss of central vision and is the third leading cause of irreversible blindness worldwide. The exact mechanisms driving the progression of this macular degenerative condition remain elusive, and as of now, there are no available preventative measures for dry AMD. According to ancient records, ginseng affects the eyes by brightening them and enhancing wisdom. Modern pharmacological research shows that the active ingredients in ginseng, ginsenosides, may be used to prevent or improve eye diseases that threaten vision. Some articles have reported that ginsenoside Rg3 can treat diabetic retinopathy in mice, but no reports exist on its effects and mechanisms in AMD. Therefore, the role and mechanism of ginsenoside Rg3 in AMD warrant further study. This study aims to investigate the effects of Rg3 on AMD and its underlying molecular mechanisms. We established a mouse model of AMD to examine the impact of ginsenoside Rg3 on NaIO3-induced apoptosis in the retina and to explore the related intrinsic mechanisms. The in vivo results indicated that ginsenoside Rg3 prevents NaIO3-induced apoptosis in retinal pigment epithelial cells by inhibiting reactive oxygen species production and preventing the reduction in mitochondrial membrane potential. Additionally, we assessed the levels of protein expression within the apoptosis pathway. Ginsenoside Rg3 decreased the expression of Bax, cleaved caspase-3, and cleaved caspase-9 proteins. Additionally, it increased the expression of Bcl-2 by decreasing P-JNK levels. Moreover, our in vivo results showed that ginsenoside Rg3 enhanced retinal structure, increased the relative thickness of the retina, and decreased the extent of disorganization in both the inner and outer nuclear layers. Ginsenoside Rg3 may safeguard the retina against NaIO3-induced cell apoptosis by attenuating reactive-oxygen-species-mediated mitochondrial dysfunction, in which the JNK signaling pathway is also involved. These findings suggest that ginsenoside Rg3 has the potential to prevent or attenuate the progression of AMD and other retinal pathologies associated with NaIO3-mediated apoptosis.

Keywords: age-related macular degeneration; apoptosis; ginsenoside Rg3; retinal pigment epithelium; sodium iodate.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
The structure of ginsenoside Rg3 (A). Representative H&E-stained retinal sections from the four groups were obtained between 600 and 900 μm from the optic nerve in both the superior and inferior hemiretina (B). Quantitative analysis of the number of acellular capillaries per field in retinas (C). The protective effects of ginsenoside Rg3 on retinal thickness in NaIO3-treated mice were evaluated using OCT, the length of the yellow section marks the thickness of the mouse retina (D). Retinal photography was used to assess the protective effects of ginsenoside Rg3 on NaIO3-treated mice (E). Fundus fluorescein angiography (FFA) was employed to determine the protective role of ginsenoside Rg3 in NaIO3-treated mice (F). Note: Values are expressed as mean ± S.D. *** p < 0.001 vs. normal group; ## p < 0.01, ### p < 0.001 vs. AMD group (n = 3).
Figure 2
Figure 2
The influence of ginsenoside Rg3 administration on the modulation of apoptosis-related protein levels (A). Examination of protein expression associated with apoptosis (B). Note: Values are expressed as mean ± S.D. ** p < 0.01 vs. normal group; # p < 0.05, ## p < 0.01 vs. AMD group (n = 3).
Figure 3
Figure 3
JNK protein levels after in vivo treatment with diverse concentrations of ginsenoside Rg3 and NaIO3 (A). Statistical scanning of JNK expression (B). All values are expressed as mean ± S.D., ** p < 0.01 vs. normal group, ## p < 0.01 vs. AMD group (n = 3).
Figure 4
Figure 4
The effects of NaIO3 on RPE cell activity (A). Effect of ginsenoside Rg3 on the activity of RPE cells (B). Effect of ginsenoside Rg3 on NaIO3-induced RPE cytotoxicity (C); H&E staining of RPE cells induced by NaIO3 (D). The level of LDH released in RPE cells induced by NaIO3 (E). Effects of ginsenoside Rg3 with different concentrations (1, 2, and 4 μM) on ROS generation in NaIO3-induced RPE cells (F). The relative fluorescence density of ROS, the blue fluorescence is DAPI, and the red fluorescence is ROS. (G). All values are expressed as mean ± S.D. * p < 0.05, ** p < 0.01, *** p < 0.001 vs. normal group; # p < 0.05, ## p < 0.01 ### p < 0.001 vs. NaIO3 group (n = 3).
Figure 5
Figure 5
Inhibitory effect of ginsenoside Rg3 on NaIO3-induced apoptosis of RPE cells (A). The fluorescence levels were measured (B). Flow cytometry was utilized to examine the impact of ginsenoside Rg3 on NaIO3−induced apoptosis in RPE cells (C) and the percentage of apoptosis (D). The effect of ginsenoside Rg3 on the inhibition of mitochondrial membrane potential induced by NaIO3 in RPE cells was assessed (E), and the fluorescence intensities were measured and quantified (F). All values are expressed as mean ± S.D. ** p < 0.01, *** p < 0.001 vs. normal group; # p < 0.05, ## p < 0.01 vs. NaIO3 group (n = 3).
Figure 5
Figure 5
Inhibitory effect of ginsenoside Rg3 on NaIO3-induced apoptosis of RPE cells (A). The fluorescence levels were measured (B). Flow cytometry was utilized to examine the impact of ginsenoside Rg3 on NaIO3−induced apoptosis in RPE cells (C) and the percentage of apoptosis (D). The effect of ginsenoside Rg3 on the inhibition of mitochondrial membrane potential induced by NaIO3 in RPE cells was assessed (E), and the fluorescence intensities were measured and quantified (F). All values are expressed as mean ± S.D. ** p < 0.01, *** p < 0.001 vs. normal group; # p < 0.05, ## p < 0.01 vs. NaIO3 group (n = 3).
Figure 6
Figure 6
The effect of ginsenoside Rg3 treatment on the improvement of apoptosis protein levels (A). Apoptosis protein expression analysis (B). Note: Values are expressed as mean ± S.D. * p < 0.05, ** p < 0.01, *** p < 0.001 vs. normal group; # p < 0.05, ## p < 0.01, ### p < 0.001 vs. NaIO3 group (n = 3).
Figure 7
Figure 7
Expression levels of JNK proteins after in vitro treatment with different concentrations of ginsenoside Rg3 and NaIO3 (A). Scanning quantitative analysis of JNK (B). Molecular docking pattern of Rg3-JNK (C). All values were expressed as mean ± S.D., ** p < 0.01 vs. normal group, # p < 0.05 vs. NaIO3 group (n = 3).
Figure 8
Figure 8
The schematic diagram of molecular mechanism of ginsenoside Rg3 against NaIO3-induced ocular toxicity.
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