Ginsenoside Rg1 ameliorates the senescence and neurite injury of retinal ganglion cells in DR via targeting VDR and promoting mitochondrial biogenesis.

BACKGROUND

Injury of retinal ganglion cells (RGCs) is one of the earliest signs of diabetic retinopathy (DR), preceding retinal microvascular abnormalities. Driven by metabolic and biochemical cascades, diabetes-dependent senescence in the retinal neural cells is responsible for neurodegeneration and subsequent permanent visual loss. This study investigated the involvement of ginsenoside Rg1 (Rg1) in neuropathy associated with DR to identify a possible therapeutic target.

METHODS

The anti-aging and synaptogenesis effects, and neuroprotective mechanism of Rg1 were investigated in high glucose-induced RGCs and STZ-induced DR mice.

RESULTS

Rg1 effectively reduced the β-galactosidase activity, promoted the neurite outgrowth, and reversed the expression of senescence and synaptic development-related proteins. Mechanistically, the compromised mitochondrial biogenesis induced by hyperglycaemia manifested as a critical driver of functional and structural impairments in RGCs. Meanwhile, Rg1 interacts with VDR to potentiate transcription of PGC-1α via the VDR/cAMP/PKA/CREB pathway. Activation of PGC-1α by Rg1 revitalized hyperglycaemia-hampered mitochondrial biogenesis, and resultantly alleviated senescence and neurite outgrowth inhibition of RGCs both in vitro and in vivo models.

CONCLUSION

Rg1 ameliorates neuropathy of DR by activating VDR non-genomic pathway and facilitating mitochondrial biogenesis. These results suggest a therapeutic approach for mitigating neurodegeneration in early DR, and provide insights into the potential clinical application of VDR agonism with Rg1 in regulating mitochondrial quality control.