Paeoniflorin and Plycyrrhetinic Acid Synergistically Alleviate MPP⁺/MPTP-Induced Oxidative Stress through Nrf2-Dependent Glutathione Biosynthesis Mechanisms

Abstract

Recently, combination therapy has proven to be an effective strategy for treating polygenic/multifactorial/complex disorder such as Parkinson’s disease (PD). Here, we hypothesized that dual up-regulation of glutamate cysteine ligase (GCL) catalytic subunit (GCLc) and GCL modifier subunit (GCLm) via nuclear factor E2-related factor (Nrf2) contribute to the antioxidant effect of paeoniflorin (PF) synergistically with glycyrrhetinic acid (GA) (henceforth called PF/GA) in the context of MPP+/MPTP neurotoxicity. Expectedly, CompuSyn synergism/antagonism analysis showed that PF/GA exerts synergistic neuroprotection. Moreover, the antioxidant effect of PF was significantly enhanced by the combined administration of GA, although GA alone did not confer the effect. Mechanistically, PF triggered extracellular signal-regulated kinase (ERK1/2) phosphorylation, resulting in Nrf2 nuclear translocation from cytoplasmic pool via de novo synthesis in MPP+-challenged SH-SY5Y cells. Concomitantly, GA activates Akt which in turn induces nuclear accumulation of Nrf2. Especially, PF/GA up-regulated glutamate-cysteine ligase catalytic subunit (Gclc) and glutamate-cysteine ligase modifier subunit (Gclm) are formed via two separate pathways. Furthermore, these results were confirmed through pathway blockade assays using PD98059 (ERK1/2 inhibitor), LY294002 (phosphatidylinositol-3-kinase inhibitor), and shRNA-induced Nrf2 knockdown. Additionally, using a mouse MPTP-induced model of PD, we demonstrated that PF/GA synergistically ameliorates both motor deficits and oxidative stress in the ventral midbrain. In parallel, PF/GA also up-regulated both GCLc and GCLm expression at levels of transcription and translation. Conversely, antiparkinsonism and antioxidant effects of PF/GA were not observed in Nrf2-knockout MPTP-mice. Collectively, these results show that ERK1/2 and Akt activation contribute to the synergistic antioxidant effect of PF/GA. Hence, PF/GA regimen warrants further preclinical and possible clinical study for PD.

Paeoniflorin protects 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinson’s disease mice by inhibiting oxidative stress and neuronal apoptosis through activating the Nrf2/HO-1 signaling pathway

“…These results demonstrated that paeoniflorin effectively attenuated MPTP-induced motor impairment and DAn death. The neuroprotective effects of paeoniflorin observed in our study are consistent with those observed in previous studies [13,14,25].…”

“…It has been shown to be a potential therapeutic target for alleviating oxidative stress in neurotoxin-induced PD [12]. Previous studies have suggested that the neuroprotective effects of PF in 1-methyl-4-phenyl- pyridinium/1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPP + /MPTP)-induced PD models may be mediated through activation of the α-synuclein/protein kinase C subtype-σ signaling pathway and Nrf2-dependent glutathione mechanisms [13,14]. However, whether PF relieves PD by alleviating oxidative stress-induced injury via the Nrf2 pathway is not clear.…”

Pharmacological Modulation of Nrf2/HO-1 Signaling Pathway as a Therapeutic Target of Parkinson’s Disease

“…Evidence of OS existing in PD is further supported by PD animals modeled with toxins that can cause OS, which includes 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) ( Dong et al, 2021 ), rotenone ( Sharma et al, 2021 ), paraquat ( Ahmad et al, 2021 ), and 6-hydroxydopamine (6-OHDA) ( Zou et al, 2021 ). Moreover, in vivo observations revealed that several markers of OS are altered in the cerebrospinal fluid and blood samples of PD patients ( Vinish et al, 2011 ).…”

Vincamine alleviates brain injury by attenuating neuroinflammation and oxidative damage in a mouse model of Parkinson's disease through the NF‐κB and Nrf2/HO‐1 signaling pathways

“…Upon entry into cells, the neurotoxin MPTP is rapidly converted into the metabolite MPP + , and MPP+ enters dopaminergic neurons to stimulate oxidative stress and activate cell death signals. [ 55 ] A large number of studies on postmortem brain tissues of PD patients have shown that increased levels of mitochondrial complex I activity, SOD activity, and free iron levels and decreased levels of GSH level and antioxidant enzyme activity (such as CAT and GPx) could be observed in the SN of PD patients. [ 56 ] Damaged mitochondria can lead to the excessive production of ROS and the deposition of toxic wastes in the brain, which further lead to dopaminergic neuron death.…”