Polydatin Prevents Lipopolysaccharide (LPS)-Induced Parkinson's Disease via Regulation of the AKT/GSK3β-Nrf2/NF-κB Signaling Axis

Abstract

Parkinson's disease (PD) is a common neurodegenerative disease characterized by selective loss of dopaminergic neurons in the substantia nigra (SN). Neuroinflammation induced by over-activation of microglia leads to the death of dopaminergic neurons in the pathogenesis of PD. Therefore, downregulation of microglial activation may aid in the treatment of PD. Polydatin (PLD) has been reported to pass through the blood-brain barrier and protect against motor degeneration in the SN. However, the molecular mechanisms underlying the effects of PLD in the treatment of PD remain unclear. The present study aimed to determine whether PLD protects against dopaminergic neurodegeneration by inhibiting the activation of microglia in a rat model of lipopolysaccharide (LPS)-induced PD. Our findings indicated that PLD treatment protected dopaminergic neurons and ameliorated motor dysfunction by inhibiting microglial activation and the release of pro-inflammatory mediators. Furthermore, PLD treatment significantly increased levels of p-AKT, p-GSK-3βSer9, and Nrf2, and suppressed the activation of NF-κB in the SN of rats with LPS-induced PD. To further explore the neuroprotective mechanism of PLD, we investigated the effect of PLD on activated microglial BV-2 cells. Our findings indicated that PLD inhibited the production of pro-inflammatory mediators and the activation of NF-κB pathways in LPS-induced BV-2 cells. Moreover, our results indicated that PLD enhanced levels of p-AKT, p-GSK-3βSer9, and Nrf2 in BV-2 cells. After BV-2 cells were pretreated with MK2206 (an inhibitor of AKT), NP-12 (an inhibitor of GSK-3β), or Brusatol (BT; an inhibitor of Nrf2), treatment with PLD suppressed the activation of NF-κB signaling pathways and the release of pro-inflammatory mediators in activated BV-2 cells via activation of the AKT/GSK3β-Nrf2 signaling axis. Taken together, our results are the first to demonstrate that PLD prevents dopaminergic neurodegeneration due to microglial activation via regulation of the AKT/GSK3β-Nrf2/NF-κB signaling axis.

Dietary Supplementation of the Antioxidant Curcumin Halts Systemic LPS-Induced Neuroinflammation-Associated Neurodegeneration and Memory/Synaptic Impairment via the JNK/NF-κB/Akt Signaling Pathway in Adult Rats

“…Mounting studies have reported that LPS treatment inhibited the phosphorylation of Akt and GSK3- β in rat models of Parkinson's disease [26]. Our western blot and immunofluorescent results indicated that LPS treatment disrupts the survival pathway, demonstrated by a decrease in the expression and phosphorylation of Akt and GSK3- β proteins compared to saline-treated adult rats.…”

“…With respect to neuroinflammation, it has been suggested that several mechanisms are involved in the secretion of proinflammatory cytokines by astrocytes and microglial cells. One such mechanism is the LPS-induced p-JNK pathway that functions as a link between ROS/oxidative stress and neuroinflammation-mediated apoptotic neurodegeneration [4, 26, 37, 38]. It is well known that dietary curcumin is a strong candidate for the prevention of ROS/oxidative stress-mediated neuroinflammation-related neurodegeneration [39].…”

“…Furthermore, curcumin has also been shown to have a protective role in other conditions such as cancer, pancreatitis, rheumatoid arthritis, liver disease, and pulmonary dysfunction [22, 23]. In addition, curcumin protects the brain from LPS toxicity by inhibiting the production of nitric oxide (NO), prostaglandin E2 (PGE2), ROS, and proinflammatory cytokines [24–26].…”

Anti‐inflammatory effects of doxepin hydrochloride against LPS‐induced C6‐glioma cell inflammatory reaction by PI3K‐mediated Akt signaling

“…The Akt pathways have been reported to be major players in the expression of numerous proinflammatory genes. Seldom reports demonstrated that activation of the Akt signaling pathway by LPS can induce the release of proinflammatory cytokines, and Huang et al's animal experiments showed that LPS did not activate Akt phosphorylation significantly in rats. But in the front part of our experiment, we found LPS could downregulate the expression of p‐Akt in C6 cells.…”

Resveratrol Derivatives as Potential Treatments for Alzheimer’s and Parkinson’s Disease

“…In a rat model of LPS-induced PD, polydatin ameliorated motor dysfunction and protected dopaminergic neurons through the decrease of microglial activation and pro-inflammatory mediators. Furthermore, the levels of p-Akt and Nrf-2 were increased and the activation of NF-κB was suppressed by polydatin in the substantia nigra (Huang et al, 2018).…”