Abstract
The pathogenic mechanism of Parkinson's disease (PD) remains to be elucidated; however, mitochondrial dysfunction at the level of complex I and oxidative stress is suggestively involved in the development of PD. In our previous work, salidroside (Sal), an active component extracted from the medicinal plant Rhodiola rosea L., might protect dopaminergic (DA) neurons through modulating ROS–NO-related pathway. However, the mechanism of Sal-induced neuroprotective effects against PD remains poorly understood. Therefore, we further investigated whether Sal plays neuroprotective effects by activating complex I via DJ-1/Nrf2-mediated antioxidant pathway. The results showed that Sal remarkably attenuated MPP+/MPTP-induced decline in cell viability, accompanied by decreases in reactive oxygen species (ROS), malondialdehyde (MDA), and 8-hydroxy-deoxyguanosine (8-OHdG) contents and increases in the superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px), as well as glutathione (GSH) levels. Furthermore, Sal greatly improved the behavioral performance and prevented the severe reduction of TH-positive neuron numbers in the substantia nigra (SN). Moreover, in comparison with the MPP+/MPTP group, Sal increased the nuclear translocation of DJ-1 and Nrf2 and the mitochondrial translocation of DJ-1, accompanied by activating complex I. Furthermore, silencing of DJ-1/Nrf2 inhibited the increase of complex I activity and cell viability elicited by Sal. Together, these results support the neuroprotective effect of Sal against MPP+/MPTP-induced DA neurons damage.
Highlights
Parkinson’s disease (PD) is a prevalent neurodegenerative movement disorder affecting 2%-3% of the population above the age of 65 worldwide [1, 2]. e hallmark of PD is the degeneration of dopaminergic (DA) neurons in the substantia nigra (SN) and the presence of Lewy bodies (LBs) [3].e etiology of PD remains unclear, but extensive evidences from postmortem brain tissues have suggested that oxidative stress and deficiency of complex I activity are related to the pathogenic mechanism of PD [4, 5].Oxidative stress, which occurs mainly due to overproduction of reactive oxygen species (ROS), activates a cascade of events leading to DA neuron degeneration [6]
To examine whether Sal alone had an effect on cell viability, we treated cells with different concentrations of Sal for 24 h. e Sal at 0–50 μM had no obvious effect on cell viability (Figure 1(b)). en, we investigated the neuroprotective effect of Sal on MPP+-induced cell toxicity, which was markedly prevented by Sal (10, 25, and 50 μM) (Figure 1(c))
We demonstrated that Sal plays a neuroprotective effect against MPP+/MPTP-induced impairment of DA neurons by preserving complex I activity via DJ-1/Nrf2-mediated antioxidant pathway, as evidenced by the following: (1) Sal pretreatment significantly increased the cell viability in MN9D cells subjected to MPP+; (2) administration of Sal notably attenuated behavioral impairments, accompanied by decreased TH-positive neurons in the SN of the MPTP-induced PD model; (3) Sal decreased the oxidative stress and increased the levels of endogenous antioxidants; (4) Sal increased the nuclear translocation of DJ-1 and Nrf2 and the mitochondrial translocation of DJ-1, accompanied by activating complex I; (5) knockdown of DJ1/Nrf2 expression with siRNA abolished the protective effects of Sal on complex I and cell viability in the MPP+induced PD model
Summary
Oxidative stress, which occurs mainly due to overproduction of reactive oxygen species (ROS), activates a cascade of events leading to DA neuron degeneration [6]. Complex I dysfunction can result in excess generation of ROS, which in turn will lead to the oxidative modification of complex I in a positive feedback loop to exacerbate complex I dysfunction [8]. Given the role of complex I in generating ROS and undergoing oxidative modification damage, it is a promising target for antioxidant therapeutic strategies. Researchers have focused on the pharmacological targeting of antioxidant gene transcription, including DJ-1 (gene: PARK7) and nuclear factor erythroid-2-related factor 2 (protein: Nrf; gene: NFE2L2), attempting to inhibit oxidative stress and deactivation of complex I and limit neuronal damage [9, 10]. One of the most relevant target genes is the transcriptional factor Nrf, a master regulator of antioxidant gene, which activates a range of antioxidant enzymes via antioxidant response element (ARE) enhancer [11]
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