Abstract
Studies have indicated that oxidative stress plays a crucial role in the development of Parkinson’s disease (PD) and other neurodegenerative conditions. Research has also revealed that nuclear factor erythroid 2-related factor 2 (Nrf2) triggers the expression of antioxidant genes via a series of antioxidant response elements (AREs), thus preventing oxidative stress. Thymoquinone (TQ) is the bioactive component of Nigella sativa, a medicinal plant that exhibits antioxidant and neuroprotective effects. In the present study we examined whether TQ alleviates in vivo and in vitro neurodegeneration induced by 1-methyl-4-phenylpyridinium (MPP+) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) by acting as an activator of the Nrf2/ARE cascade. We showed that TQ significantly reduced MPP+-mediated cell death and apoptosis. Moreover, TQ significantly elevated the nuclear translocation of Nrf2 and significantly increased the subsequent expression of antioxidative genes such as Heme oxygenase 1 (HO-1), quinone oxidoreductase (NQO1) and Glutathione-S-Transferase (GST). The application of siRNA to silence Nrf2 led to an abolishment in the protective effects of TQ. We also found that the intraperitoneal injection of TQ into a rodent model of PD ameliorated oxidative stress and effectively mitigated nigrostriatal dopaminergic degeneration by activating the Nrf2-ARE pathway. However, these effects were inhibited by the injection of a lentivirus wrapped Nrf2 siRNA (siNrf2). Collectively, these findings suggest that TQ alleviates progressive dopaminergic neuropathology by activating the Nrf2/ARE signaling cascade and by attenuating oxidative stress, thus demonstrating that TQ is a potential novel drug candidate for the treatment of PD.
Highlights
Parkinson’s disease (PD) is a non-reversible and age-linked chronic neurodegenerative condition that is typified by the depletion of nigrostriatal dopaminergic neurons
In order to investigate the therapeutic effects of TQ in PD, we investigated the expression of tyrosine hydroxylase (TH) and α-synuclein in the substantia nigra pars compacta (SNc) of an MPTP mouse model using IHC staining
We found that the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) in the SNc was significantly lower in the MPTP mice when compared with the control group (Figure 5E)
Summary
Parkinson’s disease (PD) is a non-reversible and age-linked chronic neurodegenerative condition that is typified by the depletion of nigrostriatal dopaminergic neurons. Multiple biomechanisms have been proposed to affect the mitochondria of dopaminergic neurons, result in increased production of reactive oxygen species (ROS) (Schapira and Jenner, 2011). ROS can result in covalent oxidative modifications such as the oxidation of RNA and can induce mutations in mitochondrial DNA (mtDNA), affecting the stability of nucleic acids (Angelova and Abramov, 2018). Oxidative modifications are known to interfere with protein homeostasis by expediting the aggregation of α-synuclein and parkin, and by dissociating the proteasome (Scudamore and Ciossek, 2018). These modifications may cause cellular dysfunction and even apoptosis. It is evident that the antioxidant pathways that regulate mechanisms to ameliorate oxidative damage may exhibit neuroprotective effects (Izumi et al, 2018)
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