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

Abstract

Parkinson's disease (PD) is a complex neurodegenerative disorder featuring both motor and nonmotor symptoms associated with a progressive loss of dopaminergic neurons in the substantia nigra pars compacta. Oxidative stress (OS) has been implicated in the pathogenesis of PD. Genetic and environmental factors can produce OS, which has been implicated as a core contributor to the initiation and progression of PD through the degeneration of dopaminergic neurons. The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) orchestrates activation of multiple protective genes, including heme oxygenase-1 (HO-1), which protects cells from OS. Nrf2 has also been shown to exert anti-inflammatory effects and modulate both mitochondrial function and biogenesis. Recently, a series of studies have reported that different bioactive compounds were shown to be able to activate Nrf2/antioxidant response element (ARE) and can ameliorate PD-associated neurotoxin, both in animal models and in tissue culture. In this review, we briefly overview the sources of OS and the association between OS and the pathogenesis of PD. Then, we provided a concise overview of Nrf2/ARE pathway and delineated the role played by activation of Nrf2/HO-1 in PD. At last, we expand our discussion to the neuroprotective effects of pharmacological modulation of Nrf2/HO-1 by bioactive compounds and the potential application of Nrf2 activators for the treatment of PD. This review suggests that pharmacological modulation of Nrf2/HO-1 signaling pathway by bioactive compounds is a therapeutic target of PD.

Keywords: Nrf2; Parkinson’s disease; heme oxygenase-1; neuroprotection; oxidative stress.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Wang, Gao, Chen, Li, Huo, Wang, Wang and Du.

Figures

FIGURE 1

The schematic pathway of major sources of oxidative stress (OS) and induction of DA neuron death in Parkinson’s disease (PD).

FIGURE 2

Schematic presentation of the mitochondrial electron transport chain and production of mitochondrial O2 •−. The mitochondrial electron transport chain produces ROS. Mitochondrial complexes I and II use electrons donated from NADH and FADH2 to reduce coenzyme Q. Coenzyme Q shuttles these electrons to complex III, where they are transferred to cytochrome c. Complex IV uses electrons from cytochrome c to reduce molecular oxygen to water. The action of complexes I, III, and IV produce a proton electrochemical potential gradient, the free energy of which is used to phosphorylate ADP at ATP synthase. Complexes I, II, and III produce superoxide through the incomplete reduction of oxygen to superoxide, whereas complexes I and II produce superoxide only into the mitochondrial matrix and complex III produces superoxide into both the matrix and the intermembrane space.

FIGURE 3

Mitochondrial dysfunction and OS in PD. The mechanism of mitochondrial dysfunction and OS highlights the inhibition of mitochondrial complex I (CI) and associated ROS production leading to loss of dopaminergic neurons in PD.

FIGURE 4

Activation of the NADPH oxidase family members. Several components and domains make up the transmembrane-active enzyme complexes of NADPH oxidase isoforms. NOX1-5 and DUOX1/DUOX2 are shown. Upon activation, an electron will be transferred from NADPH to O2 to form superoxide. NOX4-generated superoxide undergoes rapid conversion into hydrogen peroxide, which mediates many of its downstream effects. NOX5 and the DUOX enzymes are sensitive to cellular Ca2+ concentrations.

FIGURE 5

Alpha-synuclein and microglial Nox2 activation. The activation of microglia by alpha-synuclein can implicate several cell-surface receptors, such as P2X7, TLR2/4, and CR3, and subsequent activation of several kinases, such as PKC, Akt, MAPKs, PAK, and ERK1/2. This in turn could promote the phosphorylation and translocation of p47phox and subsequent Nox2 activation. Released oxygen species appear to promote microglia chemoattraction, activation, and OS. Neuronal damage leads to the release of alpha-synuclein and the TLR-agonist high mobility group box protein 1 (HMGB1).

FIGURE 6

SN neuron DA metabolism. In addition to the uptake of DA by the DA transporter (DAT) from outside, DAergic neurons in the SN produce DA under the action of tyrosine hydroxylase (TH) and aromatic amino acid decarboxylase (AADC) in the cytosol. The amino acid tyrosine is converted to L-dopa using TH, and the second L-dopa is converted to dopamine using AADC. The newly synthesized or taken up DA is immediately transported to and stored in the monoaminergic vesicles by VMAT-2, preventing the existence of free dopamine in the cytosol. Cytosolic DA oxidizes to dopamine o-quinone (DAQ), which is immediately cyclized to aminochrome, which induces mitochondrial dysfunction, endoplasmic reticulum stress (ERS), oxidative stress (OS), the aggregation of alpha-synuclein, and the dysfunction of protein degradation. Dopamine in the cytosol can be degraded by monoamine oxidase-mediated degradation to 3,4-dihydroxyphenylacetaldehyde (DOPAL), hydrogen peroxide, and ammonia, which is converted to 3,4-dihydroxyphenylacetic acid (DOPAC) by aldehyde dehydrogenase. DA can be taken up into glial cells and degraded by catechol-o-methyltransferase (CMOT) or monoamine oxidase (MAO) to form homovanillic acid (HVA).

FIGURE 7

Schematic representation of bioactive compounds-mediated neuroprotective against PD through activating Nrf2/ARE/HO-1 pathway.