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.

Polyphenols from Thinned Young Apples: HPLC-HRMS Profile and Evaluation of Their Anti-Oxidant and Anti-Inflammatory Activities by Proteomic Studies

“…In addition to these proteins, PTGR1 and BLVRB were also found to be up-regulated, as reported in the volcano plots ( Figure 5 ). PTGR1 is an NADPH-dependent oxidoreductase which is found to be induced by NRF2 activators [ 56 ] and directly regulated by NRF2 [ 57 ]. BLVRB is found to be an NRF2 target gene and together with HMOX is critical in the heme metabolism [ 58 ] (Figure 11A).…”

“…The crucial finding is that TAP treatment over-expresses the inducible isoform of heme oxygenase (HMOX1), a well-established immunomodulator [ 65 , 66 , 67 ]; it has been proven that the induction of HMOX1 protects against the cytotoxicity caused by oxidative stress and apoptotic cell death, making HMOX1 an appealing target for the treatment of several chronic inflammatory diseases, including osteoporosis [ 68 ], cancer [ 69 ], acute kidney injury [ 70 ], retinal pigment epithelium degeneration [ 71 ] and Parkinson’s disease [ 56 , 67 ].…”

Evidence for Oxidative Pathways in the Pathogenesis of PD: Are Antioxidants Candidate Drugs to Ameliorate Disease Progression?

“…Plasma HO-1 levels in PD patients are elevated and associated with a reduction in right hippocampal volume [164]. HO-1 is induced by a myriad of natural compounds as well as various polyphenols and flavonoids and this is associated with neuroprotection across PD models [165]. Further, abrogation of neuroprotection is observed with silencing of Nrf2 or inhibition of HO-1 in various cell and animal neurodegeneration studies [156,166].…”

Epigallocatechin-3-gallate: A phytochemical as a promising drug candidate for the treatment of Parkinson’s disease

“…It is characterized by motor and non-motor symptom ( Postuma et al, 2015 ). The degeneration of dopaminergic neurons located in the substantia nigra pars compacta (SNpc) of the brainstem ( Wang et al, 2021 ), which leads to the depletion of striatal dopamine levels ( Meder et al, 2019 ), is the major pathological feature of PD, along with the presence of Lewy bodies (LBs), which mainly consist of misfolded α-synuclein, ubiquitin, PTEN-induced kinase-1 (PINK1), parkin, and other proteins, in the surviving neurons ( Cookson, 2005 ; Abeliovich and Flint, 2006 ). PD affects more than 2% of the population older than 65 years old ( Aarsland et al, 2017 ), and is becoming a major age-related health problem ( Zou et al, 2015 ; Hirsch et al, 2016 ; Savica et al, 2016 ).…”

“…Oxidative stress ( Fahn and Cohen, 1992 ; Dionísio et al, 2021 ), mitochondrial dysfunction ( Park et al, 2018 ), neuroinflammation ( Kip and Parr-Brownlie, 2022 ), iron dysregulation ( Vuuren et al, 2020 ), ferroptosis ( Ko et al, 2021 ; Mahoney-Sánchez et al, 2021 ; Wu et al, 2021 ), protein misfolding and degradation dysfunction ( Haque et al, 2022 ), and environmental and genetic factors ( Kline et al, 2021 ) probably play an important role in the pathogenesis of PD. The available therapeutic options for PD are limited, and only provide symptomatic relief, rather than halting the progression of the disease, in addition to having serious side effects ( Wang et al, 2021 ). Increasing numbers of studies have been performed to identify neuroprotective compounds that can prevent dopaminergic neuron injury, and thereby retard disease progression and add further benefits to current therapy ( Kujawska and Jodynis-Liebert, 2018 ; Dos Santos et al, 2022 ).…”