Targeting Nrf2 for the treatment of Duchenne Muscular Dystrophy

Abstract

Imbalances in redox homeostasis can result in oxidative stress, which is implicated in various pathological conditions including the fatal neuromuscular disease Duchenne Muscular Dystrophy (DMD). DMD is a complicated disease, with many druggable targets at the cellular and molecular level including calcium-mediated muscle degeneration; mitochondrial dysfunction; oxidative stress; inflammation; insufficient muscle regeneration and dysregulated protein and organelle maintenance. Previous investigative therapeutics tended to isolate and focus on just one of these targets and, consequently, therapeutic activity has been limited. Nuclear erythroid 2-related factor 2 (Nrf2) is a transcription factor that upregulates many cytoprotective gene products in response to oxidants and other toxic stressors. Unlike other strategies, targeted Nrf2 activation has the potential to simultaneously modulate separate pathological features of DMD to amplify therapeutic benefits. Here, we review the literature providing theoretical context for targeting Nrf2 as a disease modifying treatment against DMD.

Astragaloside IV Attenuates the Myocardial Injury Caused by Adriamycin by Inhibiting Autophagy

“…Keap1 is an antioxidant transcription factor and a reverse regulator of Nrf2 ( Kourakis et al, 2020 ). Existing data verify that adriamycin reduces the protein expression of Nrf2, but the expression of keap1 does not change with that of Nrf2.…”

“…Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that not only regulates the phase II detoxification response ( Silva-Palacios et al, 2016 ), but also regulates dominates redox homeostasis and cellular antioxidant defense ( Peng et al, 2020 ). Kelch-like ECH-associated protein 1 (Keap1) is a protein responsible for the cytoplasmic isolation of Nrf2 under physiological conditions ( Kourakis et al, 2020 ). In general, Keap1 promotes the ubiquitination and degradation of Nrf2.…”

Calming the (Cytokine) Storm: Dimethyl Fumarate as a Therapeutic Candidate for COVID-19

“…DMF is a methyl ester of fumaric acid (chemical formula C 6 H 8 O 4 ) that is hydrolysed in the small intestine to the active metabolite monomethyl fumarate [ 5 , 6 , 7 , 8 ]. DMF is a potent activator of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway which modulates inflammation and oxidative stress by upregulating cellular defence mechanisms (i.e., cytoprotection through Phase II antioxidant expression, chiefly superoxide dismutase (SOD1), NAD(P)H quinone oxidoreductase-1 (NQO1) and heme oxygenase-1 (HO-1; Figure 2 ) [ 6 , 7 , 8 , 9 ]. In addition, DMF exerts some of its effects through Nrf2-independent mechanisms: (1) indirect inhibition of the inflammatory mediator, nuclear factor kappa B (NF-κB); and (2) hydroxycarboxylic acid receptor 2 (HCAR2) activation, which modulates immune cell (particularly neutrophil) infiltration, adhesion and chemotaxis, reduces pro-inflammatory cytokine production and inhibits NF-κB ( Figure 2 ) [ 6 , 8 , 9 , 10 , 11 , 12 ].…”

Standard of care versus new-wave corticosteroids in the treatment of Duchenne muscular dystrophy: Can we do better?

“…There are many pharmacological as well as nutraceutical activators of Nrf2 including those approved for use as disease modifying treatments (DMF, MMF, DRF, ursodiol and oltipraz). Whilst no clinical trials have investigated FAEs for their dual Nrf2/HCAR2 activator action in DMD patients at present [ 123 ], the synthetic flavonone, epicatechin, which has strong anti-inflammatory properties [ 124 , 125 ] and is an Nrf2 activator [ 126 ] (in addition to several other purported mechanisms of action such as myostatin suppression), has tested favourably in the mdx mouse [ 127 , 128 ] and is in clinical development for BMD (NCT04386304) [ 129 ] (but not DMD). Given the safety and efficacy of FAEs and targeted Nrf2 activators established in other studies, further translational investigations should be undertaken to assess the therapeutic potential of novel and repurposed modulators of DMD pathology as corticosteroid alternatives.…”

“…Given the safety and efficacy of FAEs and targeted Nrf2 activators established in other studies, further translational investigations should be undertaken to assess the therapeutic potential of novel and repurposed modulators of DMD pathology as corticosteroid alternatives. This is particularly relevant since Nrf2 activation has additional benefits beyond the anti-inflammatory activity of glucocorticoids, which include energy re-balancing through mitochondrial biogenesis as well as muscle regeneration and repair [ 123 ]. Through multiple mechanisms, FAEs can also modify a more extensive cytokine profile than glucocorticoids [ 130 ].…”