The role of modulation of antioxidant enzyme systems in the treatment of neurodegenerative diseases

Abstract

Oxidative stress is a much-appreciated phenomenon associated with the progression of neurodegenerative diseases (NDDs) due to imbalances in redox homeostasis. The poor correlations between the in vitro benefits and clinical trials of direct radical scavengers have prompted research into indirect antioxidant enzymes such as Nrf2. Activation of Nrf2 leads to the upregulation of a myriad of cytoprotective and antioxidant enzymes/proteins. Traditionally, early Nrf2-activators were studied as chemoprotective agents. There is a consequential lack of clinical trials testing Nrf2 activation in NDDs. However, there is abundant evidence of their utility in pre-clinical studies. Herein, we review the endogenous Nrf2 regulatory pathway and avenues for targeting this pathway. Furthermore, we provide updated information on preclinical studies for natural and synthetic Nrf2 activators. On the basis of our findings, we posit that successful therapeutics for NDDs rely on the design of potent synthetic Nrf2 activators with a careful combination of other neuroprotective activities.

Anti-Neuroinflammatory Potential of a Nectandra angustifolia (Laurel Amarillo) Ethanolic Extract

“…lates HO-1 in different cells and tissues [34]. As shown in Figure 3E, the ex trol cells to the extract did not affect the constitutive levels of the Keap-1 p marked Keap-1 reduction observed in LPS-treated cells was not amended b of NaE.…”

“…We also examined, both in resting and reactive microglial cells, the expression levels of Keap-1, a crucial inhibitor protein of the transcription factor Nrf2, which also upregulates HO-1 in different cells and tissues [34]. As shown in Figure 3E, the exposure of control cells to the extract did not affect the constitutive levels of the Keap-1 protein, and the marked Keap-1 reduction observed in LPS-treated cells was not amended by the presence of NaE.…”

HX‐1171, a Novel Nrf2 Activator, Induces NQO1 and HMOX1 Expression

“…Therefore, Nrf2 activators that produce antioxidants capable of scavenging ROS would be applied for diseases such as high glucose induced-diabetes and diabetic nephropathy. Many studies have focused on developing Nrf2 modulators, as Nrf2 activators could be preventive and therapeutic agents for neurodegenerative diseases [Obuobi et al, 2016], retinal diseases [Nakagami, 2016], chronic kidney diseases [Saito, 2013], including oxidative stress-induced diseases. HX-1171 is a novel compound that was reported to inhibit the production of nitric oxide and activate the transcription factor nuclear factor kappa B [Liu et al, 2002].…”

Evaluation of the Antioxidant Activity of the Marine Pyrroloiminoquinone Makaluvamines

“…Therefore, the Nrf2 pathway has been extensively studied and its role in neurodegenerative diseases has been confirmed. The protective effect of Nrf2 activation has led to the development of a FDA approved drug, Tecfidera (dimethyl fumarate), Biogen Idec (Cambridge, MA, USA), for the treatment of patients with relapsing multiple sclerosis and the application of Nrf2 activators for other diseases is currently being researched [28,29,30]. The development of new antioxidant molecules that have effects on mitochondria and on the antioxidant enzymes can contribute to the expansion of our knowledge about the potential of antioxidant therapies in neurodegenerative diseases.…”