The Nrf2-ARE Signalling Pathway: Promising Drug Target to Combat Oxidative Stress in Neurodegenerative Disorders

Abstract

A large body of evidence indicates that oxidative stress is a salient pathological feature in many neurodegenerative diseases, including Amyotrophic lateral sclerosis, Alzheimer's disease, and Parkinson's disease. In addition to signs of systemic oxidative stress, at the biochemical and neuropathological level, neuronal degeneration in these disorders has been shown to coincide with several markers of oxidative damage to lipids, nucleic acids, and proteins in affected brain regions. Neuroinflammatory processes, often associated with the induction of free radical generating enzymes and the accumulation of reactive astrocytes and microglial cells, are considered as a major source of oxidative stress. Given the pathogenic impact of oxidative stress and neuroinflammation, therapeutic strategies aimed to blunt these processes are considered an effective way to confer neuroprotection. Recently, the nuclear transcription factor Nrf2, that binds to the antioxidant response element (ARE) in gene promoters, has been reported to constitute a key regulatory factor in the co-ordinate induction of a battery of endogenous cytoprotective genes, including those encoding for both antioxidant- and anti-inflammatory proteins. In the present review, besides discussing recent evidence underscoring the thesis that the Nrf2-ARE signalling pathway is an attractive therapeutic target for neurodegenerative diseases, we advocate the view that chemopreventive agents might be suitable candidates to serve as lead compounds for the development of a new class of neuroprotective drugs.

Nrf2-dependent persistent oxidative stress results in stress-induced vulnerability to depression

“…Activating the Nrf2-Keap1 pathway with chemical activators is beneficial prior to/after intracerebral hemorrhage or traumatic brain injury as well as in chemical/acute models of neurodegeneration. 18,19,66 Here, we demonstrate that Nrf2 dysfunction is also central to vulnerability to depression in a double-hit scenario. Nrf2-null mice were endogenously in a vulnerable state, as indicated by results showing that mild stress was sufficient to induce a depressive phenotype.…”

The Atypical Antipsychotic Paliperidone Regulates Endogenous Antioxidant/Anti-Inflammatory Pathways in Rat Models of Acute and Chronic Restraint Stress

“…Then, NRF2 binds to the antioxidant response elements (ARE) within the promoter of antioxidant enzymes, activating their transcription [10]. The most relevant of these enzymes are heme oxygenase-1 (HO1), nicotinamide adenine dinucleotide phosphate dehydrogenase quinone 1 (NQO1), superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT) [11].…”

Targeting Nrf2-Mediated Gene Transcription by Extremely Potent Synthetic Triterpenoids Attenuate Dopaminergic Neurotoxicity in the MPTP Mouse Model of Parkinson's Disease

“…In the context of PD, NQO1 induction may be important to nigrostriatal dopaminergic neurons due its relevance in the reduction of oxidized catechol rings and ameliorating the detrimental effects of DA quinones. NQO1 is also involved in detoxification of protein-bound quinones and maintains alpha-tocopherol and coenzyme Q 10 in their reduced antioxidant states (44). Induction of HO-1 may provide resistance to chronic oxidative stress in dopaminergic neurons induced by the accumulation of iron due to its involvement in the metabolism of the pro-oxidant heme to the antioxidant pigment biliverdin (11).…”