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Nrf2/ARE Pathway Modulation by Dietary Energy Regulation in Neurological Disorders


Nrf2/ARE Pathway Modulation by Dietary Energy Regulation in Neurological Disorders

Andrea Rodrigues Vasconcelos et al. Front Pharmacol.


Nuclear factor erythroid 2-related factor 2 (Nrf2) regulates the expression of an array of enzymes with important detoxifying and antioxidant functions. Current findings support the role of high levels of oxidative stress in the pathogenesis of neurological disorders. Given the central role played by Nrf2 in counteracting oxidative damage, a number of studies have targeted the modulation of this transcription factor in order to confer neuroprotection. Nrf2 activity is tightly regulated by oxidative stress and energy-based stimuli. Thus, many dietary interventions based on energy intake regulation, such as dietary energy restriction (DER) or high-fat diet (HFD), modulate Nrf2 with consequences for a variety of cellular processes that affect brain health. DER, by either restricting calorie intake or meal frequency, activates Nrf2 thereby triggering its protective effects, whilst HFD inhibit this pathway, thereby exacerbating oxidative stress. Consequently, DER protocols can be valuable strategies in the management of central nervous system (CNS) disorders. Herein, we review current knowledge of the role of Nrf2 signaling in neurological diseases, namely Alzheimer's disease, Parkinson's disease, multiple sclerosis and cerebral ischemia, as well as the potential of energy intake regulation in the management of Nrf2 signaling.

Keywords: Alzheimer’s disease; Nrf2; Parkinson’s disease; aging; cerebral ischemia; dietary energy restriction; high-fat diet; multiple sclerosis.


Schematic representation of Nrf2 signaling in homeostasis and a deregulated environment. (A) Oxidative molecules (e.g., ROS and RNS) produced by cellular respiration or neurotransmission activate the protective antioxidant pathway by dissociation of the Nrf2/KEAP1 complex. When dissociated from the cytosolic protein KEAP1, Nrf2 translocates to the cell nucleus, triggering the expression of several homeostatic genes with the ARE sequence in their promoters, including GPx, SOD, HO-1, GST, and CAT. When inactivated, Nrf2 is sequestered by KEAP1 and targeted for ubiquitination and proteasomal degradation. (B) Altered homeostasis promotes excessive ROS/RNS production that can activate glial cells (astrocytes and microglia) that release proinflammatory and danger molecules patterns, which disrupts neuronal communication and the nature of glial activities. Green arrows represent activation and truncated red lines, inhibition (abbreviations: ACh, acetylcoline; DA, dopamine; CAT, catalase; Glu, glutamate; GPx, Glutathione Peroxidase; GST, glutathione S-transferase; HO-1, heme oxigenase 1; RNS, reactive nitrogen species; ROS, reactive oxygen species; SOD, superoxide dismutase; Ub, ubiquitin; ATP, adenosine triphosphate).
The role of Nrf2 modulation by dietary interventions on brain health. HFD inhibit Nrf2 in the brain, whereas DER is able to activate this transcription factor. When activated, Nrf2 triggers the expression of several neuroprotective genes that counteract oxidative stress and neuroinflammation, preventing the onset of neurological disorders and underlying pathological processes. Green arrows represent activation and truncated red lines, inhibition (abbreviations: DER, dietary energy restriction; HFD, high-fat diet).
The role of NRF2 and dietary interventions (DER and HFD) on the modification of the BBB. Neurological diseases, such as AD, PD, MS, and ischemic stroke, can lead to BBB disruption. However, Nrf2 protects neurons and the BBB against oxidative stress and inflammation-induced damage. Astrocytes, microglia and neurons produce Nrf2 that activates the expression of antioxidant and anti-inflammatory genes to the maintenance of neuronal health and BBB integrity. Nrf2 protective effects on BBB can be modulated by DER and HFD, modifying the release of inflammatory mediators by glial cells in neurodegenerative diseases. Green arrows represent activation and truncated red lines, inhibition (abbreviations: BBB, blood-brain barrier; DER, dietary energy restriction; HFD, high-fat diet, MS, multiple sclerosis; PD, Parkinson’s disease; DER, dietary energy restriction; HFD, high-fat diet).

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