Modulation of Nrf2/ARE Pathway by Food Polyphenols: A Nutritional Neuroprotective Strategy for Cognitive and Neurodegenerative Disorders

Abstract

In recent years, there has been a growing interest, supported by a large number of experimental and epidemi-ological studies, for the beneficial effects of some phenolic substances, contained in commonly used spices and herbs, in preventing various age-related pathologic conditions, ranging from cancer to neurodegenerative diseases. Although the exact mechanisms by which polyphenols promote these effects remain to be elucidated, several reports have shown their ability to stimulate a general xenobiotic response in the target cells, activating multiple defense genes. Data from our and other laboratories have previously demonstrated that curcumin, the yellow pigment of curry, strongly induces heme-oxygenase-1 (HO-1) expression and activity in different brain cells via the activation of heterodimers of NF-E2-related factors 2 (Nrf2)/antioxidant responsive element (ARE) pathway. Many studies clearly demonstrate that activation ofNrf2 target genes, and particularly HO-1, in astrocytes and neurons is strongly protective against inflammation, oxida-tive damage, and cell death. In the central nervous system, the HO system has been reported to be very active, and its modulation seems to play a crucial role in the pathogenesis of neurodegenerative disorders. Recent and unpublished data from our group revealed that low concentrations of epigallocatechin-3-gallate, the major green tea catechin, induces HO-1 by ARE/Nrf2 pathway in hippocampal neurons, and by this induction, it is able to protect neurons against different models of oxidative damages. Furthermore, we have demonstrated that other phenolics, such as caffeic acid phenethyl ester and ethyl ferulate, are also able to protect neurons via HO-1 induction. These studies identify a novel class of compounds that could be used for therapeutic purposes as preventive agents against cognitive decline.

Protection of Cultured Cortical Neurons by Luteolin against Oxidative Damage through Inhibition of Apoptosis and Induction of Heme Oxygenase-1

“…13,14) It has been reported that several plant-derived polyphenolic compounds can exert neuroprotective action through the regulation of HO-1 expression. 44) Keeping this in consideration, the influence of this flavonoid on HO-1 expression was investigated in the H 2 O 2 -treated cells in order to further understand the molecular mechanism(s) underlying its neuroprotective activity. Luteolin caused a marked, time-dependent induction of HO-1 expression (Figs.…”

The modest impact of transcription factor Nrf2 on the course of disease in an ALS animal model

“…20 Several lines of evidences have suggested that the induction of Nrf2-regulated phase II enzymes, including HO-1, NQO1, and GCLM, etc, had strongly protective effects against oxidative damage and neuronal death. 18,21 In addition, it was reported that GCLM knockout decreased the life span of SOD1-G93A mice by 55%, which was related to the reduction of GSH. 22 To better understand the role of Nrf2 in ALS, we examined the expression of several phase II enzymes in different tissues, including lumbar spinal cord and motor cortex, of Nrf2 þ / þ and Nrf2 À / À SOD1-G93A mice (Figure 4).…”

Antioxidant Properties of Hydroxycinnamic Acids: A Review of Structure- Activity Relationships

“…Another requirement is that the compound should also generate a more stable, and therefore less injurious, intermediate molecule upon reaction with a ROS in order to be considered as a good antioxidant [4]. With the recent findings, these definitions should be broadened to encompass also agents that are capable of sequestering transition metal ions (chelation activity), inhibi-tion of enzymes involved in ROS production and induction of endogenous defense mechanisms such as antioxidant enzymes [18].Large scale epidemiologic cohort studies in different populations have provided evidence that consumption of dietary antioxidants is associated with reduced risks of heart diseases and neurodegeneration [19,20]. Although a number of interventional trials have failed to prove the usefulness of antioxidants for disease management, the use of disease specific, target-directed antioxidants in carefully chosen patients with higher levels of oxidative stress may prove useful in management of certain diseases [14,21,22].…”