Activation of the Keap1/Nrf2 pathway for neuroprotection by electrophillic phase II inducers

Abstract

Electrophilic neurite outgrowth-promoting prostaglandin (NEPP) compounds protect neurons from oxidative insults. At least part of the neuroprotective action of NEPPs lies in induction of hemeoxygenase-1 (HO-1), which, along with other phase II enzymes, serve as a defense system against oxidative stress. Here, we found that, by using fluorescent tags and immunoprecipitation assays, NEPPs are taken up preferentially into neurons and bind in a thiol-dependent manner to Keap1, a negative regulator of the transcription factor Nrf2. By binding to Keap1, NEPPs prevent Keap1-mediated inactivation of Nrf2 and, thus, enhance Nrf2 translocation into the nucleus of cultured neuronal cells. In turn, Nrf2 binds to antioxidant͞ electrophile-responsive elements of the HO-1 promoter to induce HO-1 expression. Consistent with this notion, NEPP induction of an HO-1 reporter construct is prevented if the antioxidant-responsive elements are mutated. We show that NEPPs are neuroprotective both in vitro from glutamate-related excitotoxicity and in vivo in a model of cerebral ischemia͞reperfusion injury (stroke). Our results suggest that NEPPs prevent excitotoxicity by activating the Keap1͞ Nrf2͞HO-1 pathway. Because NEPPs accumulate preferentially in neurons, they may provide a category of neuroprotective compounds, distinct from other electrophilic compounds such as tertbutylhydroquinone, which activates the antioxidant-responsive element in astrocytes. NEPPs thus represent a therapeutic approach for stroke and neurodegenerative disorders.hemeoxygenase-1 ͉ middle cerebral artery occlusion ͉ neurite outgrowth-promoting prostaglandin ͉ stroke ͉ neurodegenerative diseases

The Flavanol (−)-Epicatechin Prevents Stroke Damage through the Nrf2/HO1 Pathway

“…Increasing evidence suggests that HO1 can be upregulated through the Nrf2/ARE-mediated pathway (Satoh et al, 2006;Zhao et al, 2006). We have shown that Nrf2, a key regulator of the HO1 gene, has an important role in protection against cerebral ischemic stroke (Shah et al, 2007).…”

Acrolein: Sources, metabolism, and biomolecular interactions relevant to human health and disease

“…Both events would lead to elevated levels of active Nrf2 and Nrf2 nuclear accumulation. Although the details of the molecular mechanisms of the Nrf2-mediated response to electrophile stress remain to be elucidated, it seems somewhat provocative to suggest that, at low concentration, acrolein may actually exert cytoprotective effects by inducing phase II enzymes via activation of Nrf2 [119].…”

Cerebroprotective activity of 3-benzylxanthine derivative - compound Ale-15, in conditions of bilateral common carotid arteries ligation (ischemic stroke)

“…[5][6][7][8][9] The accumulation of ROS in neurons results in lipid peroxidation, protein oxidation, DNA damage, and finally cell death. [5][6][7][8][9] Nowadays an active search for new cerebroprotectors is being carried out among compounds, that affect the compensatory shunt of ATP synthesis in conditions of cerebral ischemia, that modulate glutamate-and GABAergic systems, regulate activity of Ca-channels and system of nitrogen oxide, and also among antioxidants, neuropeptides, expression inhibitors of proinflammatory cytokines and antagonists of IL-1β-receptors. 2,10 Strong interrelation between disorder of energetic and plastic metabolism, their effect on course and prognosis of disease are often ignored while making treatment regimens; the main pathogenic treatment is deemed to be hemodynamic recovery.…”