Activation of Nrf2-driven antioxidant enzymes by cardamonin confers neuroprotection of PC12 cells against oxidative damage

Abstract

Oxidative stress represents a disorder of the redox equilibrium between the production of free radicals and the capability of cells to eliminate them. As subversion of this redox balance is thought to initiate various diseases, living cells maintain a redox equilibrium diligently. More and more pieces of evidence show that oxidative stress has already become a common risk factor in the pathogenesis of neurodegenerative disorders. So, considerable importance has been given to the prevention of oxidative stress as a potential therapeutic strategy. It is well known that the Nrf2-ARE pathway represents one of the most important cellular endogenous defense mechanisms against oxidative stress. Activation of Nrf2 signaling induces the transcriptional regulation of multiple ARE-dependent antioxidant defense genes. Here, we showed that cardamonin (CD), a chalcone isolated from Alpinia katsumadai, attenuated cell death induced by hydrogen peroxide (HO) and 6-hydroxydopamine (6-OHDA) in PC12 cells. Pretreatment of PC12 cells with CD dose-dependently upregulated the expression of phase II antioxidant molecules governed by Nrf2. In contrast, CD failed to provide neuroprotection after silencing Nrf2 expression, indicating that this cytoprotection may be mediated by the activation of transcription factor Nrf2. Our results demonstrate that CD is a novel small molecule activator of Nrf2 in PC12 cells, and suggest that CD may be a potential candidate for the prevention of oxidative stress-mediated neurodegenerative disorders.

High throughput small molecule screening reveals NRF2-dependent and - independent pathways of cellular stress resistance

“…Nrf2 inducers are under development for a variety of inflammatory, metabolic, degenerative, and neoplastic diseases 65 . The induction of Nrf2 signaling by cardamonin that we observe is consistent with prior reports in the literature [66][67][68] . In this regard, NRF2 levels and target gene expression are elevated in skin fibroblasts derived from long-lived Snell dwarf mice, likely contributing to the multiplex stress resistance observed in these cells 37 .…”

Neuroprotective effect of diosgenin in a mouse model of diabetic peripheral neuropathy involves the Nrf2/HO-1 pathway

“…Nrf2 is a critical transcription factor of the antioxidant defence system that induces the expression of phase II detoxification enzymes (HO-1, NQO1 and epoxide hydrolase, etc.) [48]. HO-1 has also been found to have potential neurovascular protective properties in diabetic neuropathy [49].…”

Neuroprotection of mangiferin against oxidative damage via arousing Nrf2 signaling pathway in PC12 cells

“…A count of 1 × 10 6 cells/dish was cultured in 60‐mm dishes for 24 h. After cells were pretreated with Mg for additional 24 h, H 2 O 2 , or 6‐OHDA was added to injure the cells for 12 h. Then, the supernatant was collected for the measurement of LDH activity as described in our previous work .…”