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Analogs of imine resveratrol alleviate oxidative stress-induced neurotoxicity in PC12 cells via activation of Nrf2.

ABSTRACT: Oxidative stress is closely associated with neurodegenerative, cardiovascular and metabolic diseases. Resveratrol and related compounds have shown great potential as antioxidants via either direct scavenging of abundant reactive oxygen species (ROS) or activation of the Kelch-like ECH-associated protein 1-nuclear factor (erythroid-derived 2)-like 2-antioxidant response elements pathway. In the present study, we evaluated imine resveratrol analogs (IRAs) for their neuroprotective effects against ROS in PC12 cells, which are a commonly employed model system for studies of neuronal development and function. We identified that IRA-3 (4-[[(4-hydroxyphenyl)methylene]amino]-phenol) was more potent than resveratrol at rescuing PC12 cells from H2 O2 -induced oxidative damage, exhibiting a recovery percentage of 60.4% at 50 μm. Our findings suggest that the neuroprotective effect of IRA-3 was achieved via multiple routes, including direct scavenging of ROS, rescue of endogenous antioxidants and activation of the Kelch-like ECH-associated protein 1-nuclear factor (erythroid-derived 2)-like 2-antioxidant response elements pathway. Our results suggest that IRA-3 may have potential for development into a possible treatment for neurodegenerative diseases.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC8329772 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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Analogs of imine resveratrol alleviate oxidative stress-induced neurotoxicity in PC12 cells via activation of Nrf2.

Zhang Yin Y Wang Zhixiong Z Yang Jiehong J He Yu Y Wan Haitong H Li Chang C

FEBS open bio 20210702 8

Oxidative stress is closely associated with neurodegenerative, cardiovascular and metabolic diseases. Resveratrol and related compounds have shown great potential as antioxidants via either direct scavenging of abundant reactive oxygen species (ROS) or activation of the Kelch-like ECH-associated protein 1-nuclear factor (erythroid-derived 2)-like 2-antioxidant response elements pathway. In the present study, we evaluated imine resveratrol analogs (IRAs) for their neuroprotective effects against ...[more]

PMID: 34056861

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Project description:Although resveratrol exerts manifold antitumorigenic effects in vitro, its efficacy against malignancies in vivo seems limited. This has been increasingly recognized in recent years and has prompted scientists to search for structurally related compounds with more promising anticarcinogenic and/or pharmacokinetic properties. A class of structurally modified resveratrol derivatives, so-called resveratrol imine analogs (IRA's), might meet these requirements. Therefore, the biological activity of five of these compounds was examined and compared to that of resveratrol. Firstly, the antiproliferative potency of all five IRA's was investigated using the p53 wildtype-carrying colorectal carcinoma cell line HCT-116wt. Then, using the former and a panel of various other tumor cell lines (including the p53 knockout variant HCT-116p53-/-), the growth-inhibiting and cell cycle-disturbing effects of the most potent IRA (IRA 5, 2-[[(2-hydroxyphenyl)methylene]amino]-phenol) were studied as was its influence on cyclooxygenase-2 expression and activity. Finally, rat liver microsomes were used to determine the metabolic stability of that compound. IRA 5 was clearly the most potent compound in HCT-116wt cells, with an unusually high IC50-value of 0.6 μM. However, in the other five cell lines used, the antiproliferative activity was mostly similar to resveratrol and the effects on the cell cycle were heterogeneous. Although all cell lines were affected by treatment with IRA 5, cells expressing functional p53 seemed to react more sensitively, suggesting that this protein plays a modulating role in the induction of IRA 5-mediated biological effects. Lastly, IRA 5 led to contradictory effects on cyclooxygenase-2 expression and activity and was less glucuronidated than resveratrol. As IRA 5 is approximately 50 times more toxic towards HCT-116wt cells, exerts different effects on the cyclooxygenase-2 and is metabolized to a lesser extent, it shows certain advantages over resveratrol and could therefore serve as basis for additional chemical modifications, potentially yielding compounds with more favorable biological and pharmacokinetic features.

Dataset Information

Analogs of imine resveratrol alleviate oxidative stress-induced neurotoxicity in PC12 cells via activation of Nrf2.

Publications

Analogs of imine resveratrol alleviate oxidative stress-induced neurotoxicity in PC12 cells via activation of Nrf2.

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