Journal
EUROPEAN JOURNAL OF PHARMACOLOGY
Volume 818, Issue -, Pages 470-479Publisher
ELSEVIER
DOI: 10.1016/j.ejphar.2017.11.023
Keywords
Antioxidant enzyme; Chemical library; Nrf2-ARE pathway; Parkinson's disease
Categories
Funding
- Platform for Drug Discovery, Informatics, and Structural Life Science from the Ministry of Education, Culture, Sports, Science and Technology, Japan
- Platform Project for Supporting Drug Discovery and Life Science Research - Japan Agency for Medical Research and Development (AMED), Japan
- Smoking Research Foundation, Japan
- Grants-in-Aid for Scientific Research [15K07965] Funding Source: KAKEN
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The nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response element (ARE) pathway, which induces the production of antioxidant enzymes, is a possible therapeutic target for treating diseases related to oxidative stress. Nrf2 activators often exhibit cytotoxicity due to nonspecific electrophilic reactions with thiol groups. We screened a chemical library to explore Nrf2 activators with a wide safety margin. In at least in vitro experiments, TPNA10168, identified from the library, showed a higher efficacy in Nrf2 activation and a lower cytotoxicity than sulforaphane, a well-known Nrf2 activator. The present study demonstrated the protective effect of TPNA10168 against 6-hydroxydopamine-induced cytotoxicity. In PC12 cells, NAD(P)H:quinone oxidoreductase 1 was upregulated by TPNA10168 and participated in the protective effect. In primary mesencephalic cultures, heme oxygenase-1, upregulated by TPNA10168 in astrocytes, provided protection of dopaminergic neurons via a guanylate cyclase/protein kinase G signaling pathway via carbon monoxide. These results suggest that the compound identified from the chemical library may be suitable as a neuroprotective agent with the ability to induce antioxidant enzymes.
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