Small molecule activators of the Nrf2-HO-1 antioxidant axis modulate heme metabolism and inflammation in BV2 microglia cells.

Roberta Foresti 1, * Sandip Bains 2 Tamil Selvi Pitchumony 2 Lisandra De Castro Brás 2 Filippo Drago 3 Jean-Luc Dubois-Randé 1, 4 Claudio Bucolo 3 Roberto Motterlini 1, *
* Auteur correspondant
1 IMRB - Institut Mondor de Recherche Biomédicale
2 Department of Drug Discovery and Development
3 Department of Clinical and Molecular Biomedicine
4 Service de cardiologie
Abstract : The nuclear factor erythroid derived 2-related factor 2 (Nrf2) and the antioxidant protein heme oxygenase-1 (HO-1) are crucial components of the cellular stress response. These two systems work together to combat oxidative stress and inflammation and are attractive drug targets for counteracting different pathologies, including neuroinflammation. We aimed to identify the most effective Nrf2/HO-1 activators that modulate the inflammatory response in microglia cells. In the present study, we searched the literature and selected 56 compounds reported to activate Nrf2 or HO-1 and analyzed them for HO-1 induction at 6 and 24h and cytotoxicity in BV2 microglial cells in vitro. Approximately 20 compounds up-regulated HO-1 at the concentrations tested (5-20 μM) with carnosol, supercurcumin, cobalt protoporphyrin-IX and dimethyl fumarate exhibiting the best induction/low cytotoxicity profile. Up-regulation of HO-1 by some compounds resulted in increased cellular bilirubin levels but did not augment the expression of proteins involved in heme synthesis (ALAS 1) or biliverdin reductase. Bilirubin production by HO-1 inducers correlated with their potency in inhibiting nitrite production after challenge with interferon-γ (INF-γ) or lipopolysaccharide (LPS). The compounds down-regulated the inflammatory response (TNF-α, PGE2 and nitrite) more strongly in cells challenged with INF-γ than LPS, and silencing HO-1 or Nrf2 with shRNA differentially affected the levels of inflammatory markers. These findings indicate that some small activators of Nrf2/HO-1 are effective modulators of microglia inflammation and highlight the chemical scaffolds that can serve for the synthesis of potent new derivatives to counteract neuroinflammation and neurodegeneration.
Keywords : BV2 microglia Nrf2 HO-1 small molecule activators heme metabolism inflammation
Type de document :
Article dans une revue
Pharmacological Research, Elsevier, 2013, 76, pp.132-48. 〈10.1016/j.phrs.2013.07.010〉
Liste complète des métadonnées

Littérature citée [44 références]  Voir  Masquer  Télécharger
http://www.hal.inserm.fr/inserm-00903755
Contributeur : Georges Guellaen <>
Soumis le : mercredi 13 novembre 2013 - 08:10:05
Dernière modification le : jeudi 28 janvier 2016 - 01:06:41
Document(s) archivé(s) le : vendredi 14 février 2014 - 15:25:23

Fichier

YPHRS-D-13-00198_accepted.pdf
Fichiers produits par l'(les) auteur(s)

Identifiants

Collections

IMRB | UPEC-UPEM

Citation

Roberta Foresti, Sandip Bains, Tamil Selvi Pitchumony, Lisandra De Castro Brás, Filippo Drago, et al.. Small molecule activators of the Nrf2-HO-1 antioxidant axis modulate heme metabolism and inflammation in BV2 microglia cells.. Pharmacological Research, Elsevier, 2013, 76, pp.132-48. 〈10.1016/j.phrs.2013.07.010〉. 〈inserm-00903755〉

Exporter

BibTeX TEI DC DCterms EndNote

Partager

Métriques

Consultations de la notice

616

Téléchargements de fichiers

1003

Contact

support.ccsd.cnrs.fr
hal.support@ccsd.cnrs.fr
Logo CCSD