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

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.

Inhibition of neuroinflammation in BV2 microglia by the biflavonoid kolaviron is dependent on the Nrf2/ARE antioxidant protective mechanism

“…To our knowledge, this is the first study demonstrating that kolaviron could activate the Nrf2/HO-1 system in the microglia. Similar effects have been shown for natural antioxidants such as tiliroside [31] and other Small molecule activators of the Nrf2-HO-1 [32].…”

Microglia regulate blood clearance in subarachnoid hemorrhage by heme oxygenase-1

“…In contrast, induction of HO-1 exerts potent protective effects in numerous preclinical disease models including sepsis, trauma, vascular proliferative disease, acute lung and liver injury, and cancer (1)(2)(3)(4)(5). A number of recent reports have demonstrated the benefits of HO-1 in the CNS, including the eye (6) and brain (7)(8)(9)(10)(11)(12). In the brain, expression of each HO isoform follows a distinct spatial and cell-specific distribution pattern.…”

Regulation of dimethyl-fumarate toxicity by proteasome inhibitors

“…4,[7][8][9][10] In addition to its actions on immune cells, DMF also suppresses the inflammatory biology of microglia and astrocytes. [11][12][13][14][15] As activated microglia and reactive astrocytes play key roles in the biology and progression of GBM tumors in vivo, DMF represents one potential drug which could alter GBM growth and the growth of other tumor types in vivo. 16,17 Proteasome inhibitors e.g., velcade, carfilzomib inhibit the activity of the 20S proteasome.…”