Molecular hydrogen may activate the transcription factor Nrf2 to alleviate oxidative stress through the hydrogen-targeted porphyrin

Abstract

Oxidative stress is one of the major causes of most age-dependent neurodegenerative disorders. Neurons accumulate oxidative damage over time due to post-mitotic cells. Thus, modulation of oxidative stress is essential to overcome these disorders. Molecular hydrogen (H2) has great potential for treating various diseases and improving quality of life by exerting multiple functions including anti-oxidation, anti-inflammation, and energy metabolism promotion. Among these functions, H2 activates a transcription factor, nuclear factor erythroid 2-related factor 2 (Nrf2) to enhance the transcription of transcribe a broad range of anti-stress enzymes, including antioxidant enzymes. There was an elusive contradiction between H2 and Nrf2 because Nrf2 is activated in response to oxidative stress, whereas H2 has a reducing potential. The target molecule for H2 has recently been identified as the oxidized form of Fe-porphyrin conjugated with the -OH group (PrP-Fe(III)-OH). As the initial step, the hydroxyl radical (•OH) oxidizes heme (PrP-Fe(II)) to form PrP-Fe(III)-OH. Then, H2 reacts with PrP-Fe(III)-OH to produce PrP-Fe(III)-H and H2O. In turn, Fe(III) with H has the potential to act as an electrophile to oxidize Kelch-like ECH-associated protein 1 (Keap1), resulting in activating Nrf2. Thus, when the original highly damaging electrophilicity of •OH is buffered by H2 and its target porphyrin, the electrophilicity provided by •OH can indirectly activate Nrf2 to reduce oxidative stress. Even without lowering the dosage, the effect of alleviated potent is considered to be hormesis-like. This “Therapeutic Brief” propose that the alleviated oxidative potent of •OH functions to activate Nrf2 as hormesis-like.
Keywords: Hematin, hydroxyl radical, molecular hydrogen, Nrf2, oxidative stress, porphyrin