Phenothiazine antioxidants increase mitochondrial biogenesis and frataxin levels in Friedreich’s Ataxia cells

Omar Khdour, Indrajit Bandyopadhyay, Nishant Visavadiya, Sandipan Roy Chowdhury, Sidney M Hecht; MedChemComm ( IF 2.342 ) Pub Date : 2018-07-26 , DOI: 10.1039/C8MD00274F

Friedreich’s ataxia (FRDA) is a progressive neurodegenerative disease that is linked to transcriptional repression of the nuclear FXN gene encoding the essential mitochondrial protein frataxin (FXN). Compounds that increase frataxin levels may enable effective therapeutic intervention for blunting disease progression. Recently, we showed that lipophilic methylene violet (MV) and methylene blue (MB) analogues both conferred benefit to cultured FRDA cells in several regards, including ROS suppression, maintenance of mitochondrial membrane potential and increased ATP production. Some of the MB analogues were also shown to promote increased frataxin levels and mitochondrial biogenesis. Presently, we report that two of the MV analogues studied previously (1 and 2) also increased frataxin levels and mitochondrial biogenesis significantly. Because the substitution pattern in the two series of compounds was not the same, we also prepared new MV derivatives having the same substitution pattern as the original MB derivatives studied to enable a more direct comparison. Two of the new MV compounds, 4b and 6b, exhibited enhanced antioxidant capability, increased frataxin levels and mitochondrial biogenesis, and improved aconitase activity. These encouraging findings demonstrated that the MV analogues had better overall activity with less cytotoxicity.

Phenothiazine antioxidants increase mitochondrial biogenesis and frataxin levels in Friedreich’s Ataxia cells