Potent antioxidant and mitochondrial-protective effects of ATH434, a moderate affinity iron chaperone

A plethora of neurologic disease presents with brain iron accumulation. Among these disorders are Parkinson's disease (PD) and Multiple System Atrophy (MSA). Development of interventions logically has focused on the iron-dependent oxidant stress characteristic of these pathologies. This focus is represented using iron chelators on the one hand and antioxidant therapy on the other. Here we provide evidence that ATH434, a small-molecule drug candidate with similar and moderate affinity for both ferrous and ferric iron (K_d ∼10⁻⁶), exhibits both electron (ET) and hydrogen atom transfer (HAT) antioxidant activity. Previous studies have shown that ATH434 promotes cellular iron efflux, reduces excess brain iron and aggregated α-synuclein, improves neuronal survival, and restores motor performance in murine PD and MSA models. ATH434 has been granted Orphan drug and Fast Track designation by the FDA. Here we have established that ATH434 is a robust antioxidant. We have demonstrated that it protects mitochondrial function and suppresses lipid hydroperoxidation in a menadione-induced model of oxidative stress in a glutamatergic neuronal cell line, HT22. Comparison of the electron transfer and hydrogen atom transfer activities of ATH434 with structurally related congeners provided insight into this compound's structural features that support its varied antioxidant activity. These behaviors were consistent with the fact that cyclic voltammetry demonstrated ATH434 exhibits a chemically reversible electrode potential of 328.5 mV, unique to all antioxidants and iron chelators examined in this report. Our results indicate that ATH434 has the capacity to manage excess tissue iron and the oxidant stress induced by that iron.