Mingu Gordon Park

Hydrogen peroxide (H₂O₂) contributes to oxidative stress in Alzheimer’s disease (AD), yet conventional antioxidants that directly scavenge H₂O₂ have shown limited therapeutic efficacy. Here, we investigated K34 (3,3″-dihydroxy-6′-desmethyl terphenyllin), a catechol-bearing para-terphenyl isolated from the marine fungus Penicillium janthinellum 168CLC-17.1, as an indirect H₂O₂-decomposing agent. Complementary cell-free assays showed that K34 promoted peroxidase-dependent H₂O₂ decomposition, including Hb-supported H₂O₂ decomposition, while molecular docking predicted a plausible binding pose near the Hbβ heme pocket. In amyloid-β₄₂ (Aβ₄₂)-stimulated primary astrocytes, K34 reduced intracellular H₂O₂. In APPswe/PSEN1dE9 (APP/PS1) mice subjected to focal GFAP-inducible diphtheria toxin receptor (fGiD), systemic K34 attenuated memory impairment, preserved NeuN-positive neurons, reduced GFAP immunoreactivity, and improved hippocampal spike probability. K34 also exhibited low passive blood–brain barrier (BBB) permeability and limited inhibition of five major cytochrome P450 (CYP) isoforms under the tested conditions. These findings extend Hb-supported H₂O₂ decomposition to a structurally distinct marine natural product and support further evaluation of K34 as an antioxidant scaffold for modulating oxidative stress-associated neurodegenerative phenotypes.

Monoamine oxidase-B (MAOB) has been believed to mediate the degradation of monoamine neurotransmitters such as dopamine. However, this traditional belief has been challenged by demonstrating that it is not MAOB but MAOA which mediates dopamine degradation. Instead, MAOB mediates the aberrant synthesis of GABA and hydrogen peroxide (H₂O₂) in reactive astrocytes of Parkinson’s disease (PD). Astrocytic GABA tonically suppresses the dopaminergic neuronal activity, whereas H₂O₂ aggravates astrocytic reactivity and dopaminergic neuronal death. Recently discovered reversible MAOB inhibitors reduce reactive astrogliosis and restore dopaminergic neuronal activity to alleviate PD symptoms in rodents. In this perspective, we redefine the role of MAOB for the aberrant suppression and deterioration of dopaminergic neurons through excessive GABA and H₂O₂ synthesis of reactive astrocytes in PD.