Direct Quantification of Neuroprotective Effect of Single‐Atom Catalyst on Neurochemical Transmission by Multi‐Spatiotemporal Electrochemistry

Abstract Maintaining redox homeostasis through biocatalytic reactions has emerged as a widely studied neuroprotective strategy for various brain disorders and injuries. However, current research on neuroprotection primarily focuses on functional and behavioral assessments. The impact of neuroprotective interventions on neurotransmission, a critical function of the central nervous system (CNS), remains relatively underexplored. In this study, we report the first direct evidence for neuroprotective effect on neurochemical transmission by multi‐spatiotemporal electrochemistry. We employed in vivo and single‐vesicle electrochemistry to quantitatively evaluate the neuroprotective effect of an antioxidative Fe single‐atom nanozyme (Fe 1 /NC SAzyme) on neurotransmission, using a 1‐methyl‐4‐phenylpyridinium (MPP + )‐induced Parkinson's disease (PD) model. In the PD animal model, Fe 1 /NC SAzyme mitigates MPP + neurotoxicity by decreasing damage to dopaminergic neurons, increasing evoked dopamine release, attenuating spontaneous firing, and alleviating locomotor impairment. At the single‐cell level, pretreatment with Fe 1 /NC SAzyme inhibits MPP + effects by scavenging reactive oxygen species (ROS), increasing cell viability and ATP concentration, and enhancing the exocytotic release. This study not only provides a research paradigm for directly quantifying therapeutic mechanisms of brain disorders and injury but also reinforces a novel neuroprotective strategy through modulating the redox homeostasis with biocatalytic reactions.