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

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 (Fe₁/NC SAzyme) on neurotransmission, using a 1-methyl-4-phenylpyridinium (MPP⁺)-induced Parkinson's disease (PD) model. In the PD animal model, Fe₁/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 Fe₁/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.