A highly selective fluorescent probe for monitoring MAO-B and screening inhibitors to alleviate Parkinson's disease

Parkinson's disease (PD) represents a progressive neurodegenerative condition primarily marked by the selective loss of dopaminergic (DA) neurons within the substantia nigra (SN), leading to a consequent depletion of DA levels in the striatal (STR) region. Studies have indicated that pharmacological inhibition of monoamine oxidase B (MAO-B) activity exerts neuroprotective effects by attenuating DA catabolism in the STR, thereby enhancing DA neurotransmission and ameliorating motor impairments associated with PD. Therefore, the discovery and use of MAO-B inhibitors may be an exciting and interesting strategy for the treatment of PD. The development of effective MAO-B fluorescent probes offers significant potential for early PD diagnosis, screening MAO-B inhibitors, and investigating the molecular mechanisms involved in PD intervention. However, there are relatively few reports on specific fluorescent probes for detecting MAO-B in PD. Herein, we report the design and synthesis of an activatable fluorescent probe (DCN-MB) for sensitive and specific imaging of MAO-B in PD. Bioimaging experiments demonstrated that DCN-MB exhibits excellent imaging capabilities for detecting MAO-B in living cells, zebrafish, and PD mouse models. Modern research has confirmed that the primary active components, phenylethanoid glycosides, exhibit neuroprotective effects. Consequently, we performed a systematic review to evaluate its therapeutic potential in the PD model. Notably, using the DCN-MB probe, we successfully identified Echinacoside (ECH) as one of nine phenylethanoid glycosides and an effective MAO-B inhibitor. Further investigation revealed that ECH activates the SLC7A11/Gpx4 signaling pathway, inhibiting ferroptosis, reducing DA neuron loss, and exerting neuroprotective effects. Overall, this work provides a powerful tool for studying MAO-B-related pathological mechanisms in PD and screening potential compounds for PD prevention and treatment.