Crocetin from saffron ameliorates motor symptoms in Parkinson's disease models by improving mitochondrial function and PINK1/Parkin mediated mitophagy.

BACKGROUND

Parkinson's disease (PD) is characterized by the progressive degeneration of nigrostriatal dopaminergic neurons and is closely associated with mitochondrial dysfunction. Given the limited therapeutic options available for disease intervention, there is growing interest in identifying natural compounds that can modulate core pathological processes such as mitochondrial dysfunction. Traditional Chinese Medicine (TCM) has been identified as a promising candidate for PD, offering reduced side effects and holistic regulatory effects. Crocetin (CRO) is a bioactive compound isolated from saffron, a TCM component with reported neuroprotective properties; however, whether it improves mitochondrial function and mitophagy in PD remains unknown.

PURPOSE: This study aimed to investigate the therapeutic potential of CRO in PD and to explore its underlying mechanisms, focusing on mitochondrial function and PINK1/Parkin-mediated mitophagy.

METHODS

MES23.5 cells were modeled in vitro using MPP⁺. CRO was rationally screened from eight candidates through CCK-8 assay, and its effects on alpha-synuclein expression, oxidative stress, mitochondrial membrane potential, ATP production, and PINK1/Parkin-mediated mitophagy were evaluated in vitro. A PD model was established in C57BL/6 mice in vivo using MPTP. Motor function, tyrosine hydroxylase expression, Nissl body numbers, and neuronal firing rates were assessed in PD mice model.

RESULTS

A reduction in alpha-synuclein expression was observed following CRO treatment, accompanied by a decrease in intracellular ROS levels to approximately one-tenth of those in the model group. Mitochondrial membrane potential and ATP production were markedly restored, with ATP levels elevated 1.6-fold compared with those in the model group. In vivo, CRO may also improve motor function in PD mice, restore tyrosine hydroxylase expression in nigrostriatal regions to a normal level, and increase Nissl body numbers. Critically, CRO was proven to have the capacity to restore neuronal firing function and rescue neuronal electrophysiology.

CONCLUSION

CRO has been shown to attenuate PD-related symptoms through the restoration of mitochondrial function and the activation of PINK1/Parkin-mediated mitophagy. These findings highlight CRO as a novel therapeutic option and deepen the understanding of PD-associated mitochondrial dysfunction.