Neuroprotective Mechanisms of Paeoniflorin in Parkinson’s Models: Involvement of BDNF-Dependent PI3K/Akt and ERK/CREB Pathways

Paeoniflorin, a bioactive monoterpene glycoside derived from Paeonia lactiflora, has shown neuroprotective effects primarily associated with the promotion of brain-derived neurotrophic factor secretion. This study aims to elucidate the therapeutic potential of paeoniflorin in models of Parkinson’s disease and to investigate the role of the BDNF-mediated PI3K/Akt and ERK1/2/p90RSK/CREB signaling pathways. Notably, paeoniflorin improved motor function, reduced dopamine catabolism, and attenuated dopaminergic neuronal loss in PD mice by regulating dopamine catabolism and inhibiting turnover, indicating dopaminergic protection. In vitro, paeoniflorin pretreatment enhanced cell viability, reduced LDH release, suppressed ROS and intracellular Ca2+ overload, stabilized mitochondrial membrane potential, and attenuated MPP+-induced apoptosis. A key innovation is the dual activation and coordinated activation of the two BDNF-dependent pathways: LY294002 abolished paeoniflorin-induced BDNF/PI3K/Akt activation, while PD98059 and ERK1/2 siRNA specifically suppressed paeoniflorin-triggered phosphorylation of ERK1/2, p90RSK, and CREB. Ultimately, paeoniflorin exerts robust neuroprotection against MPTP/MPP+ neurotoxicity by synergistically activating BDNF-downstream PI3K/Akt and ERK/CREB axes. This delineation of a dual-pathway mechanism provides novel insight into the pharmacological action of paeoniflorin and supports its potential as a multifaceted therapeutic agent for Parkinson’s disease.