Ferulic Acid Exerts Neuroprotective Effects via Autophagy Induction in C. elegans and Cellular Models of Parkinson’s Disease

Abstract

Parkinson’s disease (PD) is a complex neurological disorder characterized by motor and nonmotor features. Although some drugs have been developed for the therapy of PD in a clinical setting, they only alleviate the clinical symptoms and have yet to show a cure. In this study, by employing the C. elegans model of PD, we found that ferulic acid (FA) significantly inhibited α-synuclein accumulation and improved dyskinesia in NL5901 worms. Meanwhile, FA remarkably decreased the degeneration of dopaminergic (DA) neurons, improved the food-sensing behavior, and reduced the level of reactive oxygen species (ROS) in 6-OHDA-induced BZ555 worms. The mechanistic study discovered that FA could activate autophagy in C. elegans, while the knockdown of 3 key autophagy-related genes significantly revoked the neuroprotective effects of FA in α-synuclein- and 6-OHDA-induced C. elegans models of PD, demonstrating that FA exerts an anti-PD effect via autophagy induction in C. elegans. Furthermore, we found that FA could reduce 6-OHDA- or H2O2-induced cell death and apoptosis in PC-12 cells. Moreover, FA was able to induce autophagy in stable GFP-RFP-LC3 U87 cells and PC-12 cells, while bafilomycin A1 (Baf, an autophagy inhibitor) partly eliminated the protective effects of FA against 6-OHDA- and H2O2-induced cell death and ROS production in PC-12 cells, further confirming that FA exerts an anti-PD effect via autophagy induction in vitro. Collectively, our study provides novel insights for FA as a potent autophagy enhancer to effectively prevent neurodegenerative diseases such as PD in the future.

Ameliorative effect of Luffa cylindrica fruits on Caenorhabditis elegans and cellular models of Alzheimer's disease‐related pathology via autophagy induction

“…Autophagy is a major proteolytic system responsible for the degradation of unwanted or misfolded proteins in eukaryotes (Wang & Le, 2019). Therefore, we investigated whether LCE induces autophagy in vivo using the transgenic C. elegans strain BC12921, which expresses the autophagy substrate protein SQST, homologous to the human P62 protein, in a stable manner (Long, Wu, et al, 2022). As shown in Figure 4a, both LCE and Rap (a positive autophagy inducer) significantly decreased the fluorescence intensity of SQST‐1/p62‐GFP in BC12921 worms, indicating the occurrence of autophagic flux in LCE‐treated worms.…”

“…Additionally, we employed another C. elegans strain, DA2123, to validate the autophagy‐inducing activity of LCE. In DA2123 worms, the GFP::LGG‐1 fusion protein is sequestered at the membrane of autophagosomes and forms puncta when autophagy is triggered (Long, Wu, et al, 2022). We observed that LCE‐treated DA2123 worms exhibited higher numbers of LGG‐1 + puncta in seam cells and intestinal cells compared to untreated controls, where the fluorescence was diffused (Figure 4b).…”

“…Transgenic BR5270 worms expressing human Tau protein in pan‐neuronal cells were used to assess food perception following previous methods (Long, Wu, et al, 2022). After incubating BR5270 nematodes with LCE at 20°C for 48 h, the worms were transferred to fresh NGM plates with or without bacterial lawns and allowed to move freely for 90 s to eliminate stress‐induced behavior.…”

Ferulic acid as a therapeutic agent in depression: Evidence from preclinical studies

“…Recently, several studies have shown that FA is a natural protective agent that requires further development. Ferulic acid exerts important neuroprotective effects in CNS diseases through antioxidant, anti‐inflammatory, anti‐apoptosis, alter gut microbiota and other mechanisms 110,111 . Moreover, FA was found to alleviate abnormal depressive behaviors in multiple animal depression models, underscoring the potential use of FA as a new antidepressant agent.…”

The Therapeutic Potential of Hydroxycinnamic Acid Derivatives in Parkinson’s Disease: Focus on In Vivo Research Advancements

“…Long et al found that ferulic acid (concentrations between 25 and 200 μM, with 50 μM optimal) could ameliorate pathological changes in PD due to α-synuclein accumulation and the exposure of 6-OHDA and H 2 O 2 by activating autophagy in C. elegans and PC-12 cells, and that this protective effect was eliminated by inhibiting the autophagic activity of ferulic acid through feeding to RNAi bacteria, suggesting that ferulic acid may have considerable therapeutic application for PD through autophagy. 140 Another study discovered that caffeic acid (1−10 μM) might activate the JNK/Bcl-2-mediated autophagic pathway in SH-SY5Y cells, promoting the degradation of A53T-synuclein, and reducing cellular damage brought on by A53T-synuclein. 141 The JNK signaling pathway regulates autophagy primarily through phosphorylating Bcl2 family proteins and causing them to separate from Beclin-1.…”