Ferulic Acid Activates SIRT1-Mediated Ferroptosis Signaling Pathway to Improve Cognition Dysfunction in Wilson’s Disease

Abstract

Background Wilson’s disease (WD), an autosomal recessive genetic disease, is characterized by copper metabolism disorder. WD patients may have a series of cognitive deficits in terms of neurological symptoms. Ferroptosis (FPT), a type of programmed cell death, is involved in the pathological progression of various cognitive disorders, and silent information regulator 1 (SIRT1) is considered to be a key factor in FPT. Ferulic acid (FA) is a traditional Chinese medicine monomer, with a remarkable effect in the clinical treatment of cognitive impairment-related disease. However, its intrinsic effect on FPT is still unclear. This study aims to investigate the protective effect of FA on cognitive impairment in animal and cell models of WD, and whether the pharmacological mechanism is related to the SIRT1-mediated FPT signaling pathway. Methods Copper-loaded WD rats and PC12 cells WD were used as models of cognitive dysfunction in vivo and in vitro, respectively. Morris Water Maze (MWM) was used to evaluate the spatial exploration and memory abilities of rats. HE staining was used to observe neuronal damage in the CA1 region of the rat hippocampus. Immunofluorescence (IF) was used to detect the expression of GPX4 protein. Transmission electron microscopy (TEM) was used to observe the ultrastructure of neurons. The levels of Fe2+, MDA, SOD, GSH, 4HNE, and ROS were detected. Western blot and qRT-PCR were used to detect the protein and mRNA levels of SIRT1, Nrf2, SCL7A11, and GPX4. Results In the WD copper-loaded model rats, MWM, TEM, and IF results showed that FA could promote the repair of learning and memory function, improve the morphological damage to hippocampal neurons, and maintain mitochondria integrity. In the PC12 cell experiment, the MTT method showed that FA increased the viability of copper-overloaded cell models. Western blot and qRT-PCR results confirmed that FA significantly increased the expression of proteins and mRNA in SIRT1, Nrf2, SCL7A11, and GPX4. In addition, FA reversed the expression of oxidative stress-related indicators, including MDA, SOD, GSH, 4HNE, and ROS. Conclusion FA alleviates hippocampal neuronal injury by activating SIRT1-mediated FPT, providing a valuable candidate for traditional Chinese medicine monomer for the clinical therapeutics of WD cognitive impairment.

Effect of high-frequency repetitive transcranial magnetic stimulation on cognitive impairment in WD patients based on inverse probability weighting of propensity scores

“…To date, no drugs have been recommended for the treatment of WD-related cognitive impairment. Many studies have shown that anti-copper therapy can reduce copper deposition in the liver and brain, increase urinary copper content, and improve cognitive impairment in WD patients ( Wang et al, 2023 ; Zhang et al, 2024 ). An effective and safe means of nerve regulation, TMS has achieved curative effects in the treatment of WD complicated with dystonia ( Hao et al, 2021 ) and plays an important role in improving cognitive impairment with a variety of causes.…”