Protocatechuic Acid Alleviates Neurodemyelination by Modulating PKCα-p38/MAPK Pathways in an LPC-Induced Model of Neurodegeneration

Introduction: Neuroinflammation, axonal damage, and alterations in extracellular matrix (ECM) protein expression are hallmarks of neurodegenerative diseases. Therapies that enhance recovery from brain injury are of significant clinical value. Therefore, this study investigated the antiinflammatory properties of protocatechuic acid (PCA). Methods: Neuroglial cocultures were prepared from P0-P1 rats. Demyelination was induced using LPC (0.003%). The effects of PCA (10 and 25 μg) on neurite outgrowth were assessed using morphometry software. Expression of COX-2, NF-κβ, PKC-α, and p38/MAPK was examined through immunostaining, SDS-PAGE, and Western blotting. Expression intensities were quantified using ImageJ software. Sustained repetitive neuronal firing was evaluated using the patch-clamp technique. Results: PCA increased neurite outgrowth in LPC-treated cultures after 72 hours in vitro. LPCinduced upregulation of ECM proteins TN-C, LN, and CSPGs was significantly reduced by PCA treatment compared with LPC controls. Similarly, PCA decreased the expression intensities of the pro-inflammatory markers NF-κβ and COX-2 relative to LPC controls. Furthermore, PCA reversed the sustained neuronal firing pattern observed in untreated LPC-exposed neurons. Discussion: Purified bioactive compounds commonly present in everyday foods show therapeutic potential for Parkinson’s and Alzheimer’s diseases due to their lower toxicity compared with conventional drugs. Artificial intelligence tools, such as AlphaFold and RoseTTAFold, further support drug development by predicting PCA binding modes with PKCα and P38/MAPK, thereby contributing to the design of personalized therapeutics and advancing neuroscience research. result: PCA enhanced neurite length in vitro and also increased neurite outgrowth in LPC-treated cultures after 72 hr in vitro. The higher expression intensities of ECM proteins TN-C, LN, and CSPGs induced by LPC were significantly decreased by PCA treatment compared to those by LPC control treatment. Similarly, the expression intensities of pro-inflammatory markers NF-κβ and COX-2 were decreased by PCA treatment compared to those by LPC control treatment. Furthermore, compared with no treatment, PCA reversed the sustained neuronal firing pattern. Conclusion: PCA alleviated neuroinflammation by reducing phosphorylation of PKCα and p38/MAPK.