Protocatechuic acid protects against thioacetamide-induced chronic liver injury and encephalopathy in mice via modulating mTOR, p53 and the IL-6/IL-17/IL-23 immunoinflammatory pathway

Protocatechuic acid (PCA), a natural phenolic acid, is known for antioxidant, anti-inflammatory, anti-apoptotic, and anti-fibrotic activities. However, the protective mechanisms of PCA on thioacetamide (TAA)-induced liver/ brain injury are not well addressed. Chronic liver injury was induced in mice by intraperitoneal injection of TAA (200 mg/kg, 3 times/week) for 8 weeks. Simultaneously, PCA (100, 150 mg/kg/day, p.o.) was given daily from the 4th week. Protocatechuic acid ameliorated liver and brain damage indicated by the decrease in serum activities of aminotransferases, gamma-glutamyl transferase, alkaline phosphatase, lactate dehydrogenase, levels of bilirubin, and ammonia concomitant with restoration of normal albumin levels. Additionally, PCA treatment ameliorated oxidative stress in liver and brain, confirmed by the decrease in malondialdehyde and nitric oxide levels and the increase in antioxidant activities. Moreover, PCA showed anti-inflammatory actions through downregulation of TNF-alpha expression in the liver and IL-6/IL-17/IL-23 levels in the brain, which is confirmed by the decrease in CD4(+) T brain cell numbers. Most importantly, PCA treatment showed a significant decrease in mTOR level and number of LC3 positive cells in both liver and brain tissues. Consequently, PCA could inhibit mTOR-induced apoptosis, as it showed anti-apoptotic actions through downregulation of caspase-3 expression in liver and p53 expression in liver and brain. Furthermore, liver and brain tissues of treated mice showed restoration of normal histology. It can be concluded that, several mechanisms, including: antioxidant, anti-inflammatory, anti-autophagic and anti-apoptotic activities can be implicated in the hepato-and neuroprotective potentials of PCA.