Matrine ameliorates anxiety and depression-like behaviour by targeting hyperammonemia-induced neuroinflammation and oxidative stress in CCl4 model of liver injury

Abstract

Acute or chronic liver injury is associated with hyperammonemia which induced neuroinflammation and oxidative stress in the brain. Neuroinflammation, oxidative stress, reduced neurogenesis, and apoptosis are critical factors for the development of anxiety and depression. The present study was aimed to evaluate the anxiolytic and antidepressant properties of matrine against acute liver injury in the rodent model. Acute liver injury in mice was induced by administration of the acute hepatotoxic dose of carbon tetrachloride (CCl4) (1 ml/kg, i.p.). Pretreatment of mice with matrine (50 mg/kg i.p.) remarkably ameliorated CCl4-induced anxiety and depression-like behavior as evident from the results of open field test (OFT), elevated plus maze test (EPM), light-dark box test (LDB), forced swimming test (FST), and tail suspension test (TST). Moreover, matrine significantly inhibited CCl4-induced neuroinflammation in mice by reducing pro-inflammatory cytokines such as interleukins (IL-1β, IL-6) and tumor necrosis factor-α (TNF-α) levels in the hippocampus (HC) and prefrontal cortex (PFC). CCl4-induced oxidative stress was reduced by matrine due to its potential to enhance the levels of reduced glutathione (GSH), catalase (CAT), glutathione-S-transferase (GST), and decreased the malondialdehyde (MDA), and nitrite level in the PFC and HC of mice brain. Matrine remarkably reduced the levels of corticosterone, ammonia, AST, ALT, and creatinine. Matrine pretreatment remarkably ameliorated CCl4-induced morphological liver injury. Acute pretreatment of matrine enhanced neurogenesis by increasing the number of GFAF (glial fibrillary acidic protein) positive astrocyte, BDNF (brain-derived neurotrophic factor), and VEGF (vascular endothelial growth factor) in the hippocampus of CCl4-treated mice. Pretreatment of matrine inhibited apoptosis and DNA damage in the hippocampus. The present data revealed that hyperammonemia produced due to liver injury induced oxidative stress, neuroinflammation, reduced neurogenesis and apoptosis in the hippocampus, thus, resulting in anxiety and depression. Taken together, the present results suggested that matrine has a significant antidepressant and anxiolytic effects through modulation of neuroinflammation, oxidative stress, reduced neurogenesis and apoptosis induced by CCl4 administration.

Keywords: Anxiety; CCl4; Cytokines; Depression; Matrine; Oxidative stress.