ABSTRACT
Silibinin has been shown to attenuate cognitive dysfunction and inhibit amyloid-beta (Aß) aggregation in Alzheimer's disease (AD) models. However, the underlying mechanism by which silibinin improves cognition remains poorly understood. In this study, we investigated the effect of silibinin on ß-secretase levels, Aß enzymatic degradation, and oxidative stress in the brains of APP/PS1 mice with cognitive impairments. Oral administration of silibinin for 2 months significantly attenuated the cognitive deficits of APP/PS1 mice in the Y-maze test, novel object recognition test, and Morris water maze test. Biochemical analyses revealed that silibinin decreased Aß deposition and the levels of soluble Aß1-40/1-42 in the hippocampus by downregulating APP and BACE1 and upregulating NEP in APP/PS1 mice. In addition, silibinin decreased the MDA content and increased the activities of the antioxidant enzymes CAT, SOD, and NO. Based on our findings, silibinin is a potentially promising agent for preventing AD-associated Aß pathology.
Subject(s)
Amyloid Precursor Protein Secretases/metabolism , Amyloid beta-Peptides/metabolism , Amyloid beta-Protein Precursor/metabolism , Silybin/pharmacology , Alzheimer Disease/metabolism , Animals , Antioxidants/metabolism , Cognitive Dysfunction/drug therapy , Cognitive Dysfunction/metabolism , Disease Models, Animal , Down-Regulation/drug effects , Hippocampus/drug effects , Hippocampus/metabolism , Male , Maze Learning/drug effects , Mice , Mice, Inbred C57BL , Mice, Transgenic , Up-Regulation/drug effectsABSTRACT
Silibinin has been widely used to treat liver diseases due to its antioxidant activity. However, the effects of silibinin on the central nervous system have not been thoroughly investigated. The pathological hallmarks of Alzheimer's disease are the accumulation of amyloid ß protein, development of neurofibrillary tangles and increased oxidative stress, which ultimately lead to irreversible neuronal loss and cognitive impairment. Our findings show that silibinin ameliorated memory impairments in APP/PS1 mice in the Morris water maze via suppression of oxidative stress and inhibition of apoptosis. Treatment with silibinin reduced malondialdehyde content level and increased glutathione and superoxide dismutase activity in APP/PS1 mice. A terminal deoxynucleotidyl transferase dUTP nick end labeling assay revealed an anti-apoptotic effect of silibinin. Silibinin suppressed the activation of caspase-3 by inhibiting Jun N-terminal kinase phosphorylation and the downstream hippocampal Bax/Bcl-2 ratio. Silibinin treatment significantly increased levels of synaptophysin and PSD95 in APP/PS1 transgenic mice. These results suggest that silibinin could be a potential therapeutic agent for the treatment of Alzheimer's disease.
Subject(s)
Amyloid beta-Protein Precursor/metabolism , Antioxidants/pharmacology , Maze Learning/drug effects , Memory Disorders/drug therapy , Silymarin/pharmacology , Alzheimer Disease/metabolism , Amyloid beta-Peptides/metabolism , Animals , Apoptosis/drug effects , Disease Models, Animal , Hippocampus/drug effects , Hippocampus/metabolism , Mice, Transgenic , Oxidative Stress , SilybinABSTRACT
Silibinin was reported to be effective in reversing the learning and memory deficits of several AD animal models. These improvements are thought to be regulated by various factors, including antioxidative stress, inhibition of acetylcholinesterase activity and Aß aggregation. However, there are still no reports that demonstrate the effect of silibinin on microglia activation in vivo. Thus, in this study, we used the senescence-accelerated mouse (SAMP8) strain to test the effects of silibinin on behavioral impairments and microglia activation-induced neuroinflammation. Silibinin treatment significantly rescued memory deficits in novel object recognition test and Morris water maze test. Silibinin treatment significantly attenuated microglial activation; down-regulated the level of the proinflammatory cytokine IL-6, anti-inflammatory cytokine IL-4, and inflammation-associated proteins, iNOS and COX-2; and further modulated MAPK to protect neural cells. These results suggest that silibinin could be a potential candidate for the therapy of neurodegenerative disorders.
