Effects of Anthocyanins on Neurodegeneration

Abstract

Neurodegenerative diseases (NDDs) are defined by neurodegeneration, which is a slow progressive disturbance of neuronal functions and neuronal death in specific areas of the brain, contributing to irreversible loss of memory and cognition in NDDs patients. NDDs, including Alzheimer’s disease (AD) and Parkinson’s disease (PD), is mostly involved in aging. Nowadays, a sudden increase in the aged population results in various health problems, including NDDs. These diseases become the major cause of disability and death in the aged population. Moreover, there are no drugs or cures utilizable for NDDs. Hence, it is very essential to comprehend the pathogenesis of NDDs and investigate therapeutic strategies for treating NDDs. Chronic neuroinflammation has been thought to be the main mechanism implicated in the pathogenesis of NDDs. The overactivation of microglia, which are resident immune cells in the brain and can be activated by immunological stimuli or brain damage, is the main cause of neuroinflammation.The activated microglia can release the excessive levels of inflammatory mediators,leading to neuronal damage and death in NDDs. Thus, the inhibition of microglial activationmediated inflammation,as well as neuronal cell death,might be the hopeful therapeutic approaches for NDDs. Cyanidin-3-O-glucoside (CG), classified in anthocyanin family found in purple or red-colored fruits, vegetables, and plants, has been confirmed to exert potent antiinflammatory ability. Moreover, previous studies have proved that CG can cross the blood-brain barrier and shows neuroprotective effects. However, the effect of CG on microglial activation-mediated neurodegeneration has not been reported. After ingestion, CG is rapidly catabolized to its metabolites, and its concentration is low in human plasma compared to its metabolites. Altogether, in this study, we investigated the effects of CG and its metabolites, which are cyanidin (Cy) and protocatechuic acid (PCA), on microglial activation-induced neuronal cell death by using the co-culture system of BV2 microglia cell-cultured medium and differentiated PC12 cells (neuron-like cells). Firstly, the inhibitory effects of CG, Cy, and PCA on microglial activation of lipopolysaccharide (LPS)-induced BV2 cells were investigated. The results revealed that CG and PCA, but not Cy, could restrain LPS-induced microglial activation and the production of inflammatory mediators, such as interleukin (IL)-1β, IL-6, prostaglandin E2 (PGE2), and nitric oxide, through the inactivation of nuclear factor-κB (NF-κB) and p38 mitogen-activated protein kinase (MAPK) signaling pathways. Except for TNF-α, CG could not suppress its production in LPS-activated microglia. Moreover, the inhibitory effects of CG and PCA on microglial activation could upregulate the SIRT1 level. This protein plays a beneficial role in neuroinflammation, leading to the attenuation of p65 NF-κB acetylation in activated microglia. From the co-culture system, the results indicated that a decrease of inflammatory mediator production in activated microglia, which was caused by either CG or PCA, could protect PC12 cells against microglial activation-mediated neuronal apoptosis. The anti-apoptotic effects of CG and PCA are involved in the inhibition of caspase-3 activation. The direct effects of CG and PCA on neuronal PC12 cell apoptosis induced by neurotoxic factors released from LPS-activated microglia were also determined. The results showed that CG and PCA directly rescued PC12 cells from apoptosis induced by microglial activation. These effects are related to the restraint of caspase-3 activation. Taken together, it could be suggested that CG and PCA have both indirect and direct effects against microglial activation-mediated neurodegeneration. Therefore, CG and PCA may be the promising agents used for prevention and treatment of NDDs.