Neuroprotective Effect of Gallic Acid and Ellagic Acid on LPS-induced Neuroinflammation

• Main Authors: Yu-Ling Liu, 劉昱伶
• Other Authors: Maan-Yuh Lin
• Format: Others
• Language: zh-TW
• Published: 2019
• Online Access: http://ndltd.ncl.edu.tw/handle/xv39jw

碩士 === 國立陽明大學 === 藥理學研究所 === 107 === Oxidative stress, protein aggregation and cell death appears to form a vicious cycle of CNS neurodegenerative diseases and neuroinflammation has been suggested as the center of this cycle. Indeed, over activation of glial cells, including astrocytes and microglia has been reported in brain of Parkinsonian patients. These activated glial cells reportedly release pro-inflammatory cytokines which cause neuronal damage of near-by neurons. In my study, the involvement of ERK pathway and anti-inflammatory effects of gallic acid (GA) and ellagic acid (EA) which are abundant polyphenols in the vegetables and fruits, were investigated using in vitro and in vivo approaches. In the in vitro study, BV-2 microglial cells were subjected to lipopolysaccharide (LPS, 1 μg/mL). Co-incubation of AZD6244 reduced LPS-induced phosphorylated ERK and TNF-α level in treated BV-2 microglial cells, indicating LPS-induced neuro-inflammatory is mediated via ERK activation. At the same time, EA down-regulated LPS-induced level of phosphorylated ERK, TNF-α (a pro-inflammatory cytokine), iNOS (inducible nitric oxide synthase, a pro-inflammatory enzyme) and NO production. Furthermore, GA reduced LPS-induced iNOS and NO production. Our in vivo study employed intranigral infusion of LPS (4 μg/μL) in anesthetized rats. Systemic administration of GA (50 or 100 mg/kg) and EA (100 mg/kg) attenuated LPS-induced increases in heme-oxygenase-1 level (a redox-regulated protein), α-synuclein aggregation (a hallmark of CNS neurodegeneration) and ED-1 (a biomarker of activated microglia) in the LPS-infused SN, suggesting that both GA and EA are capable of inhibiting oxidative stress and protein aggregation. Furthermore, GA and EA prevented LPS-induced caspase 3 activation (a biomarker of programmed cell death) and increased in receptor interacting protein kinase (RIPK)-3 levels (a biomarker of necroptosis), indicating that GA and EA inhibited LPS-induced apoptosis and necroptosis in the nigrostriatal dopaminergic system of rat brain. Our data suggest that ERK activation is involved in LPS-induced neuroinflammation. Both GA and EA are capable of inhibiting LPS-induced neuroinflammation. Moreover, AZD6244 was found to block LPS-induced ERK phosphorylation, suggesting, AZD6244 may be neuroprotective against the CNS neurodegenerative disease.