(E)-2-Methoxy-4-(3-(4-methoxyphenyl) prop-1-en-1-yl) Phenol Ameliorates LPS-Mediated Memory Impairment by Inhibition of STAT3 Pathway

Abstract

Alzheimer’s disease (AD) is pathologically characterized by an excessive accumulation of amyloid-beta (Aβ) fibrils within the brain. We tested the anti-inflammatory and anti-amyloidogenic effects of (E)-2-methoxy-4-(3-(4-methoxyphenyl) prop-1-en-1-yl) phenol (MMPP), a selective signal transducer and activator of transcription 3 (STAT3) inhibitor. We examined whether MMPP (5 mg/kg in drinking water for 1 month) prevents amyloidogenesis and cognitive impairment on AD model mice induced by intraperitoneal LPS (250 μg/kg daily 7 times) injections. Additionally, we investigated the anti-neuroinflammatory and anti-amyloidogenic effect of MMPP (1, 5, and 10 μg/mL) in LPS (1 μg/mL)-treated cultured astrocytes and microglial BV-2 cells. MMPP treatment reduced LPS-induced memory loss. This memory recovery effect was associated with the reduction of LPS-induced inflammatory proteins; cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) as well as activation of microglial cells and astrocytes in the brain. Furthermore, MMPP reduced LPS-induced β-secretase and Aβ generation. In in vitro study, LPS-induced expression of inflammatory proteins and amyloidogenic proteins was decreased in microglial BV-2 cells and cultured astrocytes by MMPP treatment. Moreover, MMPP treatment suppressed DNA binding activities of the activation of STAT3 in in vivo and in vitro. These results indicated that MMPP inhibits LPS-induced amyloidogenesis and neuroinflammation via inhibition of STAT3.Electronic supplementary materialThe online version of this article (doi:10.1007/s12017-017-8469-3) contains supplementary material, which is available to authorized users.

(E)-2-methoxy-4-(3-(4-methoxyphenyl) prop-1-en-1-yl) Phenol Ameliorates MPTP-Induced Dopaminergic Neurodegeneration by Inhibiting the STAT3 Pathway

“…In our study, MMPP inhibited STAT3 DNA binding and transcriptional activity, suggesting that MMPP can inhibit neuroinflammation through inactivation of astrocytes via blocking STAT3-mediated p38 and JNK MAPK pathways. Previously, we reported that MMPP has anti-inflammatory effects in inflammatory disease models such as AD, rheumatoid arthritis, and cancer [29,49,50]. We did not detect any side effects of MMPP with the effective dose of MMPP (5 mg/kg) during treatment for 30 days [29].…”

Bee venom phospholipase A2 ameliorates amyloidogenesis and neuroinflammation through inhibition of signal transducer and activator of transcription-3 pathway in Tg2576 mice

“…In addition, these substances could reduce the population of activated microglia and astrocytes by inhibiting the STAT3 signaling pathway and could exert anti-neuroinflammatory effects [48, 49]. These substances simultaneously inhibited Aβ accumulation, thereby alleviating memory impairment raising the possibility of treating AD [48, 50]. As an example, we have demonstrated that (E)-2-methoxy-4-(3-(4-methoxyphenyl) prop-1-en-1-yl) phenol inhibits the STAT3 signaling pathway, alleviates neuroinflammation, inhibits Aβ accumulation, and eventually restores memory impairment and cognitive abilities in an AD mouse model [50].…”

“…These substances simultaneously inhibited Aβ accumulation, thereby alleviating memory impairment raising the possibility of treating AD [48, 50]. As an example, we have demonstrated that (E)-2-methoxy-4-(3-(4-methoxyphenyl) prop-1-en-1-yl) phenol inhibits the STAT3 signaling pathway, alleviates neuroinflammation, inhibits Aβ accumulation, and eventually restores memory impairment and cognitive abilities in an AD mouse model [50]. Eufumi et al demonstrated that proinflammatory cytokines such as IL-6 induce phosphorylation of STAT3 and that phosphorylated STAT3 continues to activate microglia [18].…”

Dexmedetomidine inhibits inflammation in microglia cells under stimulation of LPS and ATP by c-Fos/NLRP3/caspase-1 cascades

“…Inflammation in AD can be induced by exogenous pathogens and sterile endogenous agents (Ishida et al, 2017[ 7 ]). LPS, an endotoxin isolated from gram-negative bacteria, can induce inflammatory responses, amyloidogenesis and neuronal damage, thus accelerating the progression of a neurodegenerative disease (Choi et al, 2017[ 1 ]). LPS has been widely used to conduct an experimental model of microglia activation (Choi et al, 2017[ 1 ]).…”

“…LPS, an endotoxin isolated from gram-negative bacteria, can induce inflammatory responses, amyloidogenesis and neuronal damage, thus accelerating the progression of a neurodegenerative disease (Choi et al, 2017[ 1 ]). LPS has been widely used to conduct an experimental model of microglia activation (Choi et al, 2017[ 1 ]). LPS administered into brain induces microglia activation, and results in accumulation of Aβs in both the cerebral cortex and hippocampus (Sheng et al, 2013[ 17 ]).…”