Hydroxysafflor Yellow A Inhibits Aß1-42-Induced Neuroinflammation by Modulating the Phenotypic Transformation of Microglia via TREM2/TLR4/NF-κB Pathway in BV-2 Cells.

Hydroxysafflor yellow A (HSYA) is an extract from Carthamus tinctorius L. dry flowers (Compositae). HSYA has been shown to have neuroprotective effects on several Alzheimer's disease (AD) models. However, the exact mechanisms by which HSYA regulates neuroinflammation have still not been clarified. In this study, we investigated the mechanism by which HSYA regulates microglial activation and neuroinflammation via TREM2, and further clarified its underlying molecular mechanism. We silenced TREM2 in BV-2 cells and evaluated the expression of inflammatory markers (TNF-α, IL-1ß, IL-4, IL-6, IL-10, and IL-13). The results showed that HSYA could up-regulate cell viability and improve the morphology of BV-2 cells injured by Aß1-42. The results showed that Aß1-42 could induce microglia to upregulate the expression of M1 markers (iNOS, IL-1ß, IL-6) and downregulate M2 marker (Arg-1, IL-4, IL-10, IL-13) expression. HSYA reversed the effects of Aß1-42 via TREM2, switching microglia from an M1 proinflammatory phenotype to an M2 anti-inflammatory phenotype. HSYA inhibited the Aß1-42-induced activation of the TLR4/NF-κB transduction pathway by upregulating TREM2 and regulated the transcription of inflammatory cytokines via the downstream transcription factors NF-κB p65 and IκB-α. In conclusion, HSYA regulated the microglial inflammatory phenotype by regulating microglial (M1/M2) polarization in Aß1-42-induced BV-2 cells which may be mediated by the TREM2/TLR4/NF-κB pathway.

Safflower Yellow Improves the Synaptic Structural Plasticity by Ameliorating the Disorder of Glutamate Circulation in Aß1-42-induced AD Model Rats.

Safflower yellow (SY) is the main effective component of Carthamus tinctorius L., and Hydroxysafflor yellow A (HSYA) is the single active component with the highest content in SY. SY and HSYA have been shown to have neuroprotective effects in several AD models. In this study, we aimed to clarify whether the effects of SY and HSYA on the learning and memory abilities of Aß1-42-induced AD model rats are related to the enhancement of synaptic structural plasticity in brain tissues and the amelioration of disorder of glutamate circulation. We used rats injected with Aß1-42 into the bilateral hippocampus as a model of AD. After treatment with SY and HSYA, the learning and memory abilities of the Aß1-42-induced AD model rats were enhanced, Aß deposition in the AD model rats was decreased, structural damage to dendritic spines and the loss of synaptic-associated proteins were alleviated, and the disorder of glutamate circulation was ameliorated. The results indicated that SY and HSYA improve synaptic structural plasticity by ameliorating the disorder of glutamate circulation in Aß1-42-induced AD model rats.

Safflower Yellow Improves Synaptic Plasticity in APP/PS1 Mice by Regulating Microglia Activation Phenotypes and BDNF/TrkB/ERK Signaling Pathway.

Alzheimer's disease (AD) is a common neurodegenerative disease that is always accompanied by synaptic loss in the brain. Safflower yellow (SY) is the extract of safflower, a traditional Chinese medicine, which has shown neuroprotective effects in recent studies. However, the mechanism of SY in protecting synapses remains unclear. In this study, we are going to study the mechanism of how SY treats AD in terms of synaptic plasticity. We found, via behavioral experiments, that SY treatment could improve the abilities of learning and memory in APP/PS1 mice. In addition, using Golgi staining and HE staining, we found that SY treatment could reduce the loss of dendritic spines in the pathological condition and could maintain the normal physiological state of the cells in cortex and in hippocampus. In addition, the results of immunofluorescence staining and western blotting showed that SY treatment could significantly increase the expression of synapse-related proteins. Moreover, after being treated with SY, the expression of iNOS (marker of M1 microglia) declined remarkably, and the level of Arginase-1 (marker of M2 microglia) increased significantly. Finally, we found BDNF/TrkB/ERK signaling cascade was activated. These results indicate that SY enhances synaptic plasticity in APP/PS1 mice by regulating microglia activation phenotypes and BDNF/TrkB/ERK signaling pathway.

Geniposidic acid ameliorates spatial learning and memory deficits and alleviates neuroinflammation via inhibiting HMGB-1 and downregulating TLR4/2 signaling pathway in APP/PS1 mice.

Geniposidic acid (GPA) is an extract from Eucommia ulmoides Oliv. Bark (Eucommiaceae). Accumulating evidences have reported GPA has anti-aging, anti-oxidative stress, anti-inflammatory and neurotrophic effects on neurons. However, whether GPA could alleviate memory deficits in Alzheimer's disease animal models is not clear. We aimed to investigate the effect of GPA treatment on cognitive performance, Aß deposition and glial cells activation in the transgenic mouse model of AD. 6-7 months APP/PS1 mice were given GPA for 90 days; behavioral experiments were executed to estimate the memory and spatial learning abilities of mice, and the mechanism of neuroprotective effect of GPA was investigated with a focus on amyloid-ß deposition, astrocytes and microglia activation and neuroinflammation. GPA treatment significantly improved the spatial learning and memory abilities and also decreased cerebral amyloid-ß deposition in APP/PS1 mice. Via HE staining, we found that GPA could ameliorate histopathological changes in cerebrum. We also found that GPA treatment inhibited the activation of astrocytes and microglia, down-regulated the expression of pro-inflammatory cytokines and iNOS, and up-regulated the expression of anti-inflammatory cytokines and Arg-1. In addition, GPA down-regulated the gene expression of HMGB-1 receptors (TLR2, TLR4 and RAGE) then mediated MyD88, TRAF6 and phospho-ERK1/2, subsequently modulated the expression of key AP-1 and NF-κB family members (c-Fos, c-Jun and p65). The reversal of the pro-inflammatory state suggested GPA can serves as a multi-target candidate by alleviating Aß deposition and neuroinflammation for the auxiliary therapy of Alzheimer's disease.