Hederagenin Modulates M1 Microglial Inflammatory Responses and Neurite Outgrowth

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder. Neurite atrophy and synaptic loss initiate the onset of neuronal death, while the activated M1 microglia-induced neuroinflammatory microenvironment inhibits neurite regeneration and exacerbates neuronal loss. Thus, optimizing the brain microenvironment using small compounds through suppressing activated M1 microglia and promoting neurite regrowth might be an effective therapeutic strategy for AD. We found that hederagenin (HED), a naturally occurring triterpene compound, inhibited lipopolysaccharide-induced nitric oxide generation and downregulated expression of proinflammatory cytokines, such as tumor necrosis factor-α, interleukin-1β (IL-1β), and IL-6. Further investigation of primary microglia confirmed that HED inhibited Iba-1 positive M1 microglia. However, no changes were seen in CD206 positive M2 microglia polarization. HED remarkably suppressed phosphorylated nuclear factor kappa-light-chain-enhancer of activated B cells subunit p65 signaling. In addition, HED ameliorated Aβ25-35-induced neuritic atrophy and neuronal death. Therefore, HED might be a therapeutic candidate for AD.

Dihydroquercetin ameliorates LPS-induced neuroinflammation and memory deficit

“…Therefore, there is a need to explore newer drugs for the potential treatment of neuroinflammatory disorders. There are various natural products showing promising results against oxidative stress and neuroinflammation, including carnosine ( Caruso et al., 2019 ), hederagenin ( Wang et al., 2020 ), resveratrol ( Zhang et al., 2013 ).…”

Diosmin inhibits neuroinflammation and improves cognitive deficit in lipopolysaccharide-mouse model of Alzheimer’s disease

“…Anti-in ammatory drugs, such as the non-steroidal ones, have not proven to be the best therapy for neuroin ammation due to some unresolved toxic effects and the selectivity of the blood-brain barrier (Ghlichloo and Gerriets, 2022). This has increased the need to explore novel drugs or reposition existing ones for the potential treatment of neuroin ammatory disorders (Jaeger et al, 2018;Chen et al, 2022;Wang et al 2020).…”

Hederagenin Protects PC12 Cells Against Corticosterone-Induced Injury by the Activation of the PI3K/AKT Pathway

“…Currently, there is an increasing interest in Hederagenin due to its multiple pharmacological activities including anti-hyperlipidemia, anti-inflammatory ( Takagi et al, 1980 ; Su-Hong et al, 2015 ), as well as significant cytotoxic effects in several types of cancers ( Kim et al, 2017a ; Bai et al, 2017 ; Tatia et al, 2019 ). In addition, hederagenin is also able to promote the degradation of neurodegenerative mutant disease proteins ( Wu et al, 2017 ) and may act as a therapeutic candidate for Alzheimer’s disease ( Wang et al, 2020 ) and ischemic stroke ( Yu et al, 2020 ). Recently, Hederagenin was reported to have antidepressant-like effects ( Zhou et al, 2010 ; Jin et al, 2012 ; Liang et al, 2015 ).…”