Tetrahydroxy stilbene glycoside alleviated inflammatory damage by mitophagy via AMPK related PINK1/Parkin signaling pathway

May 1, 2020Biochemical pharmacology

Tetrahydroxy stilbene glycoside reduces inflammation by promoting damaged mitochondria removal through the AMPK-linked PINK1/Parkin pathway

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Abstract

Treatment with 2,3,5,4'-Tetrahydroxystilbene-2-O-β-D-glucoside (TSG) significantly attenuated the secretion of inflammatory cytokines.

TSG is associated with a reduction in the NLRP3 inflammasome in both microglia and neurons.
Inhibition of the NLRP3 signaling pathway by TSG may lead to decreased inflammatory responses induced by LPS.
TSG promotes autophagy through the AMPK/PINK1/Parkin signaling pathway, which could enhance neuroprotection.
Lack of PINK1 was found to inhibit autophagy and mitophagy in microglia, suggesting its importance in TSG's mechanism.
Knockdown of PINK1 or Parkin resulted in the loss of TSG's protective effects, indicating their critical roles.

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Alzheimer's disease (AD) is an irreversible neurodegenerative brain disorder with complex pathogenesis. The fibrillar peptide β-amyloid (Aβ) has a chief function in the pathogenesis of AD. Emerging evidence has indicated that there is a tight relationship between inflammation, mitochondrial dysfunction and Aβ formation. 2,3,5,4'-Tetrahydroxystilbene-2-O-β-D-glucoside (TSG) is one of the main active components extracted from Polygonum multiflorum. Recent research corroborated the beneficial roles of TSG in alleviating the learning and memory of AD models. Unfortunately, the underlying mechanism of TSG remains poorly elucidated. The purpose of the present study was to investigate the effects of TSG on LPS/ATP and Aβ-induced inflammation in microglia and neurons and its underlying molecular mechanisms. Our results found that treatment with TSG significantly attenuated the secretion of inflammatory cytokines, reduced NLRP3 inflammasome, and regulated mitophagy. TSG efficiently alleviated LPS-induced inflammatory response by inhibiting the NLRP3 signaling pathway both in microglia and neuron. Meanwhile, TSG promoted autophagy involved in the AMPK/PINK1/Parkin signaling pathway, which may contribute to the protective activity. Additional mechanistic investigations to evaluate the dependence of the neuroprotective role of TSG on PINK1 revealed that a lack of PINK1 inhibited autophagy, especially mitophagy in microglia. Importantly, knockdown of PINK1 or Parkin by siRNA or CRISPR/Cas9 system abolished the protective effects of TSG. In conclusion, these phenomena suggested that TSG prevented LPS/ATP and Aβ-induced inflammation via AMPK/PINK1/Parkin-dependent enhancement of mitophagy. We found the neuroprotective effect of TSG, suggesting it may be beneficial for AD prevention and treatment by suppressing the activation of inflammation. 25-35

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Tetrahydroxy stilbene glycoside alleviated inflammatory damage by mitophagy via AMPK related PINK1/Parkin signaling pathway

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