Gut Microbiota‐Derived Indole Derivatives Alleviate Neurodegeneration in Aging through Activating GPR30/AMPK/SIRT1 Pathway

Scope Tryptophan (Trp) metabolites are closely related to neurological diseases, whereas, the underlying mechanism related to the alleviative effects of Trp metabolites on neurodegeneration in aging remains unclear. This study aims to evaluate the protective effects and mechanisms of Trp metabolites on neurodegeneration in aging process. Methods and results The neuroprotective properties of Trp metabolites are evaluated in vitro and in vivo experimental model. Trp metabolites such as indole, indole‐3‐acetic acid (IAA), indole‐3‐propionic acid (IPA), indole‐3‐lactic acid (ILA), and indole‐3‐carboxyaldehyde (Icld) could significantly reduce oxidative stress, inflammation, and neuronal apoptosis induced by H 2 O 2 in HT‐22 cells. Meanwhile, indoles could upregulate the expressions of G protein‐coupled receptor 30 (GPR30)/5ʹ‐adenosine monophosphate (AMP)‐activated protein kinase (AMPK)/silent information regulator 1 (SIRT1) pathway in vitro. Furthermore, the neuroprotective effects of IAA and IPA are unveiled through activation of GPR30/AMPK/SIRT1 pathway in d ‐galactose induced aging mice. Finally, the regulatory effects of indoles on GPR30/AMPK/SIRT1 pathway are further confirmed by pretreating HT‐22 and Neuro‐2a with GPR30 antagonist of G15. In that case, indoles are furtherly proved with inhibitory effects on neurodegeneration by activating the GPR30/AMPK/SIRT1 pathway in aging process. Conclusions The findings reveal that Trp metabolites significantly improve neurodegeneration via GPR30/AMPK/SIRT1 pathway in aging process. This study provides the potential novel intervention strategy and target to prevent the neurodegeneration.