GuiLingJi ameliorates mild cognitive impairment by targeting unsaturated fatty acid metabolism to inhibit GPR120/NF-κB mediated neuroinflammation

Background Mild cognitive impairment (MCI) is an intermediate condition between normal aging and dementia. Drug intervention is an important way to prevent MCI from developing into dementia. GuiLingJi (GLJ) is a traditional Chinese medicine formulae and it has the effect of enhancing memory. In view of the absence of special effective drugs for MCI, GLJ warrants investigation as a potential therapeutic agent. Methods This study uses a rat model of MCI, induced by D-galactose injections and a semi-high-fat diet, to explore the therapeutic efficacy of GLJ in MCI and elucidate the potential underlying pharmacological mechanisms by behavioral experiments and biochemical indexes, combined with serum and hippocampal metabolomics. Results GLJ treatment mitigated D-galactose combined with semi-high-fat diet induced impairments, including abnormal blood lipids, oxidative stress, inflammation, cholinergic dysfunction, apoptosis, and reduced brain-derived neurotrophic factors, along with hippocampal damage. LC-MS metabolomics indicated that these effects involved unsaturated fatty acid and amino acid metabolism. By normalizing linoleic acid and α-linolenic acid levels and activating GPR120, GLJ inhibited the NF-κB/TNF-α pathway. Conclusion These findings demonstrate that GLJ alleviates MCI symptoms, at least in part, by modulating fatty acid metabolism and suppressing neuroinflammation via the GPR120/NF-κB pathway. This study supports GLJ as a promising proprietary TCM formulation for MCI treatment.