Icariin maintaining TMEM119-positive microglial population improves hippocampus-associated memory in senescent mice in relation to R-3-hydroxybutyric acid metabolism

Ethnopharmacological relevance: Epimedium Tourn. ex L. is a traditional Chinese medicine used for thousands of years in China to treat forgetfulness. Icariin is a principal component of the genus Epimedium.

Aim of the study: The metabolic mechanism of icariin treating forgetfulness is explored.

Materials and methods: A D-galactose-induced senescent mouse model was employed. The cognitive performance of mice was assessed in the fear conditioning test. Hippocampal pathology was assessed in the immunohistochemistry assay. Plasma metabolome was analyzed using GC-MS method, and the differential metabolites were further identified by UPLC-MS/MS or GC-MS method. The liver function, including ALT and AST, was assessed by enzyme reaction. Icariin was administered intraperitoneally at 50 and 100 mg/kg. Mice were administered five consecutive days per week for 8 weeks.

Results: Icariin treatment improved hippocampus-related fear memory but not amygdala-related memory, whereas Pexidartinib (PLX3397), a microglial scavenger, did not. Icariin treatment maintained the TMEM119-positive microglial population and decreased the accumulation of the senescent biomarker p16 in the dorsal hippocampus in senescent mouse brains, whereas PLX3397 did not. Notably, p16 in the CA2 subregion significantly decreased in icariin-treated mice than the other hippocampal subregions. The senescent mice exhibited the circulating metabolic characteristics of mild ketoacidosis, active tricarboxylic acid (TCA) cycle, lactic acidosis, hyperglycemia, active detoxification, active cis-oleic acid metabolism, and inhibitory GABA shut. R-3-Hydroxybutyric acid primarily produced in the liver was selectively and robustly decreased by icariin treatment, which was not observed with PLX3397 treatment. The TCA cycle was rescued in senescent mice by icariin treatment. Icariin also protected liver function (plasma ALT) in D-gal-induced senescent mice.

Conclusions: Icariin may protect mouse hippocampal cognition from D-gal-induced senescence by protecting microglial homeostasis, and facilitating the utilization of R-3-hydroxybutyric acid is one of the underpins.