Ginsenoside Re mitigates memory impairments in aged GPx-1 KO mice by inhibiting the interplay between PAFR, NFκB, and microgliosis in the hippocampus.

Abstract

Ginsenoside Re (GRe) upregulates anti-aging klotho by mainly upregulating glutathione peroxidase-1 (GPx-1). However, the anti-aging mechanism of GPx-1 remains elusive. Here we investigated whether the GRe-mediated upregulation of GPx-1 modulates oxidative and proinflammatory insults. GPx-1 gene depletion altered redox homeostasis and platelet-activating factor receptor (PAFR) and nuclear factor kappa B (NFκB) expression, whereas the genetic overexpression of GPx-1 or GRe mitigated this phenomenon in aged mice. Importantly, the NFκB inhibitor pyrrolidine dithiocarbamate (PDTC) did not affect PAFR expression, while PAFR inhibition (i.e., PAFR knockout or ginkgolide B) significantly attenuated NFκB nuclear translocation, suggesting that PAFR could be an upstream molecule for NFκB activation. Iba-1-labeled microgliosis was more underlined in aged GPx-1 KO than in aged WT mice. Triple-labeling immunocytochemistry showed that PAFR and NFκB immunoreactivities were co-localized in Iba-1-positive populations in aged mice, indicating that microglia released these proteins. GRe inhibited triple-labeled immunoreactivity. The microglial inhibitor minocycline attenuated aging-related reduction in phospho-ERK. The effect of minocycline was comparable with that of GRe. GRe, ginkgolide B, PDTC, or minocycline also attenuated aging-evoked memory impairments. Therefore, GRe ameliorated aging-associated memory impairments in the absence of GPx-1 by inactivating oxidative insult, PAFR, NFkB, and microgliosis.