Esketamine prevents cognitive deficiency via intestinal flora/subdiaphragmatic vagus nerve/spleen axis after a secondary LPS exposure

Abstract

Abstract After resolution of primary infection, patients are susceptible to more severe secondary infection with unclear underlying mechanisms.To investigate whether esketamine treatment immediately after primary LPS exposure could alleviate second-infection-induced cognitive impairment. In this study, mice were injected intraperitoneally (i.p.) with lipopolysaccharides (LPS; 5 mg/kg) 10 days apart. Esketamine (10, 15 or 30 mg/kg) was i.p. injected immediately after the primary LPS injection. Splenectomy or subdiaphragmatic vagotomy (SDV) was performed 7 days before secondary LPS exposure or administration of antibiotics. Esketamine at 30 mg/kg mitigated splenomegaly at 3 and 10 days post primary LPS injection. It countered cognitive dysfunction and proinflammatory cytokine increases from secondary LPS exposure. Mice with splenectomy or SDV showed reduced proinflammatory cytokines, heightened hippocampal BDNF, and improved cognition after secondary infection, without added esketamine effect. FMT from esketamine-treated endotoxic mice to pseudo germ-free (PGF) mice attenuated hippocampal BDNF downregulation and cognitive dysfunction in PGF mice without splenectomy. FMT failed to reverse PGF mice's SDV-induced splenomegaly. Blocking BDNF signaling negated esketamine's ameliorating effects on secondary LPS-induced cognitive dysfunction. In conclusion, the intestinal flora/subdiaphragmatic vagus nerve/spleen axis-mediated downregulation of hippocampal BDNF had a profound effect on secondary LPS-induced inflammation and cognitive dysfunction.