The ketamine metabolite (2R,6R)-hydroxynorketamine (HNK) reduces depression-like behavior in mice by suppressing neuroinflammation and neuronal pyroptosis. In experiments with male C57BL/6J mice and PC12 cells, HNK lowered expression of NLRP3, caspase-1, GSDMD, and interleukin-1β at both protein and mRNA levels, lessened neuronal injury, and reduced lactate dehydrogenase release. Transcriptomic analysis identified Vcam1 as a key differentially expressed gene. Overexpressing Vcam1 increased pyroptosis markers, while HNK reduced Vcam1 expression; knocking down Vcam1 had opposite effects. HNK thus attenuates LPS-induced pyroptosis and neuroinflammation partly by downregulating the Vcam1/caspase-1/IL-1β pathway, offering insights for depression treatment.
Low doses of ketamine produce rapid antidepressant effects by activating the α7 nicotinic acetylcholine receptor (α7nAChR)-mediated cholinergic anti-inflammatory pathway. In a rat model of depression induced by lipopolysaccharide and in PC12 nerve cells, ketamine reduced neuroinflammation, improved behavior, synaptic plasticity, and Nissl bodies. Blocking α7nAChR with methyllycaconatine or α7nAChR-siRNA reversed these effects, and the degree of reversal correlated with the dose of the blocker. A specific α7nAChR agonist, GTS-21, produced similar protective effects as ketamine, confirming the pathway's role.
Ketamine combined with docosahexaenoic acid (DHA), an unsaturated fatty acid, reversed depression-like behaviors in rats exposed to lipopolysaccharide, an inflammatory trigger. The combination reduced immobility time in forced swimming and tail suspension tests and increased sucrose preference more effectively than either agent alone. It also reversed nerve damage, reduced inflammatory cytokines IL-1, IL-6, and TNF-α in the hippocampus and PC12 cells, increased brain-derived neurotrophic factor (BDNF), inhibited PP65 nuclear translocation, and suppressed NF-κB expression while increasing P-CREB and BDNF. The findings suggest that combining ketamine with DHA may offer a more effective treatment for inflammation-driven depression by inhibiting inflammatory pathways.