(2R,6R)-HNK improved LPS-induced depression-like behavior by inhibiting Vcam1/Caspase-1/IL-1β pathway.
Jinghua Zhao, Ruxin Zhang, Jiarui Pan, Ping Liu, Yuqiang Chen, Jing Zhong, Xinran Hu, Liyan Ye, Tianxiang Pan, Junlong Sun, Houhui Song, Wei Wang
International Immunopharmacology August 1, 2026 DOI: 10.1016/j.intimp.2026.116833 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | C57BL/6J male mice and PC12 cells |
| Interventions | (2R 6R)-hydroxynorketamine |
| Topics | Depression |
| Keywords | 2r,6r-hnk Neuroinflammation Pyroptosis Vcam1 |
| Key findings | (2R,6R)-HNK attenuates LPS-induced neuronal pyroptosis and neuroinflammation and ameliorates depression-like behavior in mice partially by downregulating the Vcam1/caspase-1/IL-1β pathway. |
Abstract
Depression-like behavior is closely associated with neuroinflammation. Lipopolysaccharide (LPS) can activate N-methyl-d-aspartate receptors and induce cellular pyroptosis and neuroinflammation, thereby triggering depression-like behavior in animals. The ketamine metabolite (2R,6R)-hydroxynorketamine (HNK) exerts significant antidepressant-like effects without the adverse effects associated with ketamine, such as addiction and abuse liability. However, its underlying mechanisms remain largely unclear. In this study, C57BL/6 J male mice and PC12 cells were used to establish an in vivo depression-like model and an in vitro neuroinflammatory model, respectively. The mechanism by which (2R,6R)-HNK ameliorated depression-like behavior in mice was investigated using histological staining, immunofluorescence, flow cytometry, gene transfection, western blots, RT-PCR, and other analyses. The results demonstrated that (2R,6R)-HNK significantly suppressed the protein and mRNA expression levels of NLRP3, caspase-1, GSDMD, and interleukin (IL)-1β both in vivo and in vitro. Meanwhile, neuronal injury was markedly alleviated, and lactate dehydrogenase release was reduced. Transcriptomic sequencing revealed that Vcam1 was significantly differentially expressed in different groups. Therefore, Vcam1 overexpression and si-Vcam1 vectors were subsequently transfected into PC12 cells. The results showed that Vcam1 overexpression upregulated the mRNA expression of pyroptosis-related markers, including caspase-1, caspase-11, GSDMD, and IL-1β, whereas (2R,6R)-HNK inhibited Vcam1 expression. In contrast, Vcam1 knockdown exerted opposite effects. In conclusion, (2R,6R)-HNK attenuates LPS-induced neuronal pyroptosis and neuroinflammation, and subsequently ameliorates depression-like behaviors in mice, partially by downregulating Vcam1/caspase-1/IL-1β pathway expression. The findings provide novel insights into the treatment of depression and the development of therapeutic agents for neuroinflammation-related disorders.
Comparable studies
Other preclinical and animal studies on depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psychedelics, but Not Ketamine, Produce Persistent Antidepressant-like Effects in a Rodent Experimental System for the Study of Depression Rats | 2020 | Preclinical study | |
| A Single Subanesthetic Dose of Ketamine Relieves Depression-like Behaviors Induced by Neuropathic Pain in Rats Rats with spared nerve injury (neuropathic pain model), sham-operated rats, and control... | 2011 | Animal experimental study | |
| Effects of N,N-Dimethyltryptamine on Rat Behaviors Relevant to Anxiety and Depression Adult male Sprague-Dawley rats | 2018 | Experimental study | |
| A non-hallucinogenic LSD analog with therapeutic potential for mood disorders. Mice and cultured rat cortical neurons | 2023 | Preclinical study | |
| Comparison of (R)-ketamine and lanicemine on depression-like phenotype and abnormal composition of gut microbiota in a social defeat stress model Susceptible mice after chronic social defeat stress | 2017 | Preclinical animal study |
Citations in the library
Cites 5
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
- Sustained antidepressant effect of ketamine through NMDAR trapping in the LHb Nature October 18, 2023
- Activity-dependent brain-derived neurotrophic factor signaling is required for the antidepressant actions of (2 R ,6 R )-hydroxynorketamine Proceedings of the National Academy of Sciences December 17, 2018
- Ketamine’s effect on inflammation and kynurenine pathway in depression: A systematic review Journal of Psychopharmacology June 26, 2021
- (2R,6R)-hydroxynorketamine rescues chronic stress-induced depression-like behavior through its actions in the midbrain periaqueductal gray. Neuropharmacology September 1, 2018