Journal
JOURNAL OF PSYCHIATRIC RESEARCH
Volume 144, Issue -, Pages 118-128Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jpsychires.2021.09.057
Keywords
Depression; Ketamine; LPS; TNF-alpha; Prophylactic effect; Resilience
Categories
Funding
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) [310113/2017-2]
- Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES)
- CNPq Research Productivity Fellowship
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Ketamine has been shown to prevent depressive-like behavior induced by inflammatory stressors, potentially through the suppression of the NLRP3 inflammasome-driven signaling pathway.
Ketamine has emerged as a prophylactic agent against depressive-like behavior induced by stress. However, the possible pro-resilience effects of ketamine against inflammatory stressors-induced depressive-like behavior and the signaling pathways associated with this response remain to be determined. Therefore, this study investigated the ability of prophylactic ketamine administration to produce a pro-resilience effect against the depressive-like behavior induced by lipopolysaccharide (LPS - 0.83 mg/kg, i.p.) and tumor necrosis factor-alpha (TNF-alpha -0.1 fg/site, i.c.v.) administration in mice. The possible contribution of the NLRP3 inflammasome-driven signaling pathway to this effect was evaluated in the ventral hippocampus. A single administration of ketamine (5 mg/kg, i.p.) given 1 week before the LPS or TNF-alpha administration prevented the depressive-like behavior induced by these inflammatory stressors in the tail suspension test (TST) and splash test (SPT). On the other hand, a lower dose of ketamine (1 mg/kg, i.p.) failed to produce a similar effect. The administration of LPS, but not TNF-alpha, increased the immunocontent of the microglial marker Iba-1 in the ventral hippocampus. LPS increased the immunocontent of all proteins related to NLRP3 signaling, namely ASC, NLRP3, TXNIP, cleaved caspase-1, and IL-1 beta in this brain region, while TNF-alpha only increased ASC and NLRP3 immunocontent. Ketamine administered at the dose of 5 mg/kg, but not at 1 mg/kg, prevented the increase on the immunocontent of NLRP3 inflammasome complex components and regulators induced by LPS or TNF-alpha administration. Collectively, these findings suggest that ketamine elicits a pro-resilient phenotype against inflammatory stressors-induced depressive-like behavior, an effect associated with the suppression of the NLRP3 inflammasome-driven signaling pathway.
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