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Background: Studies have demonstrated an important impact of systemic inflammation in the central nervous system, which could be related to psychiatric disorders’ pathophysiology. Ketamine can have anti-inflammatory proprieties, but dose-dependently effects need to be studied. Objective: To evaluate the effect of different doses of ketamine on levels of neurotrophins and inflammatory cytokines in the brains of rats. Methods: Wistar rats were submitted to the cecal ligation and puncture (CLP) model of sepsis. Thirty days after the CLP procedure, the rats received an intraperitoneal injection (i.p.) of ketamine (5, 15, or 25 mg/kg) or saline, once a day for seven days. The rats were killed 30 minutes after the last i.p. injection. The frontal cortex, hippocampus, and striatum were dissected for analysis of IL-1𝛽, IL-6, IL-10, TNF-α, BDNF, NGF, NT-3, and GDNF levels. Results: CLP increased the levels of IL-1𝛽, IL-6, IL-10, and TNF-α levels in the frontal cortex and/or hippocampus of rats. Besides, BDNF levels were decreased by CLP in all structures analyzed. NGF and GDNF were decreased only in the hippocampus. Ketamine at 5 mg/kg reversed all alterations caused by CLP and per se increased the levels of BDNF and NGF in the frontal cortex and/or hippocampus. Ketamine at 15 mg/kg increased BDNF and NGF levels. In turn, Ketamine at 25mg/kg potentiates the inflammatory injury on the brain induced by CLP. Conclusion:We suggest that ketamine could work differently in a systemic inflammation environment, and caution needs to be taken depending on the inflammatory history of the patient.

Evidence suggest that prenatal immune system disturbance contributes largely to the pathophysiology of neuropsychiatric disorders. A bacterial infection animal model widely accepted is administration of lipopolysaccharide (LPS). We investigated if maternal immune activation (MIA) could induce inflammatory alterations, oxidative damage and damage to blood brain barrier integrity (BBB) and placental barrier (PB) in fetal brain and pregnant Wistar rats. On gestational day 15, Wistar pregnant rats received LPS (0.25 mg/kg) to induce MIA. After 6, 12 and 24 h, fetus brain, placenta, and amniotic fluid were collected to evaluate early effects of LPS. Other group of rats from postnatal day (PND) 54 received injection of ketamine at the doses of 5, 15, and 25 mg/kg. On PND 60 rats were subjected to the spontaneous locomotor activity and pre-pulse inhibition test (PPI). MIA increased oxidative stress in the amniotic fluid and fetal brain. The BBB integrity in the hippocampus and cerebral cortex as well integrity of PB in the placenta and fetus brain were dysregulated after LPS induction. We also found elevated levels of cytokines such as interleukin (IL)-1β, IL-2, IL-4, IL-5, interferon (IFN)-γ, macrophage colony stimulating factor (M-CSF), IL-6, IL-10, IL-18, macrophage inflammatory protein (MIP)-3a, tumor necrosis factor (TNF)-α-, IL-7, MIP-1a and erythropoietin. Rats that receive MIA plus ketamine had locomotor activity impairment and a deficit in the PPI. In the present study, it was concluded that MIA increased the permeability of BBB and PB, the circulation of inflammatory mediators in fetal brains. This immune response in the prenatal period may be responsible for the behavioral changes in the adult life of offspring induced by MIA.