Effects of ketamine on endotoxin and traumatic brain injury induced cytokine production in the rat

Abstract

Background: Endotoxemia from lipopolysaccharide (LPS) induces systemic cytokine production, whereas traumatic brain injury (TBI) increases intracerebral cytokine production. In anesthetic doses, ketamine has potent anti-inflammatory properties. However, its anti-inflammatory effects at subanesthetic doses and its effects on TBI-induced inflammation have not been fully investigated. We hypothesized that ketamine would attenuate both LPS- and TBI-induced inflammatory responses.

Methods: Male rats received intraperitoneal (i.p.) ketamine (70 mg/kg, 7 mg/kg, or 1 mg/kg) or saline 1 hour before LPS (20 mg/kg i.p.) or saline. Five hours after LPS, rats were killed. Serum was collected for cytokine analysis. In other experiments, male rats were given ketamine (7 mg/kg i.p.) or saline 1 hour before induction of TBI with controlled cortical impact (or sham). One hour and 6 hours after injury, brain was extracted for analysis of cerebral edema and cytokine production.

Results: LPS increased the serum concentrations of interleukin (IL)-1α, IL-1β, IL-6, IL-10, tumor necrosis factor-α, and interferon-γ. Ketamine dose dependently attenuated these changes. TBI caused cerebral edema and increased concentrations of cerebral IL-1α, IL-1β, IL-6, IL-10, and tumor necrosis factor-α. However, ketamine had minimal effect on TBI-induced inflammation.

Conclusions: Although ketamine did not seem to exert any beneficial effects against TBI in the rat, it did not exacerbate cytokine production or enhance cerebral edema as some studies have suggested.

Figures

Figure 1

Brain of the rat. The site of direct injury and penumbra were isolated after sacrifice for measurement of tissue percent water and tissue cytokine concentrations.

Figures 2A-B

Effects of intraperitoneal ketamine (K; 70, 7, and 1 mg/kg), administered 1 hour prior to intraperitoneal lipopolysaccharide (LPS, 20 mg/kg), on serum concentrations of IL-1α (2A) and IL-1β (2B) 5 hours after LPS. Data are mean serum cytokine concentration (pg/mL) ± SEM. * p < 0.05 versus Saline; ** p < 0.05 vs Saline-LPS; *** p < 0.05 vs Ketamine (1 mg/kg)-LPS; n = 8 for Saline-Saline, n = 10 for all other groups.

Figures 3A-B

Effects of intraperitoneal ketamine (K; 70, 7, and 1 mg/kg), administered 1 hour prior to intraperitoneal lipopolysaccharide (LPS, 20 mg/kg), on serum concentrations of IL-6 (3A) and IL-10 (3B) 5 hours after LPS. Data are mean serum cytokine concentration (pg/mL) ± SEM. * p < 0.05 versus Saline; ** p < 0.05 vs Saline-LPS; *** p < 0.05 vs Ketamine (1 mg/kg)-LPS; n = 8 for Saline-Saline, n = 10 for all other groups.

Figures 4A-B

Effects of intraperitoneal ketamine (K; 70, 7, and 1 mg/kg), administered 1 hour prior to intraperitoneal lipopolysaccharide (LPS, 20 mg/kg), on serum concentrations of TNF-α (4A) and IFN-γ (4B) 5 hours after LPS. Data are mean serum cytokine concentration (pg/mL) ± SEM. * p < 0.05 versus Saline; ** p < 0.05 vs Saline-LPS; *** p < 0.05 vs Ketamine (1 mg/kg)-LPS; **** p < 0.05 vs Ketamine (1 mg/kg)-LPS; n = 8 for Saline-Saline, n = 10 for all other groups.