minocycline and Endotoxemia

Antibiotics might, apart from an antimicrobial effect, also exert anti-inflammatory effects. The novel antibiotic tigecycline, potentially useful in septic shock from gram-negative multiresistant bacteria, is structurally related to antibiotics with known anti-inflammatory properties. However, its anti-inflammatory effects have not been previously explored in vivo. Using a sterile integrative porcine sepsis model, we investigated the anti-inflammatory and circulatory effects of tigecycline in comparison with doxycycline and placebo. Eighteen pigs were randomized to receive tigecycline 100 mg, doxycycline 200 mg, or placebo and subjected to 6-h endotoxin infusion at 0.5 μg kg(-1) h(-1). Markers of inflammation, nitric oxide production, vascular permeability, hemodynamics, organ dysfunction, tissue metabolism, and acid-base parameters were monitored. Peak plasma tumor necrosis factor-α was lower in the doxycycline group (P = 0.031) but not in the tigecycline group (P = 0.86) compared with placebo, with geometric mean plasma concentrations of 16, 79, and 63 ng mL(-1), respectively. Mean arterial pressure was higher 4 to 6 h in the tigecycline group, with values at 6 h of 107 ± 9 mmHg compared with the placebo and doxycycline groups (85 ± 27 mmHg and 90 ± 32 mmHg, respectively; P = 0.025). The white blood cell and the neutrophil granulocyte counts were less reduced in the doxycycline group but not in the tigecycline group at 4 to 6 h (P = 0.009 and P = 0.019, respectively). Other markers of inflammation, organ dysfunction, tissue metabolism, and acid-base parameters were unaffected by tigecycline. Consistent with known anti-inflammatory properties, doxycycline yielded decreased tumor necrosis factor-α levels. Tigecycline did not affect cytokine levels but counteracted hypotension and hypoperfusion.

Topics: Animals; Doxycycline; Endotoxemia; Hemodynamics; Inflammation; Male; Minocycline; Random Allocation; Swine; Tigecycline

Activation of the peripheral innate immune system stimulates the secretion of CNS cytokines that modulate the behavioral symptoms of sickness. Excessive production of cytokines by microglia, however, may cause long-lasting behavioral and cognitive complications. The purpose of this study was to determine if minocycline, an anti-inflammatory agent and purported microglial inhibitor, attenuates lipopolysaccharide (LPS)-induced neuroinflammation, sickness behavior, and anhedonia.. In the first set of experiments the effect of minocycline pretreatment on LPS-induced microglia activation was assessed in BV-2 microglia cell cultures. In the second study, adult (3-6 m) BALB/c mice received an intraperitoneal (i.p.) injection of vehicle or minocycline (50 mg/kg) for three consecutive days. On the third day, mice were also injected (i.p.) with saline or Escherichia coli LPS (0.33 mg/kg) and behavior (i.e., sickness and anhedonia) and markers of neuroinflammation (i.e., microglia activation and inflammatory cytokines) were determined. In the final study, adult and aged BALB/c mice were treated with the same minocycline and LPS injection regimen and markers of neuroinflammation were determined. All data were analyzed using Statistical Analysis Systems General Linear Model procedures and were subjected to one-, two-, or three-way ANOVA to determine significant main effects and interactions.. Minocycline blocked LPS-stimulated inflammatory cytokine secretion in the BV-2 microglia-derived cell line and reduced LPS-induced Toll-like-receptor-2 (TLR2) surface expression on brain microglia. Moreover, minocycline facilitated the recovery from sickness behavior (i.e., anorexia, weight loss, and social withdrawal) and prevented anhedonia in adult mice challenged with LPS. Furthermore, the minocycline associated recovery from LPS-induced sickness behavior was paralleled by reduced mRNA levels of Interleukin (IL)-1beta, IL-6, and indoleamine 2, 3 dioxygenase (IDO) in the cortex and hippocampus. Finally, in aged mice, where exaggerated neuroinflammation was elicited by LPS, minocycline pretreatment was still effective in markedly reducing mRNA levels of IL-1beta, TLR2 and IDO in the hippocampus.. These data indicate that minocycline mitigates neuroinflammation in the adult and aged brain and modulates the cytokine-associated changes in motivation and behavior.

Topics: Age Factors; Animals; Cell Line; Cerebral Cortex; Dietary Sucrose; Drug Evaluation, Preclinical; Endotoxemia; Endotoxins; Exploratory Behavior; Food Preferences; Hippocampus; Interleukin-1beta; Interleukin-6; Male; Mice; Mice, Inbred BALB C; Microglia; Minocycline; Mood Disorders; RNA, Messenger; Sick Role; Social Behavior Disorders; Specific Pathogen-Free Organisms; Toll-Like Receptor 2