Prophylactic maternal N-acetylcysteine in rats prevents maternal inflammation-induced offspring cerebral injury shown on magnetic resonance imaging.

OBJECTIVE: Maternal infection or inflammation may induce fetal inflammatory responses associated with fetal injury and cerebral palsy. We sought to assess the inflammation-associated neuroprotective potential of prophylactic N-acetyl-cysteine (NAC). We examined the effect of NAC on prevention of maternal lipopolysaccharide (LPS)-induced neonatal brain injury using magnetic resonance imaging. STUDY DESIGN: Pregnant Sprague Dawley dams (n = 5-8) at embryonic day 18 received intraperitoneal injection of LPS or saline at time 0. Animals were randomized to receive 2 intravenous injections of NAC or saline (time -30 and 120 minutes). Pups were delivered spontaneously and allowed to mature until postnatal day 25. Female offspring were examined by magnetic resonance brain imaging and analyzed using voxel-based analysis after spatial normalization. T2 relaxation time was used to assess white matter injury and diffusion tensor imaging for apparent diffusion coefficient (ADC) to assess white and gray matter injury. RESULTS: Offspring of LPS-treated dams exhibited significantly increased T2 levels and increased ADC levels in white and gray matter (eg, hypothalamus, motor cortex, corpus callosum, thalamus, hippocampus), consistent with diffuse cerebral injury. In contrast, offspring of NAC-treated LPS dams demonstrated similar T2 and ADC levels as control in both white and gray matter. CONCLUSION: Maternal NAC treatment significantly reduced evidence of neonatal brain injury associated with maternal LPS. These studies suggest that maternal NAC therapy may be effective in human deliveries associated with maternal/fetal inflammation.

N-acetyl-cysteine (NAC) attenuates LPS-induced maternal and amniotic fluid oxidative stress and inflammatory responses in the preterm gestation.

OBJECTIVE: Maternal infection is associated with oxidative stress and inflammation. We sought to determine whether N-acetyl-cysteine can decrease maternal oxidative stress and the inflammatory response in preterm gestation. STUDY DESIGN: Pregnant rats 16 days, were treated with (1) lipopolysaccharide, (2) N-acetyl-cysteine 120 minutes after lipopolysaccharide, or (3) saline solution (intraperitoneal). Six hours after lipopolysaccharide administration, serum lipid peroxide formation (LPO), tumor necrosis factor-α, interleukin-6, and interleukin-1ß levels in maternal serum and amniotic fluid were determined. RESULTS: Lipopolysaccharide significantly increased maternal serum lipid peroxide formation (24-118.5 nmol/mL; P < .05), and maternal serum and amniotic fluid tumor necrosis factor-α, interleukin-6, and interleukin-1ß. N-acetyl-cysteine treatment after lipopolysaccharide significantly attenuated lipid peroxide formation (47.5 nmol/mL) and proinflammatory cytokines response in maternal serum and amniotic fluid. CONCLUSION: Maternal and amniotic fluid oxidative stress and inflammatory stimulation are attenuated by N-acetyl-cysteine even when administered after lipopolysaccharide. These results suggest that N-acetyl-cysteine may protect the fetus from adverse sequelae associated with inflammatory stimulation.

Maternal lipopolysaccharide-induced inflammation during pregnancy programs impaired offspring innate immune responses.

OBJECTIVE: Because the fetal innate immune system is responsive, while still maturing during the preterm period, we hypothesized that the early activation of fetal inflammatory pathways may have an impact on the ultimate expression of immune competency. STUDY DESIGN: Pregnant Sprague Dawley rats (n = 7; Harlan Sprague Dawley Inc, Jerusalem, Israel) at 18 days gestation received intraperitoneal injections of saline solution or lipopolysaccharides (500 microg/kg). Pups were delivered spontaneously. At postnatal day 24, pups received intraperitoneal lipopolysaccharide (100 microg/kg), and plasma cytokine levels were measured before and 4 hours after lipopolysaccharide administration. RESULTS: In response to lipopolysaccharides, pups of the lipopolysaccharide-injected dams had significantly (P < .05) reduced interleukin-6 (median [25th,75th percentile], 229 [84,6086] vs 4745 [2765,6643] pg/mL), interleukin-1beta (median [25th,75th percentile], 820 [125,1196] vs 1682 [1515,2127] pg/mL), tumor necrosis factor-alpha (median [25th,75th percentile], 4.8 [1.2,91] vs 163 [46,205] pg/mL), and interleukin-10 responses, when compared with saline solution-injected dams. CONCLUSION: Maternal lipopolysaccharide exposure suppresses offspring innate immune response to inflammatory stimuli. These results suggest that maternal inflammatory exposures during pregnancy may impair newborn infant innate responses and increase susceptibility to infection.

Prophylactic maternal n-acetylcysteine before lipopolysaccharide suppresses fetal inflammatory cytokine responses.

OBJECTIVE: Maternal infection or inflammation may induce fetal inflammatory responses and potentially fetal brain injury. We sought to determine whether prophylactic n-acetylcysteine (NAC), a known antiinflammatory, may modulate the fetal cytokine response to maternal lipopolysaccharide (LPS). STUDY DESIGN: Pregnant Sprague Dawley rats (20/21 days = 0.95 gestation; n = 35) received intraperitoneal NAC (300 mg/kg) or saline at time 0 and LPS (500 microg/kg) or saline at 30 minutes. An additional group received NAC following saline. At 6 hours, rats were killed and interleukin (IL)-6, IL-1 beta, and IL-10 levels were determined in fetal and maternal blood. RESULTS: Following maternal LPS, fetal blood IL-6 (median [25th, 75th] 50 [27, 50] to 2072 [448, 4853] pg/mL) and IL-1 beta (74 [10, 139] to 391 [284, 797] pg/mL) significantly increased. NAC before LPS significantly reduced the fetal IL-6 and IL-1 beta response. Fetal IL-10 was not attenuated by any treatment. NAC attenuated both maternal pro- and antiinflammatory responses to LPS. CONCLUSION: Maternal NAC suppressed fetal and maternal inflammatory responses to maternal LPS. These results suggest that prophylactic NAC may protect the fetus from maternal inflammation.