Yuval Ginsberg1, Nizar Khatib2, Boaz Weiss3, Shay Arison2, Michael G Ross4, Zeev Weiner2, Ron Beloosesky3. 1. Department of Obstetrics and Gynecology, Rambam Medical Center, Haifa, Israel. Electronic address: y_ginsberg@rambam.health.gov.il. 2. Department of Obstetrics and Gynecology, Rambam Medical Center, Haifa, Israel. 3. Department of Obstetrics and Gynecology, Sheba Medical Center, Tel Hashomer, Israel. 4. Department of Obstetrics and Gynecology, Harbor-UCLA Medical Center and Los Angeles Biomedical Institute, Torrance, CA, United States.
Abstract
OBJECTIVE: As maternal treatment with magnesium sulfate (MG) may protect the fetal brain, we sought to assess the inflammation associated neuroprotective potential of MG and its association to interleukin 1β (IL-1β). METHODS: Pregnant Sprague-Dawley rats at 18-day gestation received i.p. lipopolysaccharide (LPS) or saline. Dams were randomized to treatment with s.c. saline (control), or MG prior to or following the i.p. injection, resulting in three groups. At the end of the treatment, fetal brain IL-1β was quantified for 18 pregnant rats (six of each group). Another 18 pregnant rats delivered spontaneously and pups were allowed to mature. At postnatal day 25, female offspring were examined by magnetic resonance imaging (MRI) and analyzed using voxel based analysis. Apparent diffusion coefficient (ADC) and T2 relaxation protocols were performed to assess white and gray matter injury. RESULTS: Offspring of LPS-treated dams exhibited (1) significantly increased T2 levels, and (2) increased ADC levels in white and gray matter, consistent with diffuse cerebral injury. Offspring of MG-treated LPS dams demonstrated similar T2 and ADC levels as control dams. Fetal brain IL-1β was significantly increased following maternal LPS compared to control (0.125±0.01 vs 0.100±0.01u, p<0.05). No significant decrease in IL-1β level was observed in response to maternal MG. CONCLUSIONS: Maternal LPS-induced neonatal brain injury can be prevented by maternal MG. Maternal MG therapy may be effective in human deliveries associated with maternal/fetal inflammation. The absence of a decrease in fetus brain levels of IL-1β following MG treatment implies that the mechanism of MG is not through inhibition of IL-1β production. SIGNIFICANCE STATEMENT: Intrauterine fetal exposure to maternal inflammation and pro-inflammatory cytokines is associated with adverse offspring neurological outcomes. Although its precise mechanism is not elucidated, magnesium sulfate (MG) is commonly used as neuroprotection for white matter brain injuries in preterm fetuses. A proposed mechanism involves the ability of MG to reduce pro-inflammatory cytokine levels. In the current study, we used a rat model of LPS-induced maternal inflammation to investigate the short-term effect of MG on fetal brain IL-1β levels, and its long-term neuroprotective effect on the offspring brain by using MRI. We demonstrated that maternal administration of MG can prevent long-term neonatal brain injury but, since no decrease was observed in fetal brain IL-1β levels, the neuro-protective mechanism of MG is not mediated by inhibition of IL-1β production.
OBJECTIVE: As maternal treatment with magnesium sulfate (MG) may protect the fetal brain, we sought to assess the inflammation associated neuroprotective potential of MG and its association to interleukin 1β (IL-1β). METHODS: Pregnant Sprague-Dawley rats at 18-day gestation received i.p. lipopolysaccharide (LPS) or saline. Dams were randomized to treatment with s.c. saline (control), or MG prior to or following the i.p. injection, resulting in three groups. At the end of the treatment, fetal brain IL-1β was quantified for 18 pregnant rats (six of each group). Another 18 pregnant rats delivered spontaneously and pups were allowed to mature. At postnatal day 25, female offspring were examined by magnetic resonance imaging (MRI) and analyzed using voxel based analysis. Apparent diffusion coefficient (ADC) and T2 relaxation protocols were performed to assess white and gray matter injury. RESULTS: Offspring of LPS-treated dams exhibited (1) significantly increased T2 levels, and (2) increased ADC levels in white and gray matter, consistent with diffuse cerebral injury. Offspring of MG-treated LPS dams demonstrated similar T2 and ADC levels as control dams. Fetal brain IL-1β was significantly increased following maternal LPS compared to control (0.125±0.01 vs 0.100±0.01u, p<0.05). No significant decrease in IL-1β level was observed in response to maternal MG. CONCLUSIONS: Maternal LPS-induced neonatal brain injury can be prevented by maternal MG. Maternal MG therapy may be effective in human deliveries associated with maternal/fetal inflammation. The absence of a decrease in fetus brain levels of IL-1β following MG treatment implies that the mechanism of MG is not through inhibition of IL-1β production. SIGNIFICANCE STATEMENT: Intrauterine fetal exposure to maternal inflammation and pro-inflammatory cytokines is associated with adverse offspring neurological outcomes. Although its precise mechanism is not elucidated, magnesium sulfate (MG) is commonly used as neuroprotection for white matter brain injuries in preterm fetuses. A proposed mechanism involves the ability of MG to reduce pro-inflammatory cytokine levels. In the current study, we used a rat model of LPS-induced maternal inflammation to investigate the short-term effect of MG on fetal brain IL-1β levels, and its long-term neuroprotective effect on the offspring brain by using MRI. We demonstrated that maternal administration of MG can prevent long-term neonatal brain injury but, since no decrease was observed in fetal brain IL-1β levels, the neuro-protective mechanism of MG is not mediated by inhibition of IL-1β production.
Authors: Bérénice Le Dieu-Lugon; Nicolas Dupré; Céline Derambure; François Janin; Bruno J Gonzalez; Stéphane Marret; Arnaud Arabo; Philippe Leroux Journal: Int J Mol Sci Date: 2021-04-20 Impact factor: 5.923