Maternal Inflammation, Fetal Brain Implications and Suggested Neuroprotection: A Summary of 10 Years of Research in Animal Models

Abstract

A growing body of evidence implies that maternal inflammation during pregnancy is associated with increased risk of neurodevelopmental disorders in the offspring. The pathophysiological mechanisms by which maternal inflammation evokes fetal brain injury and contributes to long-term adverse neurological outcomes are not completely understood. In this review, we summarize 10 years of our research experience on maternal inflammation and the implications upon the fetal/offspring brain. We review our findings regarding the underlying mechanisms that connects maternal inflammation and fetal brain injuries (e.g. cytokines, oxidative stress); we discuss our imaging, pathological and behavioral test results which support brain damage following maternal inflammation; and finally we describe some of the therapeutic strategies which might prevent the damage.

Figure 1

Suggested Mechanism of Fetal Brain Injury Following Maternal Inflammation. Probable mechanisms of fetal brain injury with in utero exposure to maternal inflammation. Reprinted from Burd et al., Copyright (2012), with permission from John Wiley and Sons, all rights reserved. ELGAN, extremely low gestation neonates; LBWI, low birth weight infants.

Figure 2

Maternal Serum, Placenta, Fetal Serum, and Fetal Brain Levels of IL-6 Following Maternal Inflammation. Interleukin-6 levels in the maternal serum, placenta, fetal serum, and fetal brain, 3–4 hours following maternal inflammation induced by LPS. *P<0.05, significant difference between control and LPS-induced maternal inflammation.

Figure 3

Neonate Learning Deterioration Following Maternal Inflammation. (A) Learning abilities of the NS group improved significantly between the first and the third months in almost every block (each block composed of 10 tests). (B) The LPS group exhibited no significant improvement in learning abilities with time. LPS, lipopolysaccharide; NS, normal saline; 1M, 1 month of age; 3M, 3 months of age. Reprinted from Lamhot et al., Copyright (2015), with permission from Elsevier. Asterisks (*): Significance (P<0.05) in the learning abilities, examined by the avoidance test in each block between 1 and 3 months. Blocks (X Axis): Each test comprised 7 blocks of 10 stimulus cycles each. Tests were administered to each rat at 1 and 3 months. Avoidance (Y Axis): Number of positive avoidance responses in each block.

Figure 4

MgSO₄ Decreases Levels of Fetal Brain nNOS and NF-κB Following Maternal Inflammation. (A) Neuronal nitric oxide synthase (nNOS). (B) Nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) activation at embryonic day 16. Comparison between four treatment groups: normal saline (SAL); MG (magnesium sulfate); LPS (lipopolysaccharide); LPS-MG (4 hours following injection). *P<0.05 compared to the LPS group. Reprinted from Beloosesky et al., Copyright (2016), with permission from Elsevier.

Figure 5

MgSO₄ Decreases Fetal Brain Injury Following Maternal Inflammation. Neonatal brain MRI analysis at one month after delivery. Averaged ADC values at significant brain regions (see Table 1), in the LPS group, the LPS/MG group, and the Saline (control) group. *P<0.05 compared to the LPS group. AudC, auditory capsule; EnC, internal capsule; CC/EC, corpus callosum and external capsule; CingCor, cingulate cortex; Hypth, hypothalamus; LPS, lipopolysaccharide; MRI, magnetic resonance imaging; MG, magnesium sulfate; SAL, saline; SupCol, superior colliculus; Th, thalamus.

Figure 6

MgSO₄ Improves Neonate Learning and Memory Abilities Following Maternal Inflammation. (A) Demonstration of significant improvement in learning abilities of the NS group, between the first and the third months in almost every block. (B) The LPS group exhibited no significant improvement with time. (C) The MG group displayed significantly better results than the NS group at 1 month of age; however, little improvement was seen at 3 months. (D) Magnesium treatment administered to LPS mothers significantly improved memory and learning abilities at both 1 and 3 months. LPS, lipopolysaccharide; MG, magnesium sulfate; NS, normal saline; 1M, 1 month of age; 3M, 3 months of age. Reprinted from Lamhot et al., Copyright (2015), with permission from Elsevier. Asterisks (*): Significance (P<0.05) in the learning abilities, examined by the avoidance test in each block between 1 and 3 months. Blocks (X Axis): Each test comprised 7 blocks of 10 stimulus cycles each. Tests were administered to each rat at 1 and 3 months. Avoidance (Y Axis): Number of positive avoidance responses in each block.

Figure 7

NAC Decreases Fetal Plasma IL-6 and IL-1β Levels Following Maternal Inflammation. Fetal plasma IL-6 and IL-1β levels after first injection. (A) Fetal plasma IL-6. (B) Fetal plasma IL-1β levels 6 hours after the first injection in the four treatment groups: SAL-SAL, SAL-LPS, SAL-NAC, and NAC-LPS. *P<0.05, significantly different from the SAL-LPS group. LPS, lipopolysaccharide; NAC, N-acetyl cysteine; SAL, saline. Reprinted from Beloosesky et al., Copyright (2009), with permission from Elsevier.

Figure 8

NAC Decreases Fetal Injury as Demonstrated by MRI Following Maternal Inflammation. T2 voxel-based t test analysis, comparing the LPS-treated and the LPS-NAC groups, both with neonatal brain MRI at day 25 after delivery. (A) Images of T2 MRI comparing the LPS group and the LPS-NAC group (higher T2 implies brain damage). The colored areas indicate significant differences in T2 between the LPS group and the LPS-NAC group. The significant regions are superimposed on T2 relaxation maps (P<0.001). (B) The graphs present averaged T2 values at significant brain regions in the LPS group, the LPS-NAC group, and the control group. The LPS group included SAL-LPS-SAL; the LPS-NAC group included NAC-LPS-NAC; the control included SAL-SAL-SAL. *P<0.05. LPS, lipopolysaccharide; MRI, magnetic resonance imaging; NAC, N-acetyl cysteine; SAL, saline. Reprinted from Beloosesky et al., Copyright (2013), with permission from Elsevier.