Neuronal Injuries Induced by Perinatal Hypoxic-Ischemic Insults Are Potentiated by Prenatal Exposure to Lipopolysaccharide: Animal Model for Perinatally Acquired Encephalopathy

Abstract

We developed an original rat model for neonatal brain lesions whereby we explored the sequential effects of infectious and hypoxic-ischemic aggressions. We investigated the influence of combined exposure to prenatal infection with neonatal hypoxic-ischemic insult. Infectious effect was produced by administrating lipopolysaccharide (LPS) intraperitoneally to pregnant rats starting on embryonic day 17. Hypoxia-ischemia (H/I) was induced in the pups at postnatal day 1 (P1) by ligature of the right common carotid artery followed by exposure to hypoxia (8% O₂) for 3.5 h. Animals were randomized into four groups: (1) control group: pups born to mothers subjected to intraperitoneal saline injection; (2) LPS group: pups exposed in utero to LPS; (3) H/I group: pups exposed to postnatal hypoxia after ligation of the right carotid artery, and (4) H/I plus LPS group: in utero exposure to LPS followed by postnatal hypoxia after ligation of the right carotid artery. Neuropathological findings in pups examined at P3 and P8 showed that groups 2, 3, and 4 presented a pattern of neuronal injury similar to those characterized as ‘selective neuronal necrosis’ within the context of human perinatal encephalopathy. Neuronal cellular injuries were particularly seen in the neocortex, mainly in parasagittal areas. The extent of neuronal cell injury in the brain of rats exposed to postnatal H/I was significantly increased by antenatal exposure to LPS. This animal model provides an experimental means to explore the respective roles of anoxic and infectious components in the pathogenesis of perinatal brain lesions and consequent cerebral palsy.

Pathogenesis of cerebral white matter injury of prematurity

“…As discussed earlier, a potentiating interaction between systemic infection/inflammation and hypoxia-ischaemia in the genesis of cerebral white matter injury is likely 64 81 – 83. Microglia may have a pivotal role in this interaction, and the deleterious effect of activation of microglia in this context likely involves the generation of ROS/RNS.…”

IL-1 Receptor Antagonist Protects against Placental and Neurodevelopmental Defects Induced by Maternal Inflammation

“…However, whether cause or effect, the precise role of inflammatory mediators in the pathophysiology of neurodevelopmental disturbances remains unclear. Experimental animal studies of maternal immune activation have further validated the association between activation of various inflammatory mediators (e.g., IL-1, TNF-a, and IL-6) in the placenta and in the perinatal brain and the occurrence of brain lesions (14,(16)(17)(18)(19)(20). Increased expression of proinflammatory cytokines, including the b form of IL-1 (IL-1b), has also been detected in the human placenta, amniotic fluid (21), newborn blood (22), and the neonatal brain (23)(24)(25) in close temporal association with the development of forebrain periventricular white matter damage.…”

“…We used an established animal model of perinatal brain damage and CP (18,(28)(29)(30) to determine the role of IL-1 on the placenta, fetal viability, and the developing brain in the context of LPS-induced maternal inflammatory response.…”

Acute on chronic exposure to endotoxin is associated with enhanced chemoreflex responses in preterm fetal sheep

“…Although acute preexposure to LPS 3 to 6 h before hypoxiaischemia in neonatal rodents can increase brain injury (9,32,37) and similarly when LPS was given before hypoxia in chicken embryos (33), intriguingly, exposure to LPS 72 h or more before hypoxia-ischemia also markedly increases injury in rodents (9,14,21), while an intermediate time of 24 h can be protective (9). These data all involve exposure to single doses of LPS.…”