Intracisternal Application of Endotoxin Enhances the Susceptibility to Subsequent Hypoxic-Ischemic Brain Damage in Neonatal Rats

Abstract

Perinatal brain damage is associated not only with hypoxicischemic insults but also with intrauterine inflammation. A combination of antenatal inflammation and asphyxia increases the risk of cerebral palsy Ͼ70 times. The aim of the present study was to determine the effect of intracisternal (i.c.) administration of endotoxin [lipopolysaccharides (LPS)] on subsequent hypoxic-ischemic brain damage in neonatal rats. Seven-day-old Wistar rats were subjected to i.c. application of NaCl or LPS (5 g/pup). One hour later, the left common carotid artery was exposed through a midline neck incision and ligated with 6-0 surgical silk. After another hour of recovery, the pups were subjected to a hypoxic gas mixture (8% oxygen/92% nitrogen) for 60 min. The animals were randomized to four experimental groups: 1) sham control group, left common carotid artery exposed but not ligated (n ϭ 5); 2) LPS group, subjected to i.c. application of LPS (n ϭ 7); 3) hypoxic-ischemic study group, i.c. injection of NaCl and exposure to hypoxia after ligation of the left carotid artery (n ϭ 17); or 4) hypoxic-ischemic/LPS study group, i.c. injection of LPS and exposure to hypoxia after ligation of the left carotid artery (n ϭ 19). Seven days later, neonatal brains were assessed for neuronal cell damage. In a second set of experiments, rat pups received an i.c. injection of LPS (5 g/pup) and were evaluated for tumor necrosis factor-␣ expression by immunohistochemistry. Neuronal cell damage could not be observed in the sham control or in the LPS group. In the hypoxicischemic/LPS group, neuronal injury in the cerebral cortex was significantly higher than in animals that were subjected to hypoxia/ischemia after i.c. application of NaCl. Injecting LPS intracisternally caused a marked expression of tumor necrosis factor-␣ in the leptomeninges. Applying LPS intracisternally sensitizes the immature rat brain to a subsequent hypoxicischemic insult. Hypoxic-ischemic cerebral damage is an important contributor to perinatal mortality and morbidity, including long-term neurologic sequelae in term and preterm fetuses (1, 2). However, as shown in recent studies, perinatal brain injury may be associated not only with hypoxic-ischemic insults but also with an ascending intrauterine inflammation before or during birth (3). It is widely known that Gram-negative anaerobic bacteria are involved in colonization and infection of the genitourinary tract in pregnant women, which could affect labor and preterm birth. Because pregnant women with fever and bacteriuria give birth to infants with a higher incidence of neurologic defects at 1 y of age than do mothers who are free of urinary tract infection (4), it seems that human maternal endotoxemia is associated with fetal CNS damage. Furthermore, there is a growing body of evidence from epidemiologic studies that exposure to placental inflammation before or during birth is accompanied by cerebral white matter damage, especially in the very preterm fetuses, i.e. those born before 32 wk of gestation (3). In addition, the ...

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TNF gene cluster deletion abolishes lipopolysaccharide-mediated sensitization of the neonatal brain to hypoxic ischemic insult

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Chorioamnionitis: a multiorgan disease of the fetus?

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