Maternal Inflammation Exaggerates Offspring Susceptibility to Cerebral Ischemia–Reperfusion Injury via the COX-2/PGD2/DP2 Pathway Activation

Abstract

The pathogenesis of cerebral ischemia–reperfusion (I/R) injury is complex and does not exhibit an effective strategy. Maternal inflammation represents one of the most important factors involved in the etiology of brain injury in newborns. We aimed to investigate the effect of maternal inflammation on offspring susceptibility to cerebral I/R injury and the mechanisms by which it exerts its effects. Pregnant SD rats were intraperitoneally injected with LPS (300 μg/kg/day) at gestational days 11, 14, and 18. Pups were subjected to MCAO/R on postnatal day 60. Primary neurons were obtained from postnatal day 0 SD rats and subjected to OGD/R. Neurological deficits, brain injury, neuronal viability, neuronal damage, and neuronal apoptosis were assessed. Oxidative stress and inflammation were evaluated, and the expression levels of COX-2/PGD2/DP pathway-related proteins and apoptotic proteins were detected. Maternal LPS exposure significantly increased the levels of oxidative stress and inflammation, significantly activated the COX-2/PGD2/DP2 pathway, and increased proapoptotic protein expression. However, maternal LPS exposure significantly decreased the antiapoptotic protein expression, which subsequently increased neurological deficits and cerebral I/R injury in offspring rats. The corresponding results were observed in primary neurons. Moreover, these effects of maternal LPS exposure were reversed by a COX-2 inhibitor and DP1 agonist but exacerbated by a DP2 agonist. In conclusion, maternal inflammatory exposure may increase offspring susceptibility to cerebral I/R injury. Moreover, the underlying mechanism might be related to the activation of the COX-2/PGD2/DP2 pathway. These findings provide a theoretical foundation for the development of therapeutic drugs for cerebral I/R injury.

Apolipoprotein E mimetic peptide COG1410 alleviates blood‑brain barrier injury in a rat model of ischemic stroke

“…Unlike COX-1, a constitutive isoform, COX-2 is rapidly induced upon activation by inflammatory mediators during cerebral ischemia-reperfusion. Recent studies have indicated that the expression of COX-2 precedes the emergence of inflammatory factors after brain injury and that the expression of inflammatory factors induces an inflammatory cascade, leading to further cell death and tissue injury (41)(42)(43). In addition, the catalytic products of COX-2 are associated with the production of the free radical superoxide and prostanoids (44,45).…”

High Glucose Promotes Inflammation and Weakens Placental Defenses against E. coli and S. agalactiae Infection: Protective Role of Insulin and Metformin

“…This lower pro-inflammatory cytokine production may impact placental immunity in different ways. On one side, this could help to avoid an exacerbated inflammatory response at the feto-maternal interface, which may avoid fetal neurodevelopmental damage or preterm birth [ 109 , 110 , 111 ]. However, on the other hand, the inability to produce enough cytokines to fight an infectious challenge increases the host vulnerability to pathogen virulence and invasiveness, which matches with the observed prolonged maternal infection period and the higher frequencies of cervicovaginal, chorioamnionitis or puerperal infections in GDM patients [ 8 , 112 ].…”

Lipid peroxidation and neuroinflammation: A possible link between maternal fructose intake and delay of acquisition of neonatal reflexes in Wistar female rats

“…Maternal metabolic inflammation has been associated with abnormal neurodevelopment through a disrupted fetal microenvironment (Bonnin & Levitt, 2011; Li et al., 2022). A hallmark of inflammation comprises the upregulation of Cox‐2.…”