Ibuprofen Treatment Reduces the Neuroinflammatory Response and Associated Neuronal and White Matter Impairment in the Growth Restricted Newborn

Abstract

Intrauterine growth restriction (IUGR) is a condition where the fetus does not achieve optimal growth, commonly caused by placental insufficiency. The chronic decrease in blood flow restricts oxygen and nutrient supply to the fetus, which can damage numerous organ systems, with the fetal brain being particularly vulnerable. Although white matter and neuronal injury are evident in IUGR infants, the specific mechanisms underlying these changes are poorly understood. Inflammation is considered to be a main driver in exacerbating brain injury. Using a spontaneous piglet model of IUGR, we aim to determine whether administration of the anti-inflammatory drug ibuprofen will decrease inflammation at postnatal day 4 (P4). The treatment group received ibuprofen (20 mg/kg/day on day 1 and 10 mg/kg/day on days 2 and 3) in piglet formula during the morning feed each day and brains examined on P4. Markers of inflammation, apoptosis, cell proliferation, neuronal injury, and white matter injury were examined. Ibuprofen treatment ameliorated the increase in numbers of microglia and astrocytes in the parietal cortex and white matter tracts of the IUGR piglet brain on P4 as well as decreasing proinflammatory cytokines. Ibuprofen treatment prevented the reduction in apoptosis, neuronal cell counts, and myelin index in the IUGR piglets. Our findings demonstrate ibuprofen reduces the inflammatory response in the IUGR neonatal brain and concurrently reduces neuronal and white matter impairment.

Human primed endothelial colony forming cells exert neuroprotective effects in the growth restricted newborn piglet

“…Labelling with the microglia marker Iba-1 revealed microglia in the parietal cortex of NG brain that displayed characteristic ramified (resting) morphology, with long fine process extensions and even distribution across the cortex (Figure 5A). In the FGR brain, microglia displayed enlarged cell bodies and thickened retracted processes as previously reported (Figure 5A) ( 16, 35 ) with a significant increase in the number of total microglia (p=0.0007) and activated microglia (p<0.0001) in FGR when compared with NG (Figure 5C & D, respectively).…”

“…Both microglia and astrocytes are key drivers of the inflammatory response following brain injury, with the associated alterations in morphology being a hallmark to this pathway. We and others have reported early and persistent inflammation is associated with glial activation in the FGR brain ( 16, 17, 35, 37, 38 ). We examined if the administration of pECFC modulates the pro-inflammatory environment of the FGR brain.…”

“…We have previously demonstrated an increase in cellular apoptosis in the FGR brain and the ability of the anti-inflammatory ibuprofen to ameliorate this increase ( 16, 35 ). We therefore proceeded to determine whether administration of pECFC could also modulate apoptotic activity in the FGR brain.…”

“…We hypothesized that the primed ECFC (pECFC) treatment provides neuroprotection in the FGR newborn. Using a preclinical piglet model of FGR we have established ( 16, 34, 35 ), we assessed whether one dose on the first day of life in a term FGR piglet would regenerate damaged vasculature, restore the NVU, reduce brain inflammation and improve adverse neuronal and white matter changes present in the FGR newborn piglet brain.…”

The Neonatal and Juvenile Pig in Pediatric Drug Discovery and Development

“…For example, the toxic effects of isoflurane and nitrous oxide anesthesia, as measured by neuro-apoptosis, were reported to be higher in IUGR than normal pigs, which should be considered when anesthetizing infants born with IUGR [ 226 ]. Moreover, the brain damage and inflammation observed in babies and in the IUGR pig model could be reduced by administration of ibuprofen for three days [ 227 ]. Considering the recent data on ibuprofen PK in neonatal pigs, the implementation of ibuprofen for this indication (different from the labelled indication to induce closure of the patent ductus arteriosus) in the treatment of IUGR babies could soon be a fact, as the drug is registered for use in neonates and the enantiomer specific PK in small for gestational age setting (3.1-fold higher S -ibuprofen clearance in small for gestational age cases) were recently reported [ 228 ].…”