The effect of maternal pentoxifylline treatment on model of brain white matter injury

Periventricular leukomalacia, specifically characterized as white matter injury, that neonates is strongly associated with the damage of pre-myelinating oligodendrocytes. No specific therapy for PVL is presently available, because the pathogenesis is not well understood. The pathogenesis of PVL is complex and likely involves ischemia/reperfusion, free radical formation, excitotoxicity by glutamate, impaired regulation of cerebral blood flow, a procoagulant state, and inflammatory mechanisms associated with maternal and/or fetal infection. Recent studies have shown that administration of lipopolysaccharide (LPS) to pregnant rats causes white matter injury (WMI). Pentoxyfilline (PTX) is a phosphodiesterase inhibitor, supresses pro-inflammatory cytokines such as tumor necrosis factor-?, interleukin-6, and interferon-?, has been used in a range of infectious, vascular, and inflammatory conditions in adults and children. PTX is also an anti-coagulant factor with anti-inflammatory, anti-apoptotic, anti-oxidant, and cytoprotective activities. Using an established animal model of human PVL we investigated whether PTX could reduce endotoxin-induced WMI in the developing rat brain. LPS (500 microg/kg) suspension was administered intraperitoneally to pregnant rats at 18 and 19 days of gestation. PTX (60 mg/kg) was administered intraperitoneally to pregnant rats at 18,19 and 20 days of gestation. The control group was treated with pyrogen-free saline. Rats were divided into three groups: control group, LPS-treated group, LPS+PTX-treated group. Rats were kept alive till 7th days. Using immunohistochemistry techniques, we investigated the effects of maternal administration of LPS on myelin basic protein (MBP) staining, as a marker of myelination in the periventricular area in the neonatal rat brain. MBP staining was significantly less and weaker in the brains of the LPS-treated group as compared with the PTX-treated group. PTX treatment significantly reduced the number of apoptotic cells in the periventricular white matter shown on tunel and caspase-3.In conclusion, this is the first study indicating that PTX may provide protection against an LPS-induced inflammatory response and WMI in the developing rat brain. In addition, our results support the possible use of PTX treatment in pregnant women with maternal or placental infection to minimize the risk of PVL and cerebral palsy.