When stimulated, microglia secrete reactive oxygen and nitrogen species and express a variety of cytokines, which have been implicated in inflammatory and hypoxic/ischaemic brain injury. These time points correspond in both species to periods of increased susceptibility to WM injury, and hence targeting microglial activation may be especially effective in the immature brain. Similarly in the rodent, microglia are increased in density in WM and deep cortex during the first post-natal week. In the human, WM is preferentially populated with amoeboid microglia during preterm. Both human and rodent developmental studies demonstrate that the density of developing microglia in WM is higher during early development than in later life. In addition, oxidative and nitrosative stress markers are increased in the diffuse component of PVL in reactive astrocytes and pre-OLs. Post mortem studies of human PVL tissue reveal that activated microglia are abundant in the diffuse component of PVL, along with macrophages in the periventricular necrotic foci, but there is minimal microglial activation in the overlying cortex. Given that the therapeutic effect of AMPA receptor antagonists is subtotal, we aimed to investigate the role of microglial involvement in pre-OL injury. Additional studies have implicated a central role for microglia in a synergistic effect of HI and infection in WM injury. Using this model, we have previously demonstrated that WM injury after HI can be attenuated by systemic post-treatment with 6-nitro-7-sulfamoylbenzo-(f)quinoxaline-2,3-dione and topiramate, which are antagonists of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) and kainate GluR subtypes. We developed a rat model of PVL in the post-natal day 6 (P6) Long-Evans rat, in which unilateral carotid ligation and hypoxia lead to predominantly WM injury and hypomyelination. We have previously shown that pre-OLs in developing rat and human WM express GluRs. In vitro studies have demonstrated that pre-OLs are more vulnerable to injury than mature OLs under conditions of oxidative stress, oxygen-glucose deprivation and glutamate receptor (GluR)-mediated excitotoxicity. The age window of greatest susceptibility to PVL in the human brain is between 23 and 32 weeks' gestation, when subcortical WM is populated predominantly by pre-OLs, including both OL precursors and immature OLs.
While the cause of PVL is likely to be multifactorial, the present study addresses the role of the microglial responses in an in vivo model of PVL. Candidate mechanisms for this WM injury include oxidative stress, glutamate-mediated excitotoxicity and inflammation immature premyelinating OLs (pre-OLs) have been shown to be uniquely susceptible to these forms of injury compared with mature OLs. PVL describes focal WM necrosis and diffuse gliosis, resulting in hypomyelination and associated motor and cognitive disabilities. Periventricular leucomalacia (PVL) is the major pathological substrate of cerebral palsy in preterm infants suffering cerebral hypoxia/ischaemia (HI) or maternal-fetal infection, resulting in oligodendrocyte (OL) injury in developing white matter (WM).
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