Periventricular leukomalacia: the role of inflammatory mediators and microglia in pathogenesis

Periventricular leukomalacia (PVL) in the pre-term infant and in the newborn represents a major precursor of neurological dysfunction and intellectual impairment in later life. Neuropathological examination of cases with PVL reveals lesions which specifically involve periventricular areas of the deep white matter and comprise necrotic foci, selective loss of oligodendrocyte progenitor cells (OPCs), delayed myelination and axonal swelling accompanied by glial activation. The principal factors leading to white matter damage in PVL are centered around the intrinsic vulnerability of OPCs, which are susceptible to free radical-mediated damage and excitotoxicity induced by hypoxic ischaemia, cerebral hypoperfusion, as well as secondary associated events involving microglial and astrocytic activation and the release of pro-inflammatory cytokines such as tumour necrosis factor-alpha and interleukin-6. Additionally, intrauterine infection (chorioamnionitis) has also been proposed as a causative factor of PVL. Recent investigations have shown that inflammatory responses in the fetus and neonate can contribute towards neonatal brain injury and developmentally related disabilities. This article will discuss the potential contribution of inflammatory mediators and the resident immune cells of the nervous system, the microglia, to the pathological progression of PVL. These findings provide the basis for therapeutic strategies aimed at protecting the premature brain against inflammatory damage, which may prove beneficial for the treatment of PVL