Molecular mechanisms of cell death in periventricular leukomalacia

Objective: To investigate the cytokine- related molecular cascade leading to neural cell death in periventricular leukomalacia (PVL). Methods: The authors explored potential tumor necrosis factor alpha (TNF alpha) signaling pathways in human brains with PVL and conducted in situ immunohistochemical investigations to search for possible expression of cytokine receptors in these brains. They also investigated likely links to molecules potentially involved in neurocytotoxicity, particularly pathways involving nitrosative-induced apoptosis. Results: TNF alpha overexpression was associated with immune reactivity for p75TNF alpha R2 and p55TNF alpha R1 receptors in affected PVL areas. p75TNF alpha R2 labeling was intense on cerebrovascular endothelial cells in PVL areas, whereas no vascular p55TNF alpha R1 immunoreactivity was detected therein. Immune labeling for both receptors was detected on many white matter parenchymal cells. In contrast, there was no immune reactivity for either receptor in tissues taken from non-PVL areas. Additionally, in situ overexpression of inducible nitric oxide synthase was found in PVL brain regions where apoptotic cell death was detected. Conclusions: Both p75TNF alpha R2 and p55TNF alpha R1 receptors and nitric oxide may be implicated in the pathogenesis of periventricular leukomalacia.