Periventricular white matter damage in the post-natal brain in hypoxic conditions

Inflammation has been recognized as a major factor contributing to periventricular white matter (PWM) damage in neonates. Microglial cells and astrocytes play a crucial role in inflammatory response. This study investigated their role in PWM damage (PWMD) in hypoxic conditions. The potential mechanisms by which amoeboid microglial cells (AMC) and astrocytes induce oligodendrocyte and axon damage in hypoxic conditions were also examined. Wistar rats (1-day old) were subjected to hypoxia, following which upregulated tumor necrosis factor-a (TNF-a), interleukin-1ß (IL-1ß), monocyte chemoattractant protein-1 (MCP-1), chemokine (C-C motif) receptor 2 (CCR2), and macrophage-colony stimulating factor (M-CSF) expression was observed. Immunoexpression of these was specifically located in AMC from 24h-7d. However, CSF-1 receptor (CSF-1R), TNF-a and IL-1ß immunoexpression was increased in the astrocytes from 7-14d. TNF receptor 1 (TNF-R1) and IL-1 receptor 1 (IL-1R1) immunoexpression was localized in the oligodendrocytes and axons in the PWM. This was coupled with damage to oligodendrocytes and disruption of axons. The increased cell numbers of AMC in the PWM possibly resulted from the migration of AMC from nearby regions of the brain. Primary cultured microglial cells subjected to hypoxia showed enhanced expression of TNF-a, IL-1ß, MCP-1 and. M-CSF through MAP kinase or NF-kappaB signaling pathway. Primary cultured astrocytes treated with M-CSF exhibited increased expression of TNF-a and IL-1ß through MAP kinase signaling pathway. In chemotaxis assay, the medium derived from hypoxia-treated microglial cultures attracted more migratory microglial cells. Based on the above results, this study suggests that, in the course of an inflammatory response in the PWM in hypoxia, AMC might contribute to inflammation at the early phase whereas astrocytes at the late phase. Increased production of cytokines and chemokines would lead to apoptosis of oligodendrocytes, damage to axons and myelination disturbances resulting in PWM lesion.

Author dc:creator

• DENG YIYU

• PWMD, hypoxia, TNF-α, IL-1β, MCP-1, M-CSF