ROLE OF IRON AND IRON REGULATORY PROTEINS IN HYPOXIC PERIVENTRICULAR WHITE MATTER DAMAGE

Abstract

Periventricular white matter damage (PWMD) due to hypoxia remains as the major determinant of neurological morbidity in premature infants. In response to hypoxic injuries, iron accumulated drastically in PWM and was localized in amoeboid microglial cells (AMCs) and oligodendrocytes. Associated with this, the expression of proteins involved in iron transport such as the iron regulatory proteins, transferrin receptor, divalent metal transporter 1, ferroportin and ceruloplasmin was altered in AMCs and oligodendrocytes in hypoxic PWM. Iron accumulation by hypoxic microglia resulted in enhanced production of reactive oxygen species, tumor necrosis factor-a and interleukin-1ß; which was reverted back to control levels on treatment with iron chelator, deferoxamine. The protective effect exhibited by deferoxamine, occurred by inhibiting P38 induced inflammatory reactions. Furthermore, the toxic factors produced by microglia indirectly resulted in the apoptosis of oligodendrocytes. Additionally, iron accumulated within oligodendrocytes resulted in their death by inducing endoplasmic reticulum stress pathway. The present results suggest that excess iron accumulated within glial cells either directly or indirectly mediate oligodendrocyte death in hypoxic PWM in the neonatal brain.