Role of Glutamate and Its Receptors and Insulin-like Growth Factors in Hypoxia Induced Periventricular White Matter Injury

This study investigated the glutamate concentration and cellular localization of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propronic acid glutamate receptors (AMPA GluR2, GluR3, GluR4) along with insulin-like growth factors (IGF)-1 AND -2 expression in the periventricular white matter involvement in PWM injury in hypoxia. In response to hypoxia, the PWM tissue concentration of glutamate and IGF-1 as well as mRNA and protein expression of GluR2, GluR3, GluR4, IGF-1, and -2 was upregulated. Immunoexpression of GluR2/3 and GluR4 were localized in the amoeboid microglial cells (AMC) and oligodendrocytes while that of IGF-1 and -2 were confined to AMC. In primary microglial cultures subjected to hypoxia, administration of exogenous glutamate decreased IGF-1 but increased the release of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) by the cells. Furthermore, silencing of the IGF-1 and -2 genes by RNA interference in primary microglial cultures and BV-2 cells downregulated the expression of these growth factors whereas production of glutamate, TNF-alpha and IL-1 beta in these cells was upregulated. It is suggested that increased IGF-1 AND -2 expressions may be an early protective mechanism in attenuating the hypoxic damage in PWM but a subsequent glutamate-induced decrease of thesse growth factors may cause cellular injury due to excitotoxicity and increased production of inflammatory cytokines In this connection, melatomn and endaravone were beneficial in enhancing IGF-1 and reducing glutamate release. (C) 2009 Wiley-Liss, Inc.