Table 3.

Major Maturation-Dependent Factors Underlying the Three Downstream Mechanisms in PVL^*

Free Radical Attack Vulnerability of pre-OLs to free radical attack Abundant production of both ROS and RNS in PVL (by pre-OLs, microglia, astrocytes) Delayed development of antioxidant defenses in pre-OLs Acquisition of Fe++ by pre-OLs

Excitotoxicity Vulnerability of pre-OLs to excitotoxicity Exuberant expression of major glutamate transporter (source of glutamate) by pre-OLs Exuberant expression on pre-OLs of AMPA receptors, which are deficient in the GluR2 subunit and therefore are Ca2+-permeable Exuberant expression on pre-OLs of NMDA receptors, which also are Ca2+-permeable Likely mechanism of excitotoxicity is generation of ROS/RNS

Microglial Activation Central role of microglia in free radical generation Microglia, especially abundant in PVL; potent sources of ROS/RNS Presence of TLRs on microglia; activation results in release of free radicals Maturation-dependent concentration of microglia in normal cerebral white matter Microglial activation releases potentially injurious cytokines TNFα derived from microglia in diffuse PVL TNFα potentiates the maturation-dependent toxicity to pre-OLs by interferon γ (interferon γ expressed in astrocytes in diffuse PVL and interferon γ receptor expressed in pre-OLs) Microglial activation impairs glutamate transport and accentuates excitotoxicity

^*See text for references