Advancements in medical facilities have increased the survival rates of
preterm infants, yet the propensity of these infants developing white matter (WM)
damage (WMD) remains largely unaltered. It is estimated that 4-10% of premature
newborns are affected by WMD which leads to severe long term neurological
consequences such as cerebral palsy, epilepsy, hearing and vision impairments.
Currently, there is no effective treatment for WMD and all available therapies target
secondary pathologies that develop as a result of damage to white matter tissue. WMD
may occur as a result of a number of causes, with hypoxia being one of the major
underlying factors. The multi-factorial aetiology of WMD further hinders the
development of specific drugs for the treatment of this clinical condition. The
pathological hallmarks include death of oligodendrocytes, degeneration of axons,
hypomyelination, microglial activation and astrogliosis. Although role of microglia is
considered to be neuroprotective in many neurological conditions, our recent studies have
shown that microglial activation is an important event in WMD, the consequences of
which include increased release of pro-inflammatory cytokines, proteinases and
glutamate, and generation of reactive oxygen intermediates, along with undesirable
sequestration of excess iron released during hypoxia. Hence amelioration of microglial
activation has been considered as the key target in the therapy of WMD. Drugs such
as-glutamate receptor antagonists, iron chelators, antioxidants, ion channel blockers and
certain immunosuppressive agents that target microglial activation have been identified,
but their mechanism of action still remains elusive. This chapter will summarize the
currently available and potential drugs along with their mechanism of action underlying
the suppression of microglial activation for the treatment of WMD in the developing
brain.
Keywords: Developing brain, hypoxia, white matter damage, microglia,
inflammation, excitotoxicity, oxidative stress, glutamate receptor antagonist, iron
chelators, anti-inflammatory drugs, antioxidants.
