NBQX attenuates excitotoxic injury in developing white matter

The excitatory neurotransmitter glutamate is released from axons and glia u nder hypoxic/ischemic conditions. In vitro, oligodendrocytes (OLs) express non-NMDA glutamate receptors (GluRs) and are susceptible to GluR-mediated e xcitotoxicity. We evaluated the role of GluR-mediated OL excitotoxicity in hypoxic/ischemic white matter injury in the developing brain. Hypoxic/ische mic white matter injury is thought to mediate periventricular leukomalacia, an age-dependent white matter lesion seen in preterm infants and a common antecedent to cerebral palsy. Hypoxia/ischemia in rat pups at postnatal day 7 (P7) produced selective white matter lesions and OL death. Furthermore, OLs in pericallosal white matter express non-NMDA GluRs at P7. Unilateral c arotid ligation in combination with hypoxia (6% O-2 for 1 hr) resulted in s elective, subcortical white matter injury with a marked ipsilateral decreas e in immature and myelin basic protein-expressing OLs that was also signifi cantly attenuated by 6-nitro-7-sulfamoylbenzo(f) quinoxaline-2,3-dione (NBQ X). Intracerebral AMPA demonstrated greater susceptibility to OL injury at P7 than in younger or older pups, and this was attenuated by systemic pretr eatment with the AMPA antagonist NBQX. These results indicate a parallel, m aturation-dependent susceptibility of immature OLs to AMPA and hypoxia/isch emia. The protective efficacy of NBQX suggests a role for glutamate recepto r-mediated excitotoxic OL injury in immature white matter in vivo.