NMDA receptor blockade fails to alter axonal injury in focal cerebral ischemia

The ability of the NMDA receptor antagonist, MK-801, to protect myelinated axons after focal cerebral ischemia has been examined. Amyloid precursor pr otein (APP) immunocytochemistry was used to assess the anatomic extent of a xonal injury, and conventional histopathology was used to assess the volume of ischemic damage to neuronal perikarya. The middle cerebral artery was p ermanently occluded in 16 cats. The cars were treated with either vehicle o r MK-801 as a 0.5-mg/kg bolus at 15 minutes before middle cerebral artery o cclusion. followed by an infusion of 0.14 mg/kg per hour. After 6 hours, th e animals were killed and the brains processed for histology and immunocyta chemistry. The volume of neuronal necrosis was determined from 16 preselect ed coronal levels of the brain. The circumscribed zones of APP accumulation in axons were mapped onto images st the same 16 coronal levels, and quanti tative analysis was performed using a transparent counting grid, randomly p laced over each image. The histologic appearance and anatomic location of a xons with increased APP immunoreactivity was similar in animals treated wit h vehicle and MK-801. MK-801 failed to reduce the hemi spheric APP score si gnificantly. In vehicle-treated animals, there was a significant associatio n between the volume of neuronal necrosis and the amount of APP immunoreact ivity. MK-801 significantly reduced the slope of the association between th e volume of neuronal necrosis and the amount of APP immunoreactivity compar ed with that observed in vehicle-treated animals. As a result, the ratio of hemispheric APP score and volume of neuronal necrosis was significantly in creased with MK-801 treatment. The inability of NR;IDA receptor antagonists to protect axons may limit their functional efficacy in improving function al outcome after stroke.