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Experimental Neuronal Injury in the Newborn Lamb: A Comparison of N-Methyl-D-Aspartic Acid Receptor Blockade and Nitric Oxide Synthesis Inhibition on Lesion Size and Cerebral Hyperemia

ABSTRACT: The purpose of this study was to compare the effects of dizocilipine maleate (MK-801) and NG-nitro-L-arginine methyl ester (L-NAME) on focal excitotoxic brain injury and associated hemodynamic response in the newborn lamb. A 27 gauge needle was placed into the right striatum in 28 anesthetized newborn lambs. Seven animals were placed in each group. A negative control group received 0.2 mL of buffered saline, a positive control group received 5 μnol of N-methyl-D-aspartic acid (NMDA) alone, and two groups received NMDA and pretreatment with L-NAME. Ultrasound images and cerebral blood flow determinations (microspheres) were obtained before, and at 20, 40, and 60 min after, intrastrial injection. Three animals in each group underwent histopathologic evaluation. Sonographic lesions were visible immediately after intracerebral injection. Saline injection resulted in small lesions (mean volume; 13.6 ± 5 mm3) without hyperemia. NMDA alone resulted in larger lesions (92.9 ± 24 mm3) and hyperemia to both hemispheres, whereas pretreatment with MK-801 reduced lesion size (11.7 ± 6 mm3) and completely ablated cerebral hyperemia. Pretreatment with L-NAME showed no effect on lesion size (69.9 ± 20 mm3) and hyperemia only in the ipsilateral hemisphere. Sonographic lesions correlated well with gross and histopathologic appearance. We concluded that NMDA-induced focal brain injury and associated hyperemia in the newborn lamb appear to be specific NMDA receptor-mediated events. NO production probably does not play a major part in NMDA-induced neonatal neuronal injury, and may be only partly responsible for regional hyperemia during NMDA injection.