N-methyl-D-aspartate Antagonists and Apoptotic Cell Death Triggered by Head Trauma in Developing Rat Brain

• Published in: Proceedings of the National Academy of Sciences - PNAS 1999-03, Vol.96 (5), p.2508-2513
• Main Authors: Pohl, D., Bittigau, P., Ishimaru, M. J., Stadthaus, D., Hubner, C., Olney, J. W., Turski, L., Ikonomidou, C.
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Apoptosis - drug effects; Biological Sciences; Brain; Brain - drug effects; Brain - pathology; Brain - ultrastructure; Brain damage; Brain Injuries - chemically induced; Brain Injuries - pathology; Caudate Nucleus - drug effects; Caudate Nucleus - pathology; Cell death; Cell nucleus; Craniocerebral trauma; Disease Models, Animal; Dizocilpine Maleate - toxicity; Excitatory Amino Acid Antagonists - toxicity; Frontal Lobe - drug effects; Frontal Lobe - pathology; Gyrus Cinguli - drug effects; Gyrus Cinguli - pathology; Gyrus Cinguli - ultrastructure; Head injuries; In Situ Nick-End Labeling; N-Methylaspartate - antagonists & inhibitors; Nerve Degeneration - chemically induced; Nerve Degeneration - pathology; Neurons; Parietal Lobe - drug effects; Parietal Lobe - pathology; Parietal Lobe - ultrastructure; Pharmacology; Physical trauma; Piperazines - toxicity; Rats; Rats, Wistar; Rodents; Thalamus; Thalamus - drug effects; Thalamus - pathology; Time Factors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.96.5.2508

Morbidity and mortality from head trauma is highest among children. No animal model mimicking traumatic brain injury in children has yet been established, and the mechanisms of neuronal degeneration after traumatic injury to the developing brain are not understood. In infant rats subjected to precussion head trauma, two types of brain damage could be characterized. The first type of primary damage evolved within 4 hr and occurred by an excitotoxic mechanism. The second type or secondary damage evolved within 6-24 hr and occurred by an apoptotic mechanism. Primary damage remained localized to the parietal cortex at the site of impact. Secondary damage affected distant sites such as the cingulate/retrosplenial cortex, subiculum, frontal cortex, thalamus and striatum. Secondary apoptotic damage was more severe than primary excitotoxic damage. Morphometric analysis demonstrated that the N-methyl-D-aspartate receptor antagonists 3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonate and dizocilpine protected against primary excitotoxic damage but increased severity of secondary apoptotic damage. 2-Sulfo-α -phenyl-N-tert-butyl-nitrone, a free radical scavenger, did not affect primary excitotoxic damage but mitigated apoptotic damage. These observations demonstrate that apoptosis and not excitotoxicity determine neuropathologic outcome after traumatic injury to the developing brain. Whereas free radical scavengers may prove useful in therapy of head trauma in children, N-methyl-D-aspartate antagonists should be avoided because of their propensity to increase severity of apoptotic damage.