N-Methyl-D-aspartate antagonists and apoptotic cell death triggered by head trauma in developing rat brain.

Abstract

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 percussion head trauma, two types of brain damage could be characterized. The first type or 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-alpha-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.

• Authors: D Pohl, P Bittigau, M J Ishimaru, D Stadthaus, C Hübner, J W Olney, L Turski, C Ikonomidou
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 96 Issue 5 Pg. 2508-13 (Mar 02 1999) ISSN: 0027-8424 [Print] United States
• PMID: 10051673 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Excitatory Amino Acid Antagonists
• Piperazines
• N-Methylaspartate
• Dizocilpine Maleate
• 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid

Topics

• Animals
• Apoptosis (drug effects)
• Brain (drug effects, pathology, ultrastructure)
• Brain Injuries (chemically induced, pathology)
• Caudate Nucleus (drug effects, pathology)
• Disease Models, Animal
• Dizocilpine Maleate (toxicity)
• Excitatory Amino Acid Antagonists (toxicity)
• Frontal Lobe (drug effects, pathology)
• Gyrus Cinguli (drug effects, pathology, ultrastructure)
• In Situ Nick-End Labeling
• N-Methylaspartate (antagonists & inhibitors)
• Nerve Degeneration (chemically induced, pathology)
• Parietal Lobe (drug effects, pathology, ultrastructure)
• Piperazines (toxicity)
• Rats
• Rats, Wistar
• Thalamus (drug effects, pathology)
• Time Factors