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N-Methyl-D-aspartate antagonists and apoptotic cell death triggered by head trauma in developing rat brain
D Pohl1, P Bittigau, M J Ishimaru
1Department of Pediatric Neurology, Charité-Virchow Clinics, Children's Hospital, Humboldt University School of Medicine, Augustenburger Platz 1, D-13353 Berlin, Germany.
Insights
Head trauma in children causes significant damage. Apoptosis, not excitotoxicity, drives secondary brain damage, suggesting free radical scavengers may help, while N-methyl-D-aspartate antagonists could worsen outcomes.
Area of Science:
- Pediatric Traumatic Brain Injury Research
- Neuroscience
- Developmental Neurobiology
Background:
- Head trauma is a leading cause of death and disability in children.
- Current understanding of pediatric traumatic brain injury (TBI) mechanisms, particularly neuronal degeneration in the developing brain, remains limited.
- A lack of appropriate animal models hinders research into pediatric TBI.
Purpose of the Study:
- To investigate the mechanisms of neuronal degeneration following traumatic brain injury in infant rats.
- To characterize the temporal evolution and pathological features of primary and secondary brain damage after TBI.
- To evaluate the efficacy of N-methyl-D-aspartate (NMDA) receptor antagonists and free radical scavengers in mitigating TBI-induced neuropathology.
Main Methods:
- Infant rats were subjected to percussion head trauma to induce TBI.
- Brain damage was characterized by assessing primary (0-4 hours) and secondary (6-24 hours) injury.
- Morphometric analysis was used to evaluate the effects of NMDA receptor antagonists (CPP-PP, MK-801) and a free radical scavenger (SPBN) on neuronal damage.
Main Results:
- Two distinct phases of brain damage were identified: primary excitotoxic damage localized to the impact site and secondary apoptotic damage affecting distant brain regions.
- Secondary apoptotic damage was more severe than primary excitotoxic damage.
- NMDA receptor antagonists exacerbated secondary apoptotic damage, while the free radical scavenger SPBN mitigated it.
Conclusions:
- Apoptosis, rather than excitotoxicity, is the primary determinant of neuropathological outcome in pediatric TBI.
- Free radical scavengers show therapeutic potential for managing head trauma in children.
- NMDA receptor antagonists should be used with caution in pediatric TBI due to their potential to worsen secondary apoptotic damage.
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.