Pohl D, Bittigau P, Ishimaru M J, Stadthaus D, Hübner C, Olney J W, Turski L, Ikonomidou C
Department of Pediatric Neurology, Charité-Virchow Clinics, Children's Hospital, Humboldt University School of Medicine, Augustenburger Platz 1, D-13353 Berlin, Germany.
Proc Natl Acad Sci U S A. 1999 Mar 2;96(5):2508-13. 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 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.
头部创伤导致的发病率和死亡率在儿童中最高。目前尚未建立模拟儿童创伤性脑损伤的动物模型，并且对发育中大脑创伤性损伤后神经元变性的机制也尚不了解。在遭受撞击性头部创伤的幼鼠中，可以确定两种类型的脑损伤。第一种类型或原发性损伤在4小时内发展，通过兴奋性毒性机制发生。第二种类型或继发性损伤在6 - 24小时内发展，通过凋亡机制发生。原发性损伤局限于撞击部位的顶叶皮质。继发性损伤影响远处部位，如扣带回/脾后皮质、海马下托、额叶皮质、丘脑和纹状体。继发性凋亡性损伤比原发性兴奋性毒性损伤更严重。形态计量学分析表明，N - 甲基 - D - 天冬氨酸受体拮抗剂3 - (2 - 羧基哌嗪 - 4 - 基) - 丙基 - 1 - 膦酸酯和地佐环平可防止原发性兴奋性毒性损伤，但会增加继发性凋亡性损伤的严重程度。自由基清除剂2 - 磺基 - α - 苯基 - N - 叔丁基硝酮不影响原发性兴奋性毒性损伤，但可减轻凋亡性损伤。这些观察结果表明，凋亡而非兴奋性毒性决定了发育中大脑创伤性损伤后的神经病理结果。虽然自由基清除剂可能被证明对儿童头部创伤治疗有用，但由于N - 甲基 - D - 天冬氨酸拮抗剂有增加凋亡性损伤严重程度的倾向，应避免使用。
