Laroia N, McBride L, Baggs R, Guillet R
Department of Pediatrics (Neonatology), The Children's Hospital at Strong, Rochester, NY 14642, USA.
Brain Res Dev Brain Res. 1997 May 20;100(1):29-34. doi: 10.1016/s0165-3806(97)00018-7.
Hypoxic injury to the brain is mediated in part by NMDA receptors. Therefore, NMDA receptor blockade with dextromethorphan (DM), a non-competitive channel blocker, was hypothesized to ameliorate injury even when given after the hypoxic insult. Rats were exposed to 8% oxygen for 3 h on postnatal day 7. Within 20 min of exposure, animals received 30 mg/kg i.p. DM or normal saline. Littermates maintained in room air for 3 h also received DM or saline. At 14 days of age, 7 days after exposure, cortical thickness and hippocampal area were measured. At 70-90 days of age, approximately two months after exposure, in a separate group of rats, seizure threshold using pentylenetetrazol (PTZ) and passive avoidance learning and retention were determined. There were no gross changes in cellular morphology and no evidence for cellular necrosis in any of the exposure groups. However, cortical thickness was decreased in animals exposed to hypoxia. DM administration prevented this decrease. Hippocampal area was unaffected. Seizure susceptibility in adulthood was increased in animals exposed to hypoxia in the neonatal period. DM prevented the decrease in seizure threshold. There was no difference in passive avoidance learning or retention as a function of neonatal exposure condition. Mild to moderate hypoxia, previously thought not to produce any histologic changes, causes significant short-term loss of cortical thickness and long-term decrease in seizure threshold. DM appears to ameliorate these effects even when given after the hypoxic insult. These results implicate the glutamate receptor system in the pathophysiology of hypoxia damage and suggest that treatment with a glutamate receptor blocker when neonatal asphyxia is suspected would help ameliorate the consequences of such an insult.
脑缺氧损伤部分是由N-甲基-D-天冬氨酸（NMDA）受体介导的。因此，有人提出，使用右美沙芬（DM）这种非竞争性通道阻滞剂阻断NMDA受体，即使在缺氧损伤后给药，也能减轻损伤。在出生后第7天，将大鼠暴露于8%的氧气中3小时。在暴露后20分钟内，动物腹腔注射30mg/kg的DM或生理盐水。在室温空气中饲养3小时的同窝幼崽也接受DM或生理盐水注射。在14日龄，即暴露后7天，测量皮质厚度和海马体面积。在70 - 90日龄，即暴露后约两个月，在另一组大鼠中，测定使用戊四氮（PTZ）的惊厥阈值以及被动回避学习和记忆能力。在任何暴露组中，细胞形态均无明显变化，也没有细胞坏死的证据。然而，暴露于缺氧环境的动物皮质厚度降低。给予DM可防止这种降低。海马体面积未受影响。新生儿期暴露于缺氧环境的动物成年后惊厥易感性增加。DM可防止惊厥阈值降低。被动回避学习或记忆能力不受新生儿暴露条件的影响。先前认为不会产生任何组织学变化的轻度至中度缺氧，会导致皮质厚度显著短期减少以及惊厥阈值长期降低。即使在缺氧损伤后给药，DM似乎也能减轻这些影响。这些结果表明谷氨酸受体系统参与了缺氧损伤的病理生理学过程，并提示在怀疑新生儿窒息时，使用谷氨酸受体阻滞剂进行治疗将有助于减轻此类损伤的后果。
