Foster A C, Gill R, Woodruff G N
Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, United Kingdom.
J Neurosci. 1988 Dec;8(12):4745-54. doi: 10.1523/JNEUROSCI.08-12-04745.1988.
The ability of the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 to prevent neuronal degeneration in the rat striatum and hippocampus caused by intracerebral injection of excitotoxins has been examined. Excitotoxic damage was assessed after 7 d, using histological and biochemical [choline acetyltransferase (ChAT) glutamate decarboxylase (GAD)] measurements. Systemically administered MK-801 was found to protect against neurodegeneration caused by NMDA (200 nmol) and the naturally occurring NMDA receptor agonist quinolinate (120-600 nmol) but not against that induced by kainate (5 nmol) or alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA; 50 nmol), indicating a selectivity for NMDA receptor-mediated neuronal loss. Neurotoxicity caused by NMDA (200 nmol) or quinolinate (200 nmol) was prevented by MK-801 (1-10 mg/kg, i.p.) administered in a single dose after excitotoxin injection. In the striatum, significant protection of cholinergic neurons (assessed by ChAT measurements) was observed when MK-801 was given up to 5 hr after injection of NMDA or quinolinate, whereas protection of GABAergic neurons (assessed by GAD measurements) was obtained up to 2 hr. The results suggest that GABAergic neurons degenerate more rapidly than cholinergic neurons. The competitive NMDA receptor antagonist 3-[(+/-)-2-carboxypiperazin-4-yl]-propyl-1-phosphonate (100 mg/kg, i.p.) gave partial protection of striatal neurons when administered 1 hr after quinolinate injection. In the rat hippocampus, administration of 10 mg/kg MK-801 i.p. 1 hr after quinolinate injection caused almost complete protection of pyramidal and granule neurons, whereas the degeneration of CA3/CA4 pyramidal neurons caused by kainate injection was unaffected. These observations indicate that neurons in rat striatum and hippocampus do not die as an immediate consequence of exposure to high concentrations of NMDA agonists but that a delayed process is involved that requires NMDA receptor activation. In this respect, intracerebral injections of NMDA agonists may mimic the pathological changes that are thought to occur in the brain following periods of cerebral ischemia, where delayed neuronal degeneration occurs.
已对非竞争性N-甲基-D-天冬氨酸（NMDA）受体拮抗剂MK-801预防脑内注射兴奋性毒素所致大鼠纹状体和海马神经元变性的能力进行了研究。7天后，通过组织学和生化[胆碱乙酰转移酶（ChAT）、谷氨酸脱羧酶（GAD）]测量评估兴奋性毒性损伤。发现全身给予MK-801可预防由NMDA（200 nmol）和天然存在的NMDA受体激动剂喹啉酸（120 - 600 nmol）所致的神经变性，但不能预防由海藻酸（5 nmol）或α-氨基-3-羟基-5-甲基异恶唑-4-丙酸（AMPA；50 nmol）所致的神经变性，这表明其对NMDA受体介导的神经元丢失具有选择性。在注射兴奋性毒素后单次给予MK-801（1 - 1 mg/kg，腹腔注射）可预防由NMDA（200 nmol）或喹啉酸（200 nmol）所致神经毒性。在纹状体中，当在注射NMDA或喹啉酸后长达5小时给予MK-801时，观察到胆碱能神经元（通过ChAT测量评估）有显著保护作用，而对GABA能神经元（通过GAD测量评估）的保护作用可持续长达2小时。结果表明，GABA能神经元比胆碱能神经元退化得更快。竞争性NMDA受体拮抗剂3-[(±)-2-羧基哌嗪-4-基]-丙基-1-膦酸（100 mg/kg，腹腔注射）在喹啉酸注射1小时后给药可对纹状体神经元提供部分保护。在大鼠海马中，喹啉酸注射1小时后腹腔注射10 mg/kg MK-801几乎可完全保护锥体细胞和颗粒细胞，而海藻酸注射所致的CA3/CA4锥体细胞变性则不受影响。这些观察结果表明，大鼠纹状体和海马中的神经元并非因暴露于高浓度NMDA激动剂而立即死亡，而是涉及一个需要NMDA受体激活的延迟过程。在这方面，脑内注射NMDA激动剂可能模拟了脑缺血一段时间后被认为在脑中发生的病理变化，即延迟性神经元变性。
