Willis C L, Meldrum B S, Nunn P B, Anderton B H, Leigh P N
Department of Neurology, Institute of Psychiatry, Denmark Hill, London, UK.
Brain Res. 1993 Nov 5;627(1):55-62. doi: 10.1016/0006-8993(93)90748-c.
The neurotoxin beta-N-oxalylamino-L-alanine (BOAA), found in Lathyrus sativus seeds, is thought to be the causative agent of neurolathyrism. We have investigated the in vivo mechanism of action of BOAA by focal injection (1 microliter) in the dorsal hippocampus of male Wistar rats and comparing the pathological outcome with the effects of injections (1 microliter) of alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionate (AMPA), kainate (KA) or N-methyl-D-aspartate (NMDA). Cellular damage induced by the excitatory amino acids in the pyramidal (CA1-CA4) and dentate granule neurones (DG) was assessed histologically 24 h after the injection. The study shows that BOAA (50 nmol) induces hippocampal toxicity with a highly selective pattern of regional cellular damage. The CA1, CA4 and DG subfields show 70-90% neuronal injury whereas CA2 and CA3 show only minimal damage. This pattern of cellular damage is similar to that induced by AMPA (1 nmol) and NMDA (25 nmol) but not KA (0.5 nmol). BOAA-induced neurotoxicity is prevented in a dose-dependent manner by focal co-injection of the non-NMDA receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (NBQX) (1-25 nmol) but not by a dose of MK-801 (3 mg/kg i.p.) which is neuroprotective against an injection of NMDA. Delayed focal injections of NBQX (25 nmol) up to 2 h after the BOAA injection result in a significant protection of all pyramidal and granular cell regions. These results indicate that the in vivo hippocampal toxicity of BOAA is mediated by AMPA receptors rather than by KA or NMDA receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
在山黧豆种子中发现的神经毒素β-N-草酰基氨基-L-丙氨酸（BOAA）被认为是神经性山黧豆中毒的病原体。我们通过向雄性Wistar大鼠背侧海马局部注射（1微升）BOAA，并将病理结果与注射（1微升）α-氨基-3-羟基-5-甲基异恶唑-4-丙酸（AMPA）、海人酸（KA）或N-甲基-D-天冬氨酸（NMDA）的效果进行比较，研究了BOAA的体内作用机制。注射24小时后，通过组织学方法评估锥体细胞（CA1-CA4）和齿状颗粒神经元（DG）中兴奋性氨基酸诱导的细胞损伤。研究表明，BOAA（50纳摩尔）诱导海马毒性，并具有高度选择性的区域细胞损伤模式。CA1、CA4和DG亚区显示70-90%的神经元损伤，而CA2和CA3仅显示最小程度的损伤。这种细胞损伤模式与AMPA（1纳摩尔）和NMDA（25纳摩尔）诱导的模式相似，但与KA（0.5纳摩尔）诱导的不同。通过局部共同注射非NMDA受体拮抗剂2,3-二羟基-6-硝基-7-氨磺酰基苯并（F）喹喔啉（NBQX）（1-25纳摩尔），BOAA诱导的神经毒性以剂量依赖的方式得到预防，但3毫克/千克腹腔注射剂量的MK-801对注射NMDA具有神经保护作用，却不能预防BOAA诱导的神经毒性。在BOAA注射后长达2小时延迟局部注射NBQX（25纳摩尔），可对所有锥体细胞和颗粒细胞区域产生显著保护作用。这些结果表明，BOAA在体内的海马毒性是由AMPA受体介导的，而不是由KA或NMDA受体介导的。（摘要截取自250词）
