McDonald J W, Trescher W H, Johnston M V
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD.
Brain Res. 1992 Jun 26;583(1-2):54-70. doi: 10.1016/s0006-8993(10)80009-5.
The excitatory and excitotoxic actions of the endogenous excitatory amino acid (EAA) neurotransmitter, glutamate, are mediated by activation of three common subtypes of EAA receptors: N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)/quisqualate and kainate receptors. EAA neurotransmitter systems play a number of physiological roles in the regulation and organization of neural systems during development. However, excessive activation of this neurotransmitter system is also implicated in the pathophysiology of several forms of acute and chronic brain injury. In this study, the susceptibility of the developing rat brain to AMPA/quisqualate receptor mediated injury was examined at eight postnatal ages (1-90 days). The receptor agonists, AMPA (25 nmol) or quisqualate (100 nmol), were stereotaxically microinjected unilaterally into the anterior striatum. The severity of resulting brain injury was assessed 5 days later by comparison of reductions in regional cortical and striatal cross-sectional areas. Microinjection of AMPA (25 nmol) produced widespread unilateral forebrain injury in the intermediate postnatal period (days 5-28). The severity of injury resulting from microinjection of a fixed dose of AMPA (25 nmol) transiently exceeded the severity of injury in adults between PND 5-28 with peak sensitivity occurring near PND 10. At PND 1, microinjection of AMPA produced a 24.5 +/- 1.7% reduction in striatal cross-sectional area, which is similar to the response observed in adult animals, and the lesion was confined to the injection site. Susceptibility to AMPA toxicity increased 2-fold from PND 1 to PND 5. At PND 10, the age of maximal sensitivity, the excitotoxic reaction to AMPA extended throughout the entire cerebral hemisphere and the mean striatal cross-sectional area was reduced by 81.7 +/- 3.9%. With advancing postnatal age, the severity of injury progressively diminished and the lesion became confined to the injection site. The developmental pattern of sensitivity to AMPA toxicity in other brain regions differed although peak sensitivity consistently occurred near PND 10. Microinjection of quisqualate produced a developmental pattern of striatal susceptibility similar to AMPA although quisqualate was a considerable less potent neurotoxin. In additional experiments, the in vivo pharmacology of AMPA and quisqualate mediated brain injury was evaluated in a PND 7 rat model in order to determine the neurotoxic characteristics and specificity of these agonists in vivo. The severity of brain injury was assessed 5 days after intrastriatal excitotoxin injection by comparison of cerebral hemisphere weights.(ABSTRACT TRUNCATED AT 400 WORDS)
内源性兴奋性氨基酸（EAA）神经递质谷氨酸的兴奋作用和兴奋毒性作用，是由EAA受体的三种常见亚型激活介导的：N-甲基-D-天冬氨酸（NMDA）、α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）/quisqualate和海人藻酸受体。EAA神经递质系统在发育过程中对神经系统的调节和组织发挥着多种生理作用。然而，这种神经递质系统的过度激活也与几种急慢性脑损伤的病理生理学有关。在本研究中，在出生后的八个年龄段（1 - 90天）检查了发育中大鼠脑对AMPA/quisqualate受体介导损伤的易感性。将受体激动剂AMPA（25 nmol）或quisqualate（100 nmol）立体定向微量单侧注射到前纹状体中。5天后，通过比较局部皮质和纹状体横截面积的减少来评估由此产生的脑损伤的严重程度。微量注射AMPA（25 nmol）在出生后中期（第5 - 28天）产生广泛的单侧前脑损伤。固定剂量AMPA（25 nmol）微量注射所导致的损伤严重程度在出生后第5 - 28天暂时超过成年动物，在出生后第10天左右出现峰值敏感性。在出生后第1天，微量注射AMPA使纹状体横截面积减少24.5±1.7%，这与成年动物中观察到的反应相似，并且损伤局限于注射部位。对AMPA毒性的易感性从出生后第1天到第5天增加了2倍。在出生后第10天，即敏感性最高的年龄，对AMPA的兴奋毒性反应扩展到整个大脑半球，纹状体平均横截面积减少了81.7±3.9%。随着出生后年龄的增长，损伤严重程度逐渐减轻，损伤局限于注射部位。尽管峰值敏感性始终出现在出生后第10天左右，但其他脑区对AMPA毒性的敏感性发育模式有所不同。微量注射quisqualate产生的纹状体易感性发育模式与AMPA相似，尽管quisqualate是一种效力相当低的神经毒素。在额外的实验中，在出生后第7天的大鼠模型中评估了AMPA和quisqualate介导的脑损伤的体内药理学，以确定这些激动剂在体内的神经毒性特征和特异性。在纹状体内注射兴奋性毒素5天后，通过比较大脑半球重量来评估脑损伤的严重程度。（摘要截选至400字）
