Bartha E, Lovas G, Szentkuty E, Horváth E J, Palkovits M
Institute for Drug Research, Budapest, Hungary.
Neurobiology (Bp). 1998;6(2):127-39.
The neuroprotective effect of intraperitonally administered GYKI 52466 (2,3-benzodiazepine derivate) was investigated on AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxalon-propionic acid)-induced neuronal degeneration in the striatum of adult rats. The dose-dependent neurotoxic effect of AMPA was evaluated by the decrease in the activity of choline acetyltransferase (ChAT), due to degeneration of cholinergic neurons. An injection of 25 mg/kg GYKI 52466 30 min prior to the striatal application of 50 nmol AMPA, followed by repeated application of GYKI 52466 (10 times 5 mg/kg at 10 min intervals, reaching a final dose of 75 mg/kg) was able to prevent neuronal damage monitored by ChAT activity. Conversely, co-injection of GYKI 52466 (50 and 75 mg/kg) with AMPA (50 and 100 nmol) did not elicit any significant protection against the neuronal loss as measured by the ChAT enzyme activity. Therefore, one dose of agonist decreasing ChAT activity by about 40% (50 nmol) was tested on [3H]girisopam binding sites and on the immunoreactivity of glial fibrillary acid protein. The lesions were measured on methylene blue-stained serial sections with a computer assisted image analysis program (NIH Image 1.60). As a result of the AMPA treatment [3H]girisopam binding sites became depleted, and the immunoreactivity of glial fibrillary acid protein increased and on the site of the injection in the striatum a lesion developed. In the presence of AMPA (50 nmol) administered intrastriatally, GYKI 52466 (75 mg/kg i.p.) was able to make the radioactive signal of [3H]girisopam reappear. The volume of AMPA induced neuronal damage in the striatum and the extent of gliosis was reduced. These data provide evidence for the neuroprotective effect of GYKI 52466, and suggest a potential therapeutic value in some neurological disorders.
研究了腹腔注射GYKI 52466（一种2,3-苯并二氮杂卓衍生物）对成年大鼠纹状体中由α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）诱导的神经元变性的神经保护作用。AMPA的剂量依赖性神经毒性作用通过胆碱能神经元变性导致的胆碱乙酰转移酶（ChAT）活性降低来评估。在向纹状体应用50 nmol AMPA前30分钟注射25 mg/kg GYKI 52466，随后重复应用GYKI 52466（以10分钟的间隔10次注射5 mg/kg，最终剂量达75 mg/kg）能够预防通过ChAT活性监测到的神经元损伤。相反，将GYKI 52466（50和75 mg/kg）与AMPA（50和100 nmol）共同注射，并未对通过ChAT酶活性测量的神经元损失产生任何显著的保护作用。因此，对一剂使ChAT活性降低约40%（50 nmol）的激动剂进行了[3H]吉立索泮结合位点及胶质纤维酸性蛋白免疫反应性方面的测试。在亚甲蓝染色的连续切片上，使用计算机辅助图像分析程序（NIH Image 1.60）测量损伤情况。AMPA处理的结果是[3H]吉立索泮结合位点减少，胶质纤维酸性蛋白的免疫反应性增加，并且在纹状体注射部位出现了损伤。在纹状体内注射AMPA（50 nmol）的情况下，GYKI 52466（75 mg/kg腹腔注射）能够使[3H]吉立索泮的放射性信号重新出现。纹状体内AMPA诱导的神经元损伤体积以及胶质增生程度均降低。这些数据为GYKI 52466的神经保护作用提供了证据，并提示其在某些神经系统疾病中具有潜在的治疗价值。
