Rothstein J D, Kuncl R W
Department of Neurology, Johns Hopkins University, Baltimore, MD 21287, USA.
J Neurochem. 1995 Aug;65(2):643-51. doi: 10.1046/j.1471-4159.1995.65020643.x.
A dramatic loss of glutamate transport has been observed in sporadic amyotrophic lateral sclerosis and has been postulated to contribute to the disease. Experimentally, this hypothesis was corroborated by mimicking the chronic loss of glutamate transport in postnatal rat spinal cord organotypic cultures through the use of glutamate transport inhibitors. This system is characterized by a relatively selective slow loss of ventral horn motor neurons resulting from glutamate transport inhibition. In this study, spinal cord organotypic cultures were used to test various drugs to evaluate their neuroprotective properties against this slow glutamate-mediated neurotoxicity The most potent neuroprotectants were drugs that altered glutamate neurotransmission, including non-NMDA receptor antagonists (GYKI-52466, PD144216, and PD13997) and drugs that could block presynaptic release or synthesis (riluzole and gabapentin). In addition, some antioxidants (U83836E and N-t-butyl-alpha-phenylnitrone) and inhibitors of nitric oxide synthesis (NG-monomethyl-L-arginine acetate) were modestly neuroprotective. The calcium endonuclease inhibitor aurintricarboxylic acid and the calcium release inhibitor dantrolene also provided partial motor neuron protection. However, several antioxidants and calcium channel antagonists had no excitotoxic neuroprotectant activity. This system provides a preclinical screening method for the burgeoning number of drugs postulated for clinical trials in motor neuron disease and a model to evaluate the mechanisms of chronic glutamate toxicity.
在散发性肌萎缩侧索硬化症中已观察到谷氨酸转运的显著丧失，并推测这与该疾病有关。在实验中，通过使用谷氨酸转运抑制剂模拟新生大鼠脊髓器官型培养物中谷氨酸转运的慢性丧失，证实了这一假设。该系统的特征是由于谷氨酸转运抑制导致腹角运动神经元相对选择性地缓慢丧失。在本研究中，使用脊髓器官型培养物来测试各种药物，以评估它们对这种缓慢的谷氨酸介导的神经毒性的神经保护特性。最有效的神经保护剂是改变谷氨酸神经传递的药物，包括非NMDA受体拮抗剂（GYKI-52466、PD144216和PD13997）以及可阻断突触前释放或合成的药物（利鲁唑和加巴喷丁）。此外，一些抗氧化剂（U83836E和N-叔丁基-α-苯基硝酮）和一氧化氮合成抑制剂（NG-单甲基-L-精氨酸乙酸盐）具有一定程度的神经保护作用。钙核酸内切酶抑制剂金精三羧酸和钙释放抑制剂丹曲林也提供了部分运动神经元保护。然而，几种抗氧化剂和钙通道拮抗剂没有兴奋性毒性神经保护活性。该系统为越来越多拟用于运动神经元疾病临床试验的药物提供了一种临床前筛选方法，也是评估慢性谷氨酸毒性机制的模型。
