Administration of a non-NMDA antagonist, GYKI 52466, increases excitotoxic Purkinje cell degeneration caused by ibogaine.
Administration of a non-NMDA antagonist, GYKI 52466, increases excitotoxic Purkinje cell degeneration caused by ibogaine.
复制标题
施用非 NMDA 拮抗剂 GYKI 52466 会增加伊博加因引起的兴奋毒性浦肯野细胞变性。
DOI：
10.1016/j.neuroscience.2004.04.058
复制
发表时间：
2004
期刊：
影响因子：
3.3
通讯作者：
Molliver,ME
中科院分区：
文献类型：
--
作者：
O'Hearn,E;Molliver,ME
伊波甘是一种催眠致幻剂，已被建议用于临床治疗成瘾。我们之前曾报道，全身给药会导致小脑中浦肯野细胞的子集退化，主要是在蚯蚓内。切除下橄榄对伊波甘诱导的神经毒性具有保护作用，从而导致对伊波甘本身对浦肯野细胞没有直接毒性的解释。我们推测，伊波甘产生下橄榄核神经元的持续兴奋，导致攀升纤维终末谷氨酸过度释放，导致浦肯野细胞随后的兴奋性毒性损伤。伊波甘诱导的神经元变性为研究兴奋性毒性损伤提供了一个动物模型，以分析谷氨酸受体在这种损伤中的作用，并评价神经保护策略。由于非N-甲基-D-天冬氨酸受体通过攀升纤维介导浦肯野细胞的兴奋，我们推测拮抗非N-甲基-D-天冬氨酸受体的1-4-aminophenyl-methyl-7，8-methylenedioxy-5H-2，3-benzodiazepine(GYKI-52466)可能通过阻断攀升纤维突触上的谷氨酸能兴奋而起到神经保护作用。为了验证这一假设，给大鼠注射全身性伊波甘和GYKI-52466，并在小脑切片上分析神经元损伤的程度。结果表明，AMPA拮抗剂GYKI-52466(10 mg/kg，i.p.×3)对所用剂量的浦肯野细胞损伤无保护作用。相反，GYKI-52466与伊波甘联合给药会增加毒性，表现为更广泛的浦肯野细胞变性。讨论了可能支持这一结果的几个假设。尽管本研究中发现的毒性增加的原因尚未完全解释，但目前的结果表明，在某些情况下，非NMDA拮抗剂可以引起兴奋毒性损伤的增加。因此，在使用谷氨酸拮抗剂之前应谨慎行事，以降低人类临床疾病中神经元损伤的风险。此外，不同的谷氨酸受体在兴奋性毒性损伤中的作用是复杂的，值得进一步分析。
Ibogaine is a tremorigenic hallucinogen that has been proposed for clinical use in treating addiction. We previously reported that ibogaine, administered systemically, produces degeneration of a subset of Purkinje cells in the cerebellum, primarily within the vermis. Ablation of the inferior olive affords protection against ibogaine-induced neurotoxicity leading to the interpretation that ibogaine itself is not directly toxic to Purkinje cells. We postulated that ibogaine produces sustained excitation of inferior olivary neurons that leads to excessive glutamate release at climbing fiber terminals, causing subsequent excitotoxic injury to Purkinje cells. The neuronal degeneration induced by ibogaine provides an animal model for studying excitotoxic injury in order to analyze the contribution of glutamate receptors to this injury and to evaluate neuroprotective strategies. Since non-N-methyl-d-aspartate (NMDA) receptors mediate Purkinje cell excitation by climbing fibers, we hypothesized that 1-4-aminophenyl-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine (GYKI-52466), which antagonizes non-NMDA receptors, may have a neuroprotective effect by blocking glutamatergic excitation at climbing fiber synapses. To test this hypothesis, rats were administered systemic ibogaine plus GYKI-52466 and the degree of neuronal injury was analyzed in cerebellar sections. The results indicate that the AMPA antagonist GYKI-52466 (10 mg/kg i.p.×3) does not protect against Purkinje cell injury at the doses used. Rather, co-administration of GYKI-52466 with ibogaine produces increased toxicity evidenced by more extensive Purkinje cell degeneration. Several hypotheses that may underlie this result are discussed. Although the reason for the increased toxicity found in this study is not fully explained, the present results show that a non-NMDA antagonist can produce increased excitotoxic injury under some conditions. Therefore, caution should be exercised before employing glutamate antagonists to reduce the risk of neuronal damage in human clinical disorders. Moreover, the contribution of different glutamate receptors to excitotoxic injury is complex and merits further analysis.