Harkany T, Mulder J, Horvath K M, Keijser J, van der Meeberg E K, Nyakas C, Luiten P G
Department of Animal Physiology, Graduate School of Behavioural and Cognitive Neurosciences, University of Groningen, Haren, The Netherlands.
Neuroscience. 2001;108(4):629-42. doi: 10.1016/s0306-4522(01)00444-4.
Recent evidence indicates that stimulation of postsynaptic 5-HT(1A) receptors abates excitotoxic neuronal death. Here we investigated whether oral post-lesion administration of the 5-HT(1A) receptor agonist (-)-(R)-2-[4-[[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]amino]butyl]-1,2-benzisothiazol-3(2H)-one 1,1-dioxide monohydrochloride (Repinotan HCl) attenuates N-methyl-D-aspartate (NMDA) excitotoxicity (60 nmol/microl) in the rat magnocellular nucleus basalis. Repinotan HCl (1 mg/kg) was administered from day 1, 2, 3, or 6 post-surgery twice daily for five consecutive days. This delayed drug administration protocol was employed to investigate the initiation period during which 5-HT(1A) receptor agonists may significantly influence ongoing neurodegeneration processes. 8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, 1 mg/kg) served as reference compound. Twenty-four hours after drug delivery a small open-field test, while on day 14 post-surgery a passive avoidance test was performed. Effects of Repinotan HCl treatment on the survival of cholinergic magnocellular nucleus basalis neurons and their cortical projections were determined by quantitative acetylcholinesterase (AChE) and choline-acetyltransferase (ChAT) histochemistry. Moreover, AChE and ChAT activities were biochemically measured both in the cerebral cortex and in the magnocellular nucleus basalis. Repinotan HCl treatment markedly increased spontaneous activities in the small open-field at any time-point investigated. Improved memory performance was only demonstrated when Repinotan HCl was administered from day 1 post-lesion on wards. Repinotan HCl treatment from day 2 and 3 post-lesion on markedly attenuated both histochemical and neurochemical characteristics of NMDA excitotoxicity on cholinergic magnocellular nucleus basalis neurons and on their cortical projections. Whereas the neuroprotective profile of Repinotan HCl was superior to that of 8-OH-DPAT, oral administration of both 5-HT(1A) receptor agonists yielded largely equivalent behavioral recovery after NMDA infusion in the magnocellular nucleus basalis. In conclusion, the present data indicate the potent neuroprotective action of the 5-HT(1A) receptor agonist Repinotan HCl with a peak efficacy of delayed (2-3 day) post-lesion drug treatment in vivo. Post-lesion treatment with 5-HT(1A) receptor agonists may therefore be of significance in the intervention of neuronal damage associated with acute excitotoxic conditions.
最近的证据表明，刺激突触后5-HT(1A)受体可减轻兴奋性毒性导致的神经元死亡。在此，我们研究了在大鼠基底大细胞核中，在损伤后口服给予5-HT(1A)受体激动剂(-)-(R)-2-[4-[[(3,4-二氢-2H-1-苯并吡喃-2-基)甲基]氨基]丁基]-1,2-苯并异噻唑-3(2H)-酮1,1-二氧化物单盐酸盐（瑞吡坦盐酸盐）是否能减轻N-甲基-D-天冬氨酸（NMDA）兴奋性毒性（60 nmol/微升）。从手术后第1、2、3或6天开始，每天两次给予瑞吡坦盐酸盐（1 mg/kg），连续给药五天。采用这种延迟给药方案来研究5-HT(1A)受体激动剂可能对正在进行的神经退行性变过程产生显著影响的起始阶段。8-羟基-2-(二正丙基氨基)四氢萘（8-OH-DPAT，1 mg/kg）作为参考化合物。给药24小时后进行小型旷场试验，而在手术后第14天进行被动回避试验。通过定量乙酰胆碱酯酶（AChE）和胆碱乙酰转移酶（ChAT）组织化学来确定瑞吡坦盐酸盐治疗对胆碱能基底大细胞核神经元及其皮质投射存活的影响。此外，还对大脑皮质和基底大细胞核中的AChE和ChAT活性进行了生化测定。在任何研究的时间点，瑞吡坦盐酸盐治疗均显著增加了小型旷场试验中的自发活动。仅在损伤后第1天开始给予瑞吡坦盐酸盐时才表现出记忆性能的改善。损伤后第2天和第3天开始给予瑞吡坦盐酸盐治疗，显著减轻了NMDA兴奋性毒性对胆碱能基底大细胞核神经元及其皮质投射的组织化学和神经化学特征。虽然瑞吡坦盐酸盐的神经保护作用优于8-OH-DPAT，但在基底大细胞核中注入NMDA后，口服这两种5-HT(1A)受体激动剂产生的行为恢复在很大程度上是等效的。总之，目前的数据表明5-HT(1A)受体激动剂瑞吡坦盐酸盐具有强大的神经保护作用，在体内损伤后延迟（2 - 3天）给药的疗效最佳。因此，5-HT(1A)受体激动剂损伤后治疗可能对干预与急性兴奋性毒性状况相关的神经元损伤具有重要意义。
