The selective 5-HT6 receptor antagonists SB-271046 and SB-399885 potentiate NCAM PSA immunolabeling not neurogenesis, in the hippocampal of dentate granule cells, but formation of mature Wistar rats
The selective 5-HT6 receptor antagonists SB-271046 and SB-399885 potentiate NCAM PSA immunolabeling not neurogenesis, in the hippocampal of dentate granule cells, but formation of mature Wistar rats
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DOI：
10.1016/j.neuropharm.2008.03.012
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发表时间：
2008-06-01
影响因子：
4.7
通讯作者：
Regan, Ciaran M.
中科院分区：
文献类型：
--
作者：
Foley, Andrew G.;Hirst, Warren D.;Regan, Ciaran M.
虽然现在有大量证据表明5-HT 6拮抗作用导致认知能力显著改善，但对所涉及的机制和/或途径知之甚少。我们已经评估了5-HT 6受体拮抗剂SB-271046和SB-399885对神经细胞粘附分子多聚唾液酸化状态（NCAM PSA）的长期给药的后果，这是记忆巩固所必需的神经可塑性机制。药物处理动物齿状回中NCAM PSA免疫阳性神经元的定量分析显示，SB-271046和SB-399885处理后，聚唾液酸化细胞频率呈剂量依赖性增加。这些影响不能归因于神经发生增加，因为对照组和药物治疗组之间溴脱氧尿苷掺入率无明显差异。还观察到内嗅和嗅周皮质第二层中聚唾液酸化细胞的频率大幅增加，这是以前与神经发生无关的脑区。SB-271046或SB-399885的长期治疗也显著增加了对学习特异性的齿状多唾液酸化的活化。其他认知增强药物（如他克林）不会产生这种作用，并且这种作用可能将5-HT 6受体拮抗作用区分为认知过程的独特神经可塑性机制，其可能减缓或逆转年龄/神经退行性相关的记忆缺陷。(c)2008爱思唯尔有限公司保留所有权利。
While there is now substantial evidence that 5-HT6 antagonism leads to significantly improved cognitive ability, the mechanism(s) and/or pathway(s) involved are poorly understood. We have evaluated the consequence of chronic administration of the 5-HT6 receptor antagonists SB-271046 and SB-399885 on neural cell adhesion molecule polysialylation state (NCAM PSA), a neuroplastic mechanism necessary for memory consolidation. Quantitative analysis of NCAM PSA immunopositive neurons in the dentate gyrus of drug-treated animals revealed a dose-dependent increase in polysialylated cell frequency following treatment with both SB-271046 and SB-399885. These effects could not be attributed to increased neurogenesis, as no difference in the rate of bromodeoxyuridine incorporation was apparent between the control and drug-treated groups. A substantial increase in the frequency of polysialylated cells in layer II of the entorhinal and perirhinal cortices was also observed, brain regions not previously associated with neurogenesis. Chronic treatment with SB-271046 or SB-399885 also significantly increased the activation of dentate polysialylation that is specific to learning. This effect does not occur with other cognition-enhancing drugs, such as tacrine, and this action potentially differentiates 5-HT6 receptor antagonism as an unique neuroplastic mechanism for cognitive processes which may slow or reverse age/neurodegenerative related memory deficits. (c) 2008 Elsevier Ltd. All rights reserved.