Nasal Colivelin Treatment Ameliorates Memory Impairment Related to Alzheimer's Disease
Nasal Colivelin Treatment Ameliorates Memory Impairment Related to Alzheimer's Disease
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DOI：
10.1038/sj.npp.1301591
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发表时间：
2008-07
影响因子：
7.6
通讯作者：
M. Yamada;T. Chiba;J. Sasabe;K. Terashita;S. Aiso;M. Matsuoka
中科院分区：
文献类型：
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作者：
M. Yamada;T. Chiba;J. Sasabe;K. Terashita;S. Aiso;M. Matsuoka
Humanin（HN）及其衍生物，如Colivelin（CLN），在体外通过激活STAT 3抑制由与阿尔茨海默病（AD）相关的损伤诱导的神经元死亡。当直接给药至脑室或腹腔注射时，它们还改善抗胆碱能药物或可溶性毒性淀粉样蛋白-β（Aβ）在体内诱导的小鼠功能性记忆障碍。然而，体内效应的机制仍不明确。此外，从临床应用的角度来看，应开发侵入性较小且对中枢神经系统（CNS）具有特异性的药物递送方法。在这项研究中，我们表明，鼻内（中）管理CLN可以成功地转移到中枢神经系统通过嗅球。使用几个行为测试，我们已经证明，在管理CLN改善记忆障碍的AD模型中的剂量响应的方式。HN衍生物如CLN对AD相关记忆障碍的减弱似乎与隔海马区STAT 3磷酸化水平的增加相关，这表明HN衍生物的抗AD活性可能与其在体外一样通过体内STAT 3的激活来介导。我们进一步证明CLN治疗抑制Aβ诱导的内侧隔胆碱乙酰转移酶（ChAT）阳性神经元数量的减少。结合HN衍生物在体外上调神经元ChAT和囊泡乙酰胆碱转运体（VAChT）的mRNA表达的发现，推测CLN可以通过支持胆碱能神经传递来改善AD模型的记忆障碍，这至少部分是由STAT 3介导的ChAT和VAChT的转录上调介导的。
Humanin (HN) and its derivatives, such as Colivelin (CLN), suppress neuronal death induced by insults related to Alzheimer's disease (AD) by activating STAT3 in vitro. They also ameliorate functional memory impairment of mice induced by anticholinergic drugs or soluble toxic amyloid-β (Aβ) in vivo when either is directly administered into the cerebral ventricle or intraperitoneally injected. However, the mechanism underlying the in vivo effect remains uncharacterized. In addition, from the standpoint of clinical application, drug delivery methods that are less invasive and specific to the central nervous system (CNS) should be developed. In this study, we show that intranasally (in) administered CLN can be successfully transferred to CNS via the olfactory bulb. Using several behavioral tests, we have demonstrated that in administered CLN ameliorates memory impairment of AD models in a dose-responsive manner. Attenuation of AD-related memory impairment by HN derivatives such as CLN appears to be correlated with an increase in STAT3 phosphorylation levels in the septohippocampal region, suggesting that anti-AD activities of HN derivatives may be mediated by activation of STAT3 in vivo as they are in vitro. We further demonstrate that CLN treatment inhibits an Aβ induced decrease in the number of choline acetyltransferase (ChAT)-positive neurons in the medial septum. Combined with the finding that HN derivatives upregulate mRNA expression of neuronal ChAT and vesicular acetylcholine transporter (VAChT) in vitro, it is assumed that CLN may ameliorate memory impairment of AD models by supporting cholinergic neurotransmission, which is at least partly mediated by STAT3-mediated transcriptional upregulation of ChAT and VAChT.