RS-0406 Arrests Amyloid-β Oligomer-Induced Behavioural Deterioration In Vivo
RS-0406 Arrests Amyloid-β Oligomer-Induced Behavioural Deterioration In Vivo
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DOI：
10.1016/j.bbr.2010.01.044
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发表时间：
2010-06-26
影响因子：
2.7
通讯作者：
Kim, Eun-Mee
中科院分区：
文献类型：
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作者：
O'Hare, Eugene;Scopes, David I. C.;Kim, Eun-Mee
临床可获得的化合物阻止或逆转淀粉样β蛋白(Aβ)对阿尔茨海默病(AD)进行性发展的行为症状和神经病理的影响尚未成为可能。然而，一个可行的策略可能是靶向并中和可溶性Aβ寡聚体，这些寡聚体已被证明介导突触功能障碍，并在完整的有机体中产生认知缺陷。抑制Aβ聚集在治疗上具有吸引力，因为Aβ聚集是一种病理事件，针对这一事件的药物干预可能具有无毒特征。用交替水平循环比率程序对Aβ寡聚体和非肽小分子RS-0406在雄性SD大鼠体内的作用进行了研究。RS-0406已被证明能抑制Aβ(1-42)在原代培养的海马神经元中的纤维形成，并对Aβ(1-42)诱导的细胞毒性有保护作用。在目前的研究中，RS-0406改善了分泌的人Aβ寡聚体对行为的不利影响，并呈剂量依赖性地降低了Aβ寡聚体的行为影响，最高剂量为10µM，将行为维持在大约控制水平。这种影响似乎是中心的；外围的混淆已经得到了广泛的调查。这是首次发表的关于RS-0406体内效应的报告，表明RS-0406有可能作为治疗AD早期出现的行为缺陷的药物治疗干预措施，并可能作为干预AD神经病理发展的一种手段。事实上，一种可以外周给药的RS-0406类似物可能是临床治疗AD的现实候选者。(C)2010爱思唯尔B.V.保留所有权利。
Clinically accessible compounds that arrest or reverse the effects of amyloid-beta (A beta) on progressively developing behavioural symptomatology and neuropathology in Alzheimer's disease (AD) have yet to become available. However, a viable strategy may be to target and neutralise soluble A beta oligomers, which have been shown to mediate synaptic dysfunction and to produce cognitive deficits in the intact organism. Inhibiting the aggregation of A beta is therapeutically attractive, as A beta aggregation is a pathological event and pharmacological interventions targeting this are likely to have a non-toxic profile. A behavioural assay, the alternating-lever cyclic-ratio schedule, was used to assess the effect of A beta oligomers and the non-peptide small molecule RS-0406 in male Sprague-Dawley rats. RS-0406 has been shown to inhibit A beta(1-42) fibrillogenesis and protect against A beta(1-42)-induced cytotoxicity in primary hippocampal neurons. In the current study, RS-0406 ameliorated the adverse effects of secreted oligomers of human A beta on behaviour and dose dependently reduced the behavioural effects of A beta oligomers, with the highest dose, 10 mu M, maintaining behaviour approximately at control levels. This effect appeared to be central; peripheral confounds having been extensively investigated. This is the first published report on the effects of RS-0406 in vivo and indicates that RS-0406 has potential as a pharmacotherapeutic intervention for behavioural deficits seen in the early stages of AD, and possibly as an intervention in the development of AD neuropathology. Indeed, an analogue of RS-0406 that could be administered peripherally might be a realistic candidate for the clinical treatment of AD. (C) 2010 Elsevier B.V. All rights reserved.