Orally bioavailable small molecule drug protects memory in Alzheimer's disease models

NEUROBIOLOGY OF AGING

卷:34

Article

O'Hare, Eugene¹  Scopes, David I. C.²  Kim, Eun-Mee³  Palmer, Philip¹  Jones, Martyn⁴  Whyment, Andrew D.⁴  Spanswick, David^4,5  Amijee, Hozefa²  Nerou, Edmund²  McMahon, Bridgeen¹  Treherne, J. Mark²  Jeggo, Ross⁴ 

[1] Queens Univ Belfast, Sch Psychol, Belfast BT7 1NN, Antrim, North Ireland

[2] Senexis Ltd, Cambridge CB22 3AT, England

[3] Univ Ulster, Sch Psychol, Coleraine BT52 1SA, Londonderry, North Ireland

[4] NeuroSolut Ltd, Coventry CV4 7ZS, W Midlands, England

[5] Univ Warwick, Warwick Med Sch, Coventry CV4 7CL, W Midlands, England

关键词: beta-amyloid peptide;    Alzheimer's disease;    Biochemistry;    Long-term potentiation;    Operant behavior;    Therapeutics;   

DOI  :  10.1016/j.neurobiolaging.2012.10.016

来源: Elsevier

【 摘 要 】

Oligomers of beta-amyloid (A beta) are implicated in the early memory impairment seen in Alzheimer's disease before to the onset of discernable neurodegeneration. Here, the capacity of a novel orally bioavailable, central nervous system-penetrating small molecule 5-aryloxypyrimidine, SEN1500, to prevent cell-derived (7PA2 [conditioned medium] CM) A beta-induced deficits in synaptic plasticity and learned behavior was assessed. Biochemically, SEN1500 bound to A beta monomer and oligomers, produced a reduction in thioflavin-T fluorescence, and protected a neuronal cell line and primary cortical neurons exposed to synthetic soluble oligomeric A beta(1-42). Electrophysiologically, SEN1500 alleviated the in vitro depression of long-term potentiation induced by both synthetic A beta(1-42) and 7PA2 CM, and alleviated the in vivo depression of long-term potentiation induced by 7PA2 CM, after systemic administration. Behaviorally, oral administration of SEN1500 significantly reduced memory-related deficits in operant responding induced after intracerebroventricular injection of 7PA2 CM. SEN1500 reduced cytotoxicity, acute synaptotoxicity, and behavioral deterioration after in vitro and in vivo exposure to synthetic A beta and 7PA2 CM, and shows promise for development as a clinically viable disease-modifying Alzheimer's disease treatment. (C) 2013 Elsevier Inc. All rights reserved.

【 授权许可】

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