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首页> 外文期刊>Brain research >Pharmacological properties of a novel and potent gamma-secretase modulator as a therapeutic option for the treatment of Alzheimer's disease
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Pharmacological properties of a novel and potent gamma-secretase modulator as a therapeutic option for the treatment of Alzheimer's disease

机译：一种新型有效的γ-分泌酶调节剂的药理特性，可作为治疗阿尔茨海默氏病的一种治疗选择

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Previous studies of gamma-secretase inhibitors (GSIs) and Notch-sparing GIs have shown reduced amyloid-beta (A beta) peptide levels but increased Notch-related and-unrelated adverse effects. In this study, we examined the effects of compound-1 on A beta processing and cognitive function and assessed Notch-related and-unrelated adverse effects. Compound 1 reduced A beta 40 and A beta 42 levels but inversely increased A beta 37 in Neuro2a cells, leading to no net changes in total A beta levels, indicating that compound-1 is a gamma-secretase modulator (GSM). In time-course experiments, compound-1 reduced A beta 40 and A beta 42 levels in trissoluble fractions, with peak reduction at approximately 3 h after oral administration in C57BL mice. Moreover, at >1 mg/kg, compound-1 dose dependently reduced A beta 40 and A beta 42 levels in Tg2576 mice. Chronic treatment with compound-1 in Tg2576 mice for 4 months significantly reduced both soluble and insoluble A beta 42 levels and ameliorated cognitive impairments, even after drug withdrawal for 10 days following oral administration for 2 months. In contrast with compound-1, at 100-fold higher doses (100 mg/kg), the GSI LY450139 decreased HES1 mRNA expression in thymus tissues and increased the intensity of periodic acid-Schiff (PAS)-positive areas in the intestine. Moreover, the Notch sparing GSI BMS708163 led to amyloid precursor protein (APP)-beta-C-terminal fragment accumulation in mouse primary neurons. BMS708163 significantly hampered cognitive function in normal mice 1 month after administration, whereas compound-1 significantly improved cognitive function. Taken together, the present novel and orally active GSM is a promising molecule for the treatment of pathologies associated with A beta 42 and A beta 40. (c) 2016 Elsevier B.V. All rights reserved.
机译：先前对γ-分泌酶抑制剂（GSI）和保留Notch的GI的研究表明，淀粉样β（A beta）肽水平降低，但Notch相关和无关的不良反应增加。在这项研究中，我们检查了化合物1对Aβ加工和认知功能的影响，并评估了Notch相关和无关的不良反应。在Neuro2a细胞中，化合物1降低了A beta 40和A beta 42的水平，但相反地增加了A beta 37的水平，导致总A beta水平没有任何净变化，表明化合物1是伽马分泌酶调节剂（GSM）。在时程实验中，化合物1降低了三溶性级分中的A beta 40和A beta 42水平，在口服C57BL小鼠后约3 h出现峰值降低。此外，在> 1 mg / kg时，化合物1剂量依赖性地降低了Tg2576小鼠的A beta 40和A beta 42水平。在Tg2576小鼠中用化合物1长期治疗4个月，即使口服2个月后停药10天，也显着降低了可溶性和不溶性A beta 42水平并改善了认知障碍。与化合物1相反，在100倍高剂量（100 mg / kg）下，GSI LY450139降低了胸腺组织中HES1 mRNA的表达，并增加了肠道中高碘酸席夫（PAS）阳性区域的强度。此外，保留Notch的GSI BMS708163导致了小鼠原代神经元中的淀粉样前体蛋白（APP）-β-C-末端片段积聚。 BMS708163在给药1个月后显着阻碍正常小鼠的认知功能，而化合物1则显着改善了认知功能。综上所述，本发明的新型口服活性GSM是用于治疗与A beta 42和A beta 40相关的病理学的有前途的分子。（c）2016 Elsevier B.V.保留所有权利。

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