DataSheet_3_PQM130, a Novel Feruloyl–Donepezil Hybrid Compound, Effectively Ameliorates the Cognitive Impairments and Pathology in a Mouse Model of Alzheimer’s Disease.pdf

Alzheimer’s disease (AD) is the most frequent type of dementia in older people. The complex nature of AD calls for the development of multitarget agents addressing key pathogenic processes. Donepezil, an acetylcholinesterase inhibitor, is a first-line acetylcholinesterase inhibitor used for the treatment of AD. Although several studies have demonstrated the symptomatic efficacy of donepezil treatment in AD patients, the possible effects of donepezil on the AD process are not yet known. In this study, a novel feruloyl–donepezil hybrid compound (PQM130) was synthesized and evaluated as a multitarget drug candidate against the neurotoxicity induced by Aβ1-42 oligomer (AβO) injection in mice. Interestingly, PQM130 had already shown anti-inflammatory activity in different in vivo models and neuroprotective activity in human neuronal cells. The intracerebroventricular (i.c.v.) injection of AβO in mice caused the increase of memory impairment, oxidative stress, neurodegeneration, and neuroinflammation. Instead, PQM130 (0.5–1 mg/kg) treatment after the i.c.v. AβO injection reduced oxidative damage and neuroinflammation and induced cell survival and protein synthesis through the modulation of glycogen synthase kinase 3β (GSK3β) and extracellular signal–regulated kinases (ERK1/2). Moreover, PQM130 increased brain plasticity and protected mice against the decline in spatial cognition. Even more interesting is that PQM130 modulated different pathways compared to donepezil, and it is much more effective in counteracting AβO damage. Therefore, our findings highlighted that PQM130 is a potent multi-functional agent against AD and could act as a promising neuroprotective compound for anti-AD drug development.

阿尔茨海默病（AD）是老年人中最常见的痴呆类型。AD的复杂性质要求开发针对关键致病过程的多元靶点药物。多奈哌齐，一种乙酰胆碱酯酶抑制剂，是治疗AD的一线乙酰胆碱酯酶抑制剂。尽管多项研究已证实多奈哌齐治疗在AD患者中的症状改善效果，但其对AD进程的可能影响尚不清楚。在本研究中，合成并评估了一种新型的香草酰-多奈哌齐杂化化合物（PQM130），作为针对由Aβ1-42寡聚体（AβO）注射引起的神经毒性的多元靶点药物候选物。有趣的是，PQM130已在不同的体内模型中显示出抗炎活性，并在人神经元细胞中显示出神经保护活性。在老鼠中脑室内（i.c.v.）注射AβO会导致记忆障碍、氧化应激、神经退行性和神经炎症的增加。相反，PQM130（0.5-1 mg/kg）在i.c.v. AβO注射后的治疗减少了氧化损伤和神经炎症，并通过调节糖原合成酶激酶3β（GSK3β）和细胞外信号调节激酶（ERK1/2）诱导细胞存活和蛋白质合成。此外，PQM130增加了大脑可塑性，并保护老鼠免于空间认知能力的下降。更为引人注目的是，与多奈哌齐相比，PQM130调节了不同的途径，并在对抗AβO损伤方面具有更高的效果。因此，我们的研究结果强调了PQM130作为一种强大的多功能AD治疗剂，并可能作为抗AD药物开发的潜在神经保护化合物。