Department of Physiology and Pharmacology "V. Erspamer", SAPIENZA University of Rome, Rome, Italy.
Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy.
Transl Psychiatry. 2018 Jan 31;8(1):32. doi: 10.1038/s41398-017-0076-4.
In an aging society, Alzheimer's disease (AD) exerts an increasingly serious health and economic burden. Current treatments provide inadequate symptomatic relief as several distinct pathological processes are thought to underlie the decline of cognitive and neural function seen in AD. This suggests that the efficacy of treatment requires a multitargeted approach. In this context, palmitoylethanolamide (PEA) provides a novel potential adjunct therapy that can be incorporated into a multitargeted treatment strategy. We used young (6-month-old) and adult (12-month-old) 3×Tg-AD mice that received ultramicronized PEA (um-PEA) for 3 months via a subcutaneous delivery system. Mice were tested with a range of cognitive and noncognitive tasks, scanned with magnetic resonance imaging/magnetic resonance spectroscopy (MRI/MRS), and neurochemical release was assessed by microdialysis. Potential neuropathological mechanisms were assessed postmortem by western blot, reverse transcription-polymerase chain reaction (RT-PCR), and immunofluorescence. Our data demonstrate that um-PEA improves learning and memory, and ameliorates both the depressive and anhedonia-like phenotype of 3×Tg-AD mice. Moreover, it reduces Aβ formation, the phosphorylation of tau proteins, and promotes neuronal survival in the CA1 subregion of the hippocampus. Finally, um-PEA normalizes astrocytic function, rebalances glutamatergic transmission, and restrains neuroinflammation. The efficacy of um-PEA is particularly potent in younger mice, suggesting its potential as an early treatment. These data demonstrate that um-PEA is a novel and effective promising treatment for AD with the potential to be integrated into a multitargeted treatment strategy in combination with other drugs. Um-PEA is already registered for human use. This, in combination with our data, suggests the potential to rapidly proceed to clinical use.
在老龄化社会中，阿尔茨海默病（AD）的健康和经济负担日益加重。目前的治疗方法只能提供有限的症状缓解，因为几种不同的病理过程被认为是导致 AD 患者认知和神经功能下降的原因。这表明治疗的疗效需要采用多靶点方法。在这种情况下，棕榈酸乙醇酰胺（PEA）提供了一种新的潜在辅助治疗方法，可以将其纳入多靶点治疗策略中。我们使用年轻（6 个月大）和成年（12 个月大）3×Tg-AD 小鼠，通过皮下给药系统接受超微化 PEA（um-PEA）治疗 3 个月。我们使用一系列认知和非认知任务对小鼠进行测试，使用磁共振成像/磁共振波谱（MRI/MRS）进行扫描，并通过微透析评估神经化学物质的释放。通过 Western blot、逆转录聚合酶链反应（RT-PCR）和免疫荧光，在死后评估潜在的神经病理学机制。我们的数据表明，um-PEA 可改善学习和记忆，并改善 3×Tg-AD 小鼠的抑郁和快感缺失样表型。此外，它还可减少 Aβ形成、tau 蛋白磷酸化，促进海马 CA1 亚区神经元存活。最后，um-PEA 可使星形胶质细胞功能正常化、重新平衡谷氨酸能传递并抑制神经炎症。um-PEA 在年轻小鼠中的疗效特别强，表明其作为早期治疗的潜力。这些数据表明，um-PEA 是一种新型有效的 AD 治疗方法，具有与其他药物联合纳入多靶点治疗策略的潜力。um-PEA 已注册用于人体使用。这一点，再加上我们的数据，表明有可能迅速进入临床使用。
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