PDF(Pubmed)
Abstract：
Cognitive decline is believed to be associated with neurodegenerative processes involving excitotoxicity, oxidative damage, inflammation, and microvascular and blood-brain barrier dysfunction. Interestingly, research evidence suggests upregulated synthesis of lipid signaling molecules as an endogenous attempt to contrast such neurodegeneration-related pathophysiological mechanisms, restore homeostatic balance, and prevent further damage. Among these naturally occurring molecules, palmitoylethanolamide (PEA) has been independently associated with neuroprotective and anti-inflammatory properties, raising interest into the possibility that its supplementation might represent a novel therapeutic approach in supporting the body-own regulation of many pathophysiological processes potentially contributing to neurocognitive disorders. Here, we systematically reviewed all human and animal studies examining PEA and its biobehavioral correlates in neurocognitive disorders, finding 33 eligible outputs. Studies conducted in animal models of neurodegeneration indicate that PEA improves neurobehavioral functions, including memory and learning, by reducing oxidative stress and pro-inflammatory and astrocyte marker expression as well as rebalancing glutamatergic transmission. PEA was found to promote neurogenesis, especially in the hippocampus, neuronal viability and survival, and microtubule-associated protein 2 and brain-derived neurotrophic factor expression, while inhibiting mast cell infiltration/degranulation and astrocyte activation. It also demonstrated to mitigate β-amyloid-induced astrogliosis, by modulating lipid peroxidation, protein nytrosylation, inducible nitric oxide synthase induction, reactive oxygen species production, caspase3 activation, amyloidogenesis, and tau protein hyperphosphorylation. Such effects were related to PEA ability to indirectly activate cannabinoid receptors and modulate proliferator-activated receptor-α (PPAR-α) activity. Importantly, preclinical evidence suggests that PEA may act as a disease-modifying-drug in the early stage of a neurocognitive disorder, while its protective effect in the frank disorder may be less relevant. Limited human research suggests that PEA supplementation reduces fatigue and cognitive impairment, the latter being also meta-analytically confirmed in 3 eligible studies. PEA improved global executive function, working memory, language deficits, daily living activities, possibly by modulating cortical oscillatory activity and GABAergic transmission. There is currently no established cure for neurocognitive disorders but only treatments to temporarily reduce symptom severity. In the search for compounds able to protect against the pathophysiological mechanisms leading to neurocognitive disorders, PEA may represent a valid therapeutic option to prevent neurodegeneration and support endogenous repair processes against disease progression.
摘要：
认知下降被认为与神经退行性过程有关，涉及兴奋性毒性。氧化损伤，炎症,微血管和血脑屏障功能障碍。有趣的是,研究证据表明，脂质信号分子的上调合成是一种内源性的尝试，以对比这种神经变性相关的病理生理机制，恢复稳态平衡，并防止进一步的损害。在这些天然存在的分子中，棕榈酰乙醇胺（PEA）与神经保护和抗炎特性独立相关，这引起了人们的兴趣，即它的补充可能代表了一种新的治疗方法，可以支持身体自身调节许多可能导致神经认知障碍的病理生理过程。这里,我们系统地回顾了所有人类和动物研究，研究PEA及其在神经认知障碍中的生物行为相关性，发现33个合格产出。在神经变性动物模型中进行的研究表明，PEA改善神经行为功能，包括记忆和学习，通过减少氧化应激和促炎和星形胶质细胞标志物表达以及重新平衡谷氨酸能传递。发现PEA促进神经发生，尤其是在海马区,神经元的生存力和存活率，和微管相关蛋白2和脑源性神经营养因子的表达，同时抑制肥大细胞浸润/脱颗粒和星形胶质细胞活化。它还证明可以减轻β-淀粉样蛋白诱导的星形胶质细胞增生，通过调节脂质过氧化，蛋白质正糖基化，诱导型一氧化氮合酶诱导，活性氧的产生，caspase3激活，淀粉样蛋白生成，和tau蛋白过度磷酸化。这种作用与PEA间接激活大麻素受体和调节增殖物激活受体-α（PPAR-α）活性的能力有关。重要的是,临床前证据表明，PEA可能在神经认知障碍的早期阶段作为改善疾病的药物，而其在弗兰克障碍中的保护作用可能不太相关。有限的人体研究表明，补充PEA可以减少疲劳和认知障碍，后者在3项符合条件的研究中也得到了荟萃分析证实.PEA改善了全球执行功能，工作记忆,语言障碍,日常生活活动,可能通过调节皮质振荡活动和GABA能传递。目前没有确定的神经认知障碍的治疗方法，只有暂时减轻症状严重程度的治疗方法。在寻找能够预防导致神经认知障碍的病理生理机制的化合物时，PEA可以代表预防神经变性和支持内源性修复过程对抗疾病进展的有效治疗选择。
