Abstract：
Neurodegenerative diseases (NDDs) encompass a range of conditions characterized by the specific dysfunction and continual decline of neurons, glial cells, and neural networks within the brain and spinal cord. The majority of NDDs exhibit similar underlying causes, including oxidative stress, neuroinflammation, and malfunctioning of mitochondria. Elevated levels of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), alongside decreased expression of brain-derived neurotrophic factor (BDNF) and glutamate transporter subtype 1 (GLT-1), constitute significant factors contributing to the pathogenesis of NDDs. Additionally, the dual-specificity tyrosine phosphorylation-regulated kinase 1 A (DYRK1A) gene has emerged as a significant target for the treatment of NDDs at the preclinical level. It significantly contributes to developmental brain defects, early onset neurodegeneration, neuronal loss, and dementia in Down syndrome. Moreover, an impaired ubiquitin-proteosome system (UPS) also plays a pathological role in NDDs. Malfunctioning of UPS leads to abnormal protein buildup or aggregation of α-synuclein. α-Synuclein is a highly soluble unfolded protein that accumulates in Lewy bodies and Lewy neurites in Parkinson\'s disease and other synucleinopathies. Recent research highlights the promising potential of natural products in combating NDDs relative to conventional therapies. Alkaloids have emerged as promising candidates in the fight against NDDs. Harmine is a tricyclic β-carboline alkaloid (harmala alkaloid) with one indole nucleus and a six-membered pyrrole ring. It is extracted from Banisteria caapi and Peganum harmala L. and exhibits diverse pharmacological properties, encompassing neuroprotective, antioxidant, anti-inflammatory, antidepressant, etc. Harmine has been reported to mediate its neuroprotective via reducing the level of inflammatory mediators, NADPH oxidase, AChE, BChE and reactive oxygen species (ROS). Whereas, it has been observed to increase the levels of BDNF, GLT-1 and anti-oxidant enzymes, along with protein kinase-A (PKA)-mediated UPS activation. This review aims to discuss the mechanistic interplay of various mediators involved in the neuroprotective effect of harmine.
摘要：
神经退行性疾病（NDD）包括一系列以神经元的特定功能障碍和持续衰退为特征的疾病，胶质细胞,大脑和脊髓内的神经网络。大多数NDD表现出相似的根本原因，包括氧化应激,神经炎症，线粒体功能失调.乙酰胆碱酯酶（AChE）和丁酰胆碱酯酶（BChE）水平升高，脑源性神经营养因子（BDNF）和谷氨酸转运体亚型1（GLT-1）的表达降低，是导致NDDs发病的重要因素。此外,双特异性酪氨酸磷酸化调节激酶1A(DYRK1A)基因已成为临床前水平治疗NDD的重要靶点.它显著有助于大脑发育缺陷，早发性神经变性,神经元丢失，和唐氏综合症的痴呆症。此外，受损的泛素-蛋白体系统（UPS）也在NDD中起病理作用。UPS的故障导致异常的蛋白质积聚或α-突触核蛋白的聚集。α-突触核蛋白是一种高度可溶的未折叠蛋白，在帕金森病和其他突触核蛋白病中积聚在路易体和路易神经突。最近的研究强调了天然产物相对于常规疗法在对抗NDD方面的有希望的潜力。生物碱已成为对抗NDD的有希望的候选人。Harmine是三环β-咔啉生物碱（harmala生物碱），具有一个吲哚核和一个六元吡咯环。它是从巴尼斯特草caapi和PeganumharmalaL.中提取的，并具有多种药理特性，包括神经保护，抗氧化剂，抗炎,抗抑郁药,等。据报道，Harmine通过降低炎症介质的水平来介导其神经保护作用，NADPH氧化酶,AChE,BChE和活性氧（ROS）。然而,已经观察到增加BDNF的水平，GLT-1和抗氧化酶，以及蛋白激酶A（PKA）介导的UPS激活。这篇综述旨在讨论参与harmine神经保护作用的各种介质的机制相互作用。
