Division of Pharmacology, Institute of Pharmaceutical Research, GLA University, Mathura, India.
Division of Pharmaceutical Chemistry, Institute of Pharmaceutical Research, GLA University, Mathura, India.
Chem Biol Drug Des. 2024 Sep;104(3):e14619. doi: 10.1111/cbdd.14619.
Parkinson's disease (PD) stands as the second most common neurological disorder after Alzheimer's disease, primarily affecting the elderly population and significantly compromising their quality of life. The precise etiology of PD remains elusive, but recent research has shed light on potential factors, including the formation of α-synuclein aggregates, oxidative stress, neurotransmitter imbalances, and dopaminergic neurodegeneration in the substantia nigra pars compacta (SNpc) region of the brain, culminating in motor symptoms such as bradykinesia, akinesia, tremors, and rigidity. Monoamine oxidase (MAO) is an essential enzyme, comprising two isoforms, MAO-A and MAO-B, responsible for the oxidation of monoamines such as dopamine. Increased MAO-B activity is responsible for decreased dopamine levels in the SNpc region of mid brain which is remarkably associated with the pathogenesis of PD-like manifestations. Inhibitors of MAO-B enhance striatal neuronal responses to dopamine, making them valuable in treating PD, which involves dopamine deficiency. Clinically approved MAO-B inhibitors such as selegiline, L-deprenyl, pargyline, and rasagiline are employed in the management of neurodegenerative conditions associated with PD. Current therapeutic interventions including MAO-B inhibitors for PD predominantly aim to alleviate these motor symptoms but often come with a host of side effects that can be particularly challenging for the patients. While effective, they have limitations, prompting a search for alternative treatments, there is a growing interest in exploring natural products notably flavonoids as potential sources of novel MAO-B inhibitors. In line with that, the present review focuses on natural flavonoids of plant origin that hold promise as potential candidates for the development of novel MAO-B inhibitors. The discussion encompasses both in vitro and in vivo studies, shedding light on their potential therapeutic applications. Furthermore, this review underscores the significance of exploring natural products as valuable reservoirs of MAO-B inhibitors, offering new avenues for drug development and addressing the pressing need for improved treatments in PD-like pathological conditions. The authors of this review majorly explore the neuroprotective potential of natural flavonoids exhibiting notable MAO-B inhibitory activity and additionally multi-targeted approaches in the treatment of PD with clinical evidence and challenges faced in current therapeutic approaches.
帕金森病（PD）是仅次于阿尔茨海默病的第二大常见神经退行性疾病，主要影响老年人群体，并显著降低他们的生活质量。PD 的确切病因仍不明确，但最近的研究揭示了一些潜在因素，包括α-突触核蛋白聚集体的形成、氧化应激、神经递质失衡以及大脑中脑黑质致密部（SNpc）区域的多巴胺能神经退行性变，最终导致运动症状，如运动迟缓、运动不能、震颤和僵硬。单胺氧化酶（MAO）是一种重要的酶，包括两种同工酶 MAO-A 和 MAO-B，负责单胺类物质如多巴胺的氧化。MAO-B 活性的增加导致中脑 SNpc 区域多巴胺水平降低，这与 PD 样表现的发病机制密切相关。MAO-B 抑制剂可增强纹状体神经元对多巴胺的反应，因此在治疗涉及多巴胺缺乏的 PD 方面具有重要价值。临床上批准的 MAO-B 抑制剂，如司来吉兰、L-deprenyl、帕吉林和雷沙吉兰，用于治疗与 PD 相关的神经退行性疾病。目前的治疗干预措施，包括 MAO-B 抑制剂，主要旨在缓解这些运动症状，但往往伴随着一系列副作用，这对患者来说尤其具有挑战性。虽然有效，但它们存在局限性，促使人们寻找替代治疗方法，因此越来越关注探索天然产物，特别是类黄酮，作为潜在的新型 MAO-B 抑制剂来源。有鉴于此，本综述重点关注植物来源的天然类黄酮，它们作为新型 MAO-B 抑制剂候选物具有很大的潜力。讨论涵盖了体内和体外研究，阐明了它们在治疗中的潜在应用。此外，本综述强调了探索天然产物作为 MAO-B 抑制剂有价值的资源的重要性，为药物开发提供了新的途径，并解决了在 PD 样病理条件下改善治疗的迫切需求。本文作者主要探讨了具有显著 MAO-B 抑制活性的天然类黄酮的神经保护潜力，并探讨了具有临床证据和当前治疗方法面临的挑战的多靶点方法在 PD 治疗中的应用。
