Kumar Kuldeep, Aggarwal Sonal, Kandpal Ayush, Kaur Ramanpreet, Jaggi Amteshwar S, Yadav Harlokesh Narayan, Singh Dhandeep, Chopra Dimple, Singh Nirmal
Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab, 147002, India.
Department of Pharmacology, All India Institute of Medical Sciences (AIIMS), New Delhi, 110029, India.
Exp Brain Res. 2025 Apr 26;243(5):130. doi: 10.1007/s00221-025-07072-1.
Dementia is a heterogeneous syndrome characterized by the progressive deterioration of various brain functions, severely impacting cognitive, emotional, and social abilities. According to a World Health Organization (WHO) report, dementia represents a pressing global health concern, with the number of affected individuals projected to triple by 2050. Among its various subtypes, vascular dementia (VD) stands as the second most common form, following Alzheimer's disease (AD). Despite ongoing efforts in drug development, no pharmaceutical entity has yet received approval from the U.S. Food and Drug Administration (FDA) for the treatment of VD. Emerging evidence underscores the critical involvement of the brain's Renin-Angiotensin System (RAS) in the pathogenesis of multiple neurodegenerative disorders, including VD. The intricate roles of RAS components include regulating vascular tone, neuronal growth and survival, regulating cerebral blood flow and endothelial dysfunction, increasing neuroinflammation (by increasing release of IL-1, IL-6, TNF-α, microglial activation), oxidative stress and destruction of BBB integrity, mainly through Angiotensin II type 1 (AT1) and type 2 (AT2) receptors, are of significant interest in the pathophysiology of VD. However, disruptions in these signaling pathways are believed to contribute substantially to the progression of VD. This review addresses the limitations of current therapeutic approaches for VD while emphasizing the untapped potential of RAS-targeted interventions. We systematically explore the neurophysiological mechanisms of brain RAS, their role in promoting neuronal health, and the factors that compromise these pathways, ultimately leading to cognitive decline. By elucidating these mechanisms and challenges, the review offers novel insights into designing innovative RAS-based therapeutic strategies, paving the way for effective clinical management of VD. This work aspires to stimulate further research and development in this underexplored yet promising domain.
痴呆是一种异质性综合征，其特征是各种脑功能进行性衰退，严重影响认知、情感和社交能力。根据世界卫生组织（WHO）的一份报告，痴呆是一个紧迫的全球健康问题，预计到2050年受影响的人数将增加两倍。在其各种亚型中，血管性痴呆（VD）是仅次于阿尔茨海默病（AD）的第二常见形式。尽管在药物开发方面不断努力，但尚无药物实体获得美国食品药品监督管理局（FDA）批准用于治疗VD。新出现的证据强调了大脑肾素-血管紧张素系统（RAS）在包括VD在内的多种神经退行性疾病发病机制中的关键作用。RAS组分的复杂作用包括调节血管张力、神经元生长和存活、调节脑血流量和内皮功能障碍、增加神经炎症（通过增加IL-1、IL-6、TNF-α的释放、小胶质细胞活化）、氧化应激以及破坏血脑屏障完整性，主要通过1型血管紧张素II（AT1）和2型血管紧张素II（AT2）受体，这些在VD的病理生理学中具有重要意义。然而，这些信号通路的破坏被认为在很大程度上促成了VD的进展。本综述阐述了当前VD治疗方法的局限性，同时强调了以RAS为靶点的干预措施尚未开发的潜力。我们系统地探讨了大脑RAS的神经生理机制、它们在促进神经元健康中的作用以及损害这些通路的因素，最终导致认知能力下降。通过阐明这些机制和挑战，本综述为设计基于RAS的创新治疗策略提供了新的见解，为VD的有效临床管理铺平了道路。这项工作旨在激发在这个尚未充分探索但前景广阔的领域的进一步研究和开发。
