The brain angiotensin converting enzyme 2 and angiotensin-(1–7) as potential therapeutic targets for the central nervous system diseases

The renin-angiotensin system (RAS) serves as a key regulator of body fluid balance and cardiovascular homeostasis, whose dysregulation is involved in the pathogenesis of various central nervous system (CNS) diseases. Beyond their canonical functions such as vascular regulation, the constituents of the RAS, particularly angiotensin (Ang) II, exert inflammatory and oxidative injury on neurons in the brain. Meanwhile, the non-classical pathway angiotensin-converting enzyme (ACE)2/Ang-(1-7) axis shows beneficial effects against CNS diseases. Activation of cerebral ACE2/Ang-(1-7) exerts regulatory effects on neurons, endothelial cells, glial cells, and other kinds, thereby comprehensively optimizing the blood-brain barrier (BBB), neurovascular unit, and cerebral microenvironment, and ultimately modulating memory, cognition, and emotion. This review, through comprehensive literature retrieval from PubMed and Web of Science, focuses on elucidating the critical regulatory role of the ACE2/Ang-(1-7) axis in CNS diseases and provides an in-depth exploration of its associated physiological and pathological mechanisms. Future research directions will primarily concentrate on novel drug development strategies targeting the ACE2/Ang-(1-7) axis, aiming to optimize drug development potential from multiple perspectives-including BBB penetration, targeted delivery to specific lesion sites, and regulation of pathological microenvironments and targets-to achieve early intervention, precision medicine, and efficient treatment for long-term CNS diseases.