Neurotherapeutic roles of the protective arm of the renin-angiotensin system: from inflammation to cognitive rescue.

The renin-angiotensin system (RAS), traditionally recognized for its role in regulating blood pressure and fluid homeostasis, is increasingly understood to exert important effects across multiple organ systems, including the central nervous system (CNS). A local brain RAS contributes to neurovascular regulation, inflammation, oxidative stress, synaptic plasticity, and cognitive function. This review critically summarizes the neurotherapeutic relevance of the protective RAS arm, particularly the angiotensin-converting enzyme 2 (ACE2)-angiotensin-(1-7)-Mas receptor axis, the angiotensin II type 2 receptor (AT2R), and the alamandine/Mas-related G protein-coupled receptor D (MrgD) pathway. Experimental evidence suggests that these pathways may counterbalance angiotensin II type 1 receptor signaling by reducing neuroinflammation, oxidative injury, vascular dysfunction, and neuronal loss in models of ischemic stroke, Alzheimer's disease, Parkinson's disease, and multiple sclerosis. The strongest evidence remains preclinical, with most data derived from cell culture and animal models, whereas human evidence is still indirect and largely based on observational or early translational studies of RAS-modifying drugs. Important uncertainties remain regarding blood-brain barrier penetration, receptor-specific signaling, disease-stage dependency, systemic vascular effects, and reproducibility across models. Therefore, protective RAS signaling should be considered a promising but still exploratory therapeutic framework rather than an established treatment strategy for neurological disease. Future work should prioritize selective brain-penetrant agonists, validated biomarkers of central RAS activity, and rigorously designed clinical trials to determine whether modulation of ACE2-angiotensin-(1-7)-Mas, AT2R, or alamandine/MrgD signaling can produce clinically meaningful neuroprotection.