Angiotensin II AT1 Receptor Blockers Ameliorate Inflammatory Stress: A Beneficial Effect for the Treatment of Brain Disorders

Excessive allostatic load as a consequence of deregulated brain inflammation participates in the development and progression of multiple brain diseases, including but not limited to mood and neurodegenerative disorders. Inhibition of the peripheral and brain Renin-Angiotensin System by systemic administration of Angiotensin II AT(1) receptor blockers (ARBs) ameliorates inflammatory stress associated with hypertension, cold-restraint, and bacterial endotoxin administration. The mechanisms involved include: (a) decreased inflammatory factor production in peripheral organs and their release to the circulation; (b) reduced progression of peripherally induced inflammatory cascades in the cerebral vasculature and brain parenchyma; and (c) direct anti-inflammatory effects in cerebrovascular endothelial cells, microglia, and neurons. In addition, ARBs reduce bacterial endotoxin-induced anxiety and depression. Further pre-clinical experiments reveal that ARBs reduce brain inflammation, protect cognition in rodent models of Alzheimer's disease, and diminish brain inflammation associated with genetic hypertension, ischemia, and stroke. The anti-inflammatory effects of ARBs have also been reported in circulating human monocytes. Clinical studies demonstrate that ARBs improve mood, significantly reduce cognitive decline after stroke, and ameliorate the progression of Alzheimer's disease. ARBs are well-tolerated and extensively used to treat cardiovascular and metabolic disorders such as hypertension and diabetes, where inflammation is an integral pathogenic mechanism. We propose that including ARBs in a novel integrated approach for the treatment of brain disorders such as depression and Alzheimer's disease may be of immediate translational relevance.