Angiotensin II AT1 receptor blockers as treatments for inflammatory brain disorders

Abstract

The effects of brain AngII (angiotensin II) depend on AT1 receptor (AngII type 1 receptor) stimulation and include regulation of cerebrovascular flow, autonomic and hormonal systems, stress, innate immune response and behaviour. Excessive brain AT1 receptor activity associates with hypertension and heart failure, brain ischaemia, abnormal stress responses, blood–brain barrier breakdown and inflammation. These are risk factors leading to neuronal injury, the incidence and progression of neurodegerative, mood and traumatic brain disorders, and cognitive decline. In rodents, ARBs (AT1 receptor blockers) ameliorate stress-induced disorders, anxiety and depression, protect cerebral blood flow during stroke, decrease brain inflammation and amyloid-β neurotoxicity and reduce traumatic brain injury. Direct anti-inflammatory protective effects, demonstrated in cultured microglia, cerebrovascular endothelial cells, neurons and human circulating monocytes, may result not only in AT1 receptor blockade, but also from PPARγ (peroxisome-proliferator-activated receptor γ) stimulation. Controlled clinical studies indicate that ARBs protect cognition after stroke and during aging, and cohort analyses reveal that these compounds significantly reduce the incidence and progression of Alzheimer’s disease. ARBs are commonly used for the therapy of hypertension, diabetes and stroke, but have not been studied in the context of neurodegenerative, mood or traumatic brain disorders, conditions lacking effective therapy. These compounds are well-tolerated pleiotropic neuroprotective agents with additional beneficial cardiovascular and metabolic profiles, and their use in central nervous system disorders offers a novel therapeutic approach of immediate translational value. ARBs should be tested for the prevention and therapy of neurodegenerative disorders, in particular Alzheimer’s disease, affective disorders, such as co-morbid cardiovascular disease and depression, and traumatic brain injury.

Angiotensin II Peptide Vaccine Protects Ischemic Brain Through Reducing Oxidative Stress

“…28 Ang II regulates reactive oxygen species production and oxidative stress in ischemic brain. 29,30 Because the expression of 4-HNE, which was expressed in AT1R-positive neurons, and AT1R mRNA was reduced in the vaccinated rats, suppression of oxidative stress in damaged neurons through inhibition of AT1R signaling might be one of the mechanisms for the amelioration of ischemic injury. Considering that NADPH oxidase 2 is involved in the AT1R-reactive oxygen species axis in neurons 31,32 and its expression was less in the vaccinated rats, the antioxidative stress effects might be through the inhibition of NADPH oxidase 2.…”

Bidirectional asymmetry in the neurovisceral communication for the cardiovascular control: New insights

“…Particularly, brain Ang II (Saavedra 2012) facilitates the stress response whereas other component such as Ang 1-7 or Ang IV, inhibit that reaction (Fontes et al 2016). Th e homeostatic response depends on the analysis of the sensory information by central areas to elaborate a motor response conveyed by the ANS in order to quickly get eff ective control of the target organs.…”

Hepatic Expression of Serum Amyloid A1 Is Induced by Traumatic Brain Injury and Modulated by Telmisartan

“…Expression of this receptor is usually induced in response to stress and inflammation. 35,51 We found mRNA expression of AT1R to be up-regulated in the liver at 3 dpi but not at 6 hpi, compared with expression in naïve control mice (Figure 2). …”