Angiotensin II AT1 Receptor Blockade Ameliorates Brain Inflammation

Abstract

Brain inflammation plays a critical role in the pathophysiology of brain diseases of high prevalence and economic impact, such as major depression, schizophrenia, post traumatic stress disorder, Parkinson’s and Alzheimer’s disease and traumatic brain injury. Our results demonstrate that systemic administration of the centrally acting Angiotensin II AT1 receptor blocker candesartan to normotensive rats decreases the acute brain inflammatory response to administration of the bacterial endotoxin lipopolysaccharide, a model of brain inflammation. The broad anti-inflammatory effects of candesartan were seen across the entire inflammatory cascade, including decreased production and release to the circulation of centrally acting pro-inflammatory cytokines, repression of nuclear transcription factors activation in the brain, reduction of gene expression of brain pro-inflammatory cytokines, cytokine and prostanoid receptors, adhesion molecules, pro-inflammatory inducible enzymes, and reduced microglia activation. These effects are widespread, occurring not only in well-known brain target areas for circulating pro-inflammatory factors and lipopolysaccharide, i.e. hypothalamic paraventricular nucleus and the subfornical organ, but also in the prefrontal cortex, hippocampus and amygdala. Candesartan reduced the associated anorexic effects, and ameliorated associated body weight loss and anxiety. Direct anti-inflammatory effects of candesartan were also documented in cultured rat microglia, cerebellar granule cells and cerebral microvascular endothelial cells. AT1 receptor blockers are widely used in the treatment of hypertension and stroke, and their anti-inflammatory effects contribute to reduce renal and cardiac failure. Our results indicate that these compounds may offer a novel and safe therapeutic approach for the treatment of brain disorders.

Differential effect of angiotensin II and blood pressure on hippocampal inflammation in mice

“…Beyond our study, a critical role for Ang II on cerebral inflammation is supported by a previous work showing that inhibition of AT1 receptors with candesartan, a centrally acting angiotensin receptor blocker, leads to reductions in brain inflammation induced by LPS or stroke in normotensive rats [36,37]. At the same time, our results on blood pressure complement the findings of Marvar and colleagues who used a similar approach with hydralazine to demonstrate that the pressor effects of Ang II are critical for the activation of circulating T lymphocytes and the expression of vascular inflammation in mice [31].…”

Angiotensin II Peptide Vaccine Protects Ischemic Brain Through Reducing Oxidative Stress

“…These might be supported by the previous reports showing the neuroprotective and antioxidative stress effects of ARBs in the cultured neurons. [33][34][35] Another possible mechanism of protective effects of vaccination is the inhibitory effect on calpain and caspase activities because the fragmentation of spectrins, cleaved forms from full spectrin (240 kDa) by caspase-3 and calpain, was significantly reduced. Ang II increased the intracellular Ca 2+ , 36 and Ang II may have directly regulated the calpain activity in the brain, as reported in other types of tissues, such as aorta, 37 kidney, 38 and cardiomyocyte.…”

Inflammation in Fear- and Anxiety-Based Disorders: PTSD, GAD, and Beyond

“…ACE-I/ARBs are typically prescribed to decrease blood pressure and sympathetic activity (Savoia and Schiffrin, 2007). However, these agents are also capable of reducing neuroinflammation (Benicky et al, 2011;Welty et al, 2015), as angiotensin-II activity increases CRP and IL-6 release (Sano et al, 2001;Zhao et al, 2013). The promise of using ACE-I/ARBs to alleviate PTSD symptoms in traumatized individuals is highlighted by evidence indicating that traumatized individuals using ACE-I/ARB medication have decreased odds of PTSD diagnosis and fewer PTSD symptoms compared with traumatized individuals not taking these medications (Khoury et al, 2012).…”