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.

SUMMARYPoor adaptation to stress, alterations in cerebrovascular function and excessive brain inflammation play critical roles in the pathophysiology of many psychiatric and neurological disorders such as major depression, schizophrenia, post traumatic stress disorder, Parkinson's and Alzheimer's diseases and traumatic brain injury. Treatment for these highly prevalent and devastating conditions is at present very limited and many times inefficient, and the search for novel therapeutic options is of major importance. Recently, attention has been focused on the role of a brain regulatory peptide, Angiotensin II, and in the translational value of the blockade of its physiological AT 1 receptors. In addition to its well-known cardiovascular effects, Angiotensin II, through AT 1 receptor stimulation, is a pleiotropic brain modulatory factor involved in the control of the reaction to stress, in the regulation of cerebrovascular flow and the response to inflammation. Excessive brain AT 1 receptor activity is associated with exaggerated sympathetic and hormonal response to stress, vulnerability to cerebrovascular ischemia and brain inflammation, processes leading to neuronal injury. In animal models, inhibition of brain AT 1 receptor activity with systemically administered Angiotensin II receptor blockers is neuroprotective; it reduces exaggerated stress responses and anxiety, prevents stress-induced gastric ulcerations, decreases vulnerability to ischemia and stroke, reverses chronic cerebrovascular inflammation, and reduces acute inflammatory responses produced by bacterial endotoxin. These effects protect neurons from injury and contribute to increase the lifespan. Angiotensin II receptor blockers are compounds with a good margin of safety widely used in the treatment of hypertension and their anti-inflammatory and vascular protective effects contribute to reduce renal and cardiovascular failure. Inhibition of brain AT 1 receptors in humans is also neuroprotective, reducing the incidence of stroke, improving cognition and decreasing the progression of Alzheimer's disease. Blockade of AT 1 receptors offers a novel and safe therapeutic approach for the treatment of illnesses of increasing prevalence and socioeconomic impact, such as mood disorders and neurodegenerative diseases of the brain.

To clarify the mechanism of the effects of angiotensin II AT 1 receptor antagonists on adipose tissue, we treated 8 week-old male Wistar Kyoto rats with the angiotensin II AT 1 receptor antagonist Candesartan cilexetil (10 mg/kg/day) for 18 weeks. Candesartan cilexetil reduced body weight gain, decreased fat tissue mass due to hypotrophy of epididymal and retroperitoneal adipose tissue and decreased adipocyte size without changing the number of adipocytes. Candesartan cilexetil decreased serum leptin levels and epididymal leptin mRNA, increased serum adiponectin levels and epididymal adiponectin mRNA, decreased epididymal tumor-necrosis factor alpha (TNFα) mRNA, and increased fatty acid synthase mRNA. Considered free of peroxisome proliferator-activated receptor γ (PPARγ) agonist activity, Candesartan cilexetil increased epididymal expression of PPARγ mRNA. The effects of Candesartan cilexetil on adipokine production and release may be attributable to PPARγ activation and/or decrease in adipocyte cell size. In addition, Candesartan cilexetil treatment increased the expression of epididymal angiotensin II AT 2 receptor mRNA and protein and decreased the expression of renin receptor mRNA. These results suggest that Candesartan cilexetil influences lipid metabolism in adipose tissue by promoting adipose tissue rearrangement and modulating adipokine expression and release. These effects are probably consequences of local angiotensin II AT 1 receptor inhibition, angiotensin II AT 2 receptor stimulation, and perhaps additional angiotensin II -independent mechanisms. Our results indicate that the activity of local renin-angiotensin system plays an important role in adipose tissue metabolism The decrease in the pro-inflammatory cytokine TNFα and the increase in the anti-inflammatory adipokine adiponectin indicate that Candesartan cilexetil may exert significant anti-inflammatory properties.