title: Angiotensin II AT1 receptor blockade ameliorates brain inflammation.
abstract: Brain inflammation has 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 AT(1) receptor blocker (ARB) candesartan to normotensive rats decreases the acute brain inflammatory response to administration of the bacterial endotoxin lipopolysaccharide (LPS), 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 proinflammatory cytokines, repression of nuclear transcription factors activation in the brain, reduction of gene expression of brain proinflammatory cytokines, cytokine and prostanoid receptors, adhesion molecules, proinflammatory inducible enzymes, and reduced microglia activation. These effects are widespread, occurring not only in well-known brain target areas for circulating proinflammatory factors and LPS, that is, 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. ARBs 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.
authors.affiliation: Section on Pharmacology, Division of Intramural Research Programs, Department of Health and Human Services, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA. benickyj@mail.nih.gov
authors.forename: Julius
authors.initials: J
authors.lastname: Benicky
authors.forename: Enrique
authors.initials: E
authors.lastname: Sánchez-Lemus
authors.forename: Masaru
authors.initials: M
authors.lastname: Honda
authors.forename: Tao
authors.initials: T
authors.lastname: Pang
authors.forename: Martina
authors.initials: M
authors.lastname: Orecna
authors.forename: Juan
authors.initials: J
authors.lastname: Wang
authors.forename: Yan
authors.initials: Y
authors.lastname: Leng
authors.forename: De-Maw
authors.initials: DM
authors.lastname: Chuang
authors.forename: Juan M
authors.initials: JM
authors.lastname: Saavedra
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use*; D000818:Animals; D000831:Animals, Newborn; D001562:Benzimidazoles / Q000008:administration & dosage / Q000494:pharmacology; D001713:Biphenyl Compounds; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D007249:Inflammation / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000633:toxicity; D008297:Male; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D013777:Tetrazoles / Q000008:administration & dosage / Q000494:pharmacology
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D008070:Lipopolysaccharides; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; C081643:candesartan