Our first specific aim is to clarify the mechanisms involved in the beneficial effects of compounds which have not, until very recently, been considered of interest to the therapy of brain disorders. The second specific aim is to further establish the extent of therapeutic benefits of such compounds in diseases of the brain. We study a group of compounds collectively named sartans, or Angiotensin II AT1 receptor blockers (ARBs). Sartans are biphenyl derivatives with an excellent margin of safety, extensively used to treat cardiovascular and metabolic disorders because they antagonize Angiotensin II-induced vasoconstriction and pathological cellular growth and fibrosis, because they reduce peripheral inflammation and because they improve insulin sensitivity. Following our initial finding that sartans decrease hypertension-induced cerebrovascular inflammation, we later discovered that sartan treatment reduces brain ischemia, stress, and anxiety, and increases lifespan in rodent models. More recently, we established that the beneficial effects of sartans include a major amelioration of the negative effects of peripheral inflammation in the brain. Our conclusion was that several mechanisms may be responsible for the major neuroprotective effects of ARB treatment, and we continued studies to further clarify such mechanisms. During the current fiscal year, we advanced on the clarification of the anti-inflammatory effects of sartans in the brain. We hypothesized that at least part of the central anti-inflammatory and neuroprotective effects were the consequence of direct actions of ARBs on brain cells. The anti-inflammatory and neuroprotective effects of sartans (decline in inflammation-induced activation of the transcription factors nuclear factor kappa-light-chain-enhancer of activated B cells (NFkappaBalpha) and activator protein-1 (AP-1), expression of inducible nitric oxide synthase, cyclooxygenase-2 and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, reduction in the production of excess nitric oxide, prostaglandin E2, and reactive oxygen species leading to brain inflammation and neuronal injury) are widespread in the brain parenchyma. This suggested that sartans may influence multiple brain cell types. Using microglia, primary cortical neuron, primary cerebellar granule cell, and cerebral microvascular endothelial cell cultures, we discovered that ARBs ameliorate inflammation in all cell types studied. ARB neuroprotective effects were demonstrated against the bacterial endotoxin lipopolysaccharide (LPS), against excess glutamate and against the pro-inflammatory cytokine IL-1beta. Mechanisms involved include decreased activation of several protein kinases and reduced activation of the transcription factor NFkappaBalpha. We hypothesized that the major anti-inflammatory and neuroprotective effects of sartans may not be the exclusive result of AT1 receptor inhibition. In human circulating monocytes, cells expressing very few AT1 receptors, the anti-inflammatory effects of sartans were partially dependent on peroxisome proliferator-activated receptor gamma (PPARgamma) activation. We have found that some sartans may have dual mechanisms of action: anti-hypertensive, anti-growth and anti-inflammatory effects related to their inhibition of AT1 receptors, and metabolic and anti-inflammatory effects, partially the consequence of direct PPARgamma activation. We now confirm that participation of PPARgamma activation as a major component of ARB effects in THP-1 cells, in primary cultures of rat cortical microglia devoid of significant AT1 receptor expression, and in cerebellar granule cells from AT1A receptor knock-out mice. These results suggest that part of the beneficial effects of sartans are due to mechanisms independent of AT1 receptor stimulation. An additional novel finding is that ARB administration in a rodent model significantly protects the brain from traumatic brain injury. ARBs decrease lesion size, reduce neuronal injury and protect neurological function in this model. This is the first demonstration of the neuroprotective effect of ARBs in traumatic brain injury. Our work will not continue because the Section on Pharmacology was closed June 1st, 2013.

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Project End
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Budget End
Support Year
17
Fiscal Year
2013
Total Cost
$494,684
Indirect Cost
Name
U.S. National Institute of Mental Health
Department
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Hafko, Roman; Villapol, Sonia; Nostramo, Regina et al. (2013) Commercially available angiotensin II Atâ‚‚ receptor antibodies are nonspecific. PLoS One 8:e69234
Sánchez-Lemus, Enrique; Honda, Masaru; Saavedra, Juan M (2012) Angiotensin II AT1 receptor blocker candesartan prevents the fast up-regulation of cerebrocortical benzodiazepine-1 receptors induced by acute inflammatory and restraint stress. Behav Brain Res 232:84-92
Saavedra, Juan M (2012) Angiotensin II AT(1) receptor blockers as treatments for inflammatory brain disorders. Clin Sci (Lond) 123:567-90
Benicky, Julius; Hafko, Roman; Sanchez-Lemus, Enrique et al. (2012) Six commercially available angiotensin II AT1 receptor antibodies are non-specific. Cell Mol Neurobiol 32:1353-65
Saavedra, Juan M (2012) Angiotensin II AT(1) receptor blockers ameliorate inflammatory stress: a beneficial effect for the treatment of brain disorders. Cell Mol Neurobiol 32:667-81
Pang, Tao; Wang, Juan; Benicky, Julius et al. (2012) Telmisartan directly ameliorates the neuronal inflammatory response to IL-1β partly through the JNK/c-Jun and NADPH oxidase pathways. J Neuroinflammation 9:102
Chen, J; Evans, A N; Liu, Y et al. (2012) Maternal deprivation in rats is associated with corticotrophin-releasing hormone (CRH) promoter hypomethylation and enhances CRH transcriptional responses to stress in adulthood. J Neuroendocrinol 24:1055-64
Pang, Tao; Benicky, Julius; Wang, Juan et al. (2012) Telmisartan ameliorates lipopolysaccharide-induced innate immune response through peroxisome proliferator-activated receptor-γ activation in human monocytes. J Hypertens 30:87-96
Nostramo, Regina; Tillinger, Andrej; Saavedra, Juan M et al. (2012) Regulation of angiotensin II type 2 receptor gene expression in the adrenal medulla by acute and repeated immobilization stress. J Endocrinol 215:291-301
Villapol, Sonia; Yaszemski, Alexandra K; Logan, Trevor T et al. (2012) Candesartan, an angiotensin II ATýýý-receptor blocker and PPAR-ýý agonist, reduces lesion volume and improves motor and memory function after traumatic brain injury in mice. Neuropsychopharmacology 37:2817-29

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