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. In addition we addressed the possibility that reduction of brain inflammation may have behavioral correlates, and, using validated animal models, considered the effects of sartans on anxiety and depression. 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, a human acute monocytic leukemia cell line, and in primary cultures of rat cortical microglia devoid of significant AT1 receptor expression, Our earlier findings that ARBs may limit the exaggerated hormonal and sympathetic response to stress opened a second direction of study. We have initially established that ARBs restrict the stress-induced alterations in cortical gamma-aminobutyric acid (GABAA) function, as determined by cortical benzodiazepine binding. We found, more recently, that ARBs protect GABAA function during inflammatory stress. This finding explains the anti-anxiety and anti-depressant effects of ARBs in our model of inflammatory stress (prevention of LPS-induced sickness behavior, anorexia and weight loss, and reduction of LPS-induced anxiety). We have more recently discovered, in collaborative studies, that ARBs reduce depression and anxiety associated with chronic mild variable stress in a rodent model of genetic vulnerability to depression and anxiety. We have continued to clarify the mechanisms of neuroprotection and prolongation of lifespan produced by life-long sartan administration. We found that long-term sartan administration reduces age-associated brain inflammation, vascular remodeling and anxiety, and that the neuroprotective effects of ARBs persist throughout life. Our findings may, at least in part, explain the major beneficial effects of sartan therapy in Alzheimers disease reported by other groups. 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 continues with mechanistic and translational studies to further clarify the mechanisms of ARB-induced neuroprotection and anti-depressant effects. Our goals are to test our hypothesis of major therapeutic advantages of ARB use in brain disorders,including major depression, Alzheimer's disease and traumatic brain injury, and to establish a more solid base for further development of more effective, ARB-derived neuroprotective and anti-depressant compounds of translational value.

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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
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-? activation in human monocytes. J Hypertens 30:87-96
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
Pang, Tao; Wang, Juan; Benicky, Julius et al. (2012) Minocycline ameliorates LPS-induced inflammation in human monocytes by novel mechanisms including LOX-1, Nur77 and LITAF inhibition. Biochim Biophys Acta 1820:503-10
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
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
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-1? partly through the JNK/c-Jun and NADPH oxidase pathways. J Neuroinflammation 9:102

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