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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U.S. National Institute of Mental Health
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Sanchez-Lemus, Enrique; Benicky, Julius; Pavel, Jaroslav et al. (2009) In vivo Angiotensin II AT1 receptor blockade selectively inhibits LPS-induced innate immune response and ACTH release in rat pituitary gland. Brain Behav Immun 23:945-57
Larrayoz, Ignacio M; Pang, Tao; Benicky, Julius et al. (2009) Candesartan reduces the innate immune response to lipopolysaccharide in human monocytes. J Hypertens 27:2365-76
Tang, Hui; Pavel, Jaroslav; Saavedra, Juan M et al. (2009) Type-1 angiotensin receptors are expressed and transported in motor and sensory axons of rat sciatic nerves. Neuropeptides 43:81-92
Saavedra, Juan M (2009) Opportunities and limitations of genetic analysis of hypertensive rat strains. J Hypertens 27:1129-33
Benicky, Julius; Sanchez-Lemus, Enrique; Pavel, Jaroslav et al. (2009) Anti-inflammatory effects of angiotensin receptor blockers in the brain and the periphery. Cell Mol Neurobiol 29:781-92
Imboden, Hans; Patil, Jaspal; Nussberger, Juerg et al. (2009) Endogenous angiotensinergic system in neurons of rat and human trigeminal ganglia. Regul Pept 154:23-31
Macova, Miroslava; Pavel, Jaroslav; Saavedra, Juan M (2009) A peripherally administered, centrally acting angiotensin II AT2 antagonist selectively increases brain AT1 receptors and decreases brain tyrosine hydroxylase transcription, pituitary vasopressin and ACTH. Brain Res 1250:130-40
Sanchez-Lemus, Enrique; Benicky, Julius; Pavel, Jaroslav et al. (2009) Angiotensin II AT1 blockade reduces the lipopolysaccharide-induced innate immune response in rat spleen. Am J Physiol Regul Integr Comp Physiol 296:R1376-84
Sanchez-Lemus, Enrique; Murakami, Yuki; Larrayoz-Roldan, Ignacio M et al. (2008) Angiotensin II AT1 receptor blockade decreases lipopolysaccharide-induced inflammation in the rat adrenal gland. Endocrinology 149:5177-88
Macova, Miroslava; Armando, Ines; Zhou, Jin et al. (2008) Estrogen reduces aldosterone, upregulates adrenal angiotensin II AT2 receptors and normalizes adrenomedullary Fra-2 in ovariectomized rats. Neuroendocrinology 88:276-86

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