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      Telmisartan directly ameliorates the neuronal inflammatory response to IL-1β partly through the JNK/c-Jun and NADPH oxidase pathways

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          Abstract

          Background

          Blockade of angiotensin II type 1 (AT 1) receptors ameliorates brain inflammation, and reduces excessive brain interleukin-1 beta (IL-1β) production and release from cortical microglia. The aim of this study was to determine whether, in addition, AT 1 receptor blockade directly attenuates IL-1β-induced inflammatory responses in neuronal cultures.

          Methods

          SK-N-SH human neuroblasts and primary rat cortical neurons were pretreated with telmisartan followed by exposure to IL-1β. Gene expression was determined by reverse transcriptase (RT)-PCR, protein expression and kinase activation by western blotting, NADPH oxidase activity by the lucigenin method, prostaglandin E 2 (PGE 2) release by enzyme immunoassay, reactive oxygen species (ROS) generation by the dichlorodihydrofluorescein diacetate fluorescent probe assay, and peroxisome proliferator-activated receptor gamma (PPARγ) involvement was assessed with the antagonists GW9662 and T0070907, the agonist pioglitazone and the expression of PPARγ target genes ABCG1 and CD36.

          Results

          We found that SK-N-SH neuroblasts expressed AT 1 but not AT 2 receptor mRNA. Telmisartan reduced IL-1β-induced cyclooxygenase-2 (COX-2) expression and PGE 2 release more potently than did candesartan and losartan. Telmisartan reduced the IL-1β-induced increase in IL-1R1 receptor and NADPH oxidase-4 (NOX-4) mRNA expression, NADPH oxidase activity, and ROS generation, and reduced hydrogen peroxide-induced COX-2 gene expression. Telmisartan did not modify IL-1β-induced ERK1/2 and p38 mitogen-activated protein kinase (MAPK) phosphorylation or nuclear factor-κB activation but significantly decreased IL-1β-induced c-Jun N-terminal kinase (JNK) and c-Jun activation. The JNK inhibitor SP600125 decreased IL-1β-induced PGE 2 release with a potency similar to that of telmisartan. The PPARγ agonist pioglitazone reduced IL-1β-induced inflammatory reaction, whereas telmisartan did not activate PPARγ, as shown by its failure to enhance the expression of the PPARγ target genes ABCG1 and CD36, and the inability of the PPARγ antagonists GW9662 and T0070907 to modify the effect of telmisartan on COX-2 induction. The effect of telmisartan on IL-1β-stimulated COX-2 and IL-1R1 mRNA expression and ROS production was replicated in primary rat cortical neurons.

          Conclusions

          Telmisartan directly ameliorates IL-1β-induced neuronal inflammatory response by inhibition of oxidative stress and the JNK/c-Jun pathway. Our results support the hypothesis that AT 1 receptor blockers are directly neuroprotective, and should be considered for the treatment of inflammatory conditions of the brain.

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          Most cited references63

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          International union of pharmacology. XXIII. The angiotensin II receptors.

          The cardiovascular and other actions of angiotensin II (Ang II) are mediated by AT(1) and AT(2) receptors, which are seven transmembrane glycoproteins with 30% sequence similarity. Most species express a single autosomal AT(1) gene, but two related AT(1A) and AT(1B) receptor genes are expressed in rodents. AT(1) receptors are predominantly coupled to G(q/11), and signal through phospholipases A, C, D, inositol phosphates, calcium channels, and a variety of serine/threonine and tyrosine kinases. Many AT(1)-induced growth responses are mediated by transactivation of growth factor receptors. The receptor binding sites for agonist and nonpeptide antagonist ligands have been defined. The latter compounds are as effective as angiotensin converting enzyme inhibitors in cardiovascular diseases but are better tolerated. The AT(2) receptor is expressed at high density during fetal development. It is much less abundant in adult tissues and is up-regulated in pathological conditions. Its signaling pathways include serine and tyrosine phosphatases, phospholipase A(2), nitric oxide, and cyclic guanosine monophosphate. The AT(2) receptor counteracts several of the growth responses initiated by the AT(1) and growth factor receptors. The AT(4) receptor specifically binds Ang IV (Ang 3-8), and is located in brain and kidney. Its signaling mechanisms are unknown, but it influences local blood flow and is associated with cognitive processes and sensory and motor functions. Although AT(1) receptors mediate most of the known actions of Ang II, the AT(2) receptor contributes to the regulation of blood pressure and renal function. The development of specific nonpeptide receptor antagonists has led to major advances in the physiology, pharmacology, and therapy of the renin-angiotensin system.
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            Inflammatory neurodegeneration and mechanisms of microglial killing of neurons.

            Inflammatory neurodegeneration contributes to a wide variety of brain pathologies. A number of mechanisms by which inflammatory-activated microglia and astrocytes kill neurons have been identified in culture. These include: (1) acute activation of the phagocyte NADPH oxidase (PHOX) found in microglia, (2) expression of the inducible nitric oxide synthase (iNOS) in glia, and (3) microglial phagocytosis of neurons. Activation of PHOX (by cytokines, beta-amyloid, prion protein, lipopolysaccharide, ATP, or arachidonate) causes microglial proliferation and inflammatory activation; thus, PHOX is a key regulator of inflammation. However, activation of PHOX alone causes little or no death, but when combined with iNOS expression results in apparent apoptosis via peroxynitrite production. Nitric oxide (NO) from iNOS expression also strongly synergizes with hypoxia to induce neuronal death because NO inhibits cytochrome oxidase in competition with oxygen, resulting in glutamate release and excitotoxicity. Finally, microglial phagocytosis of these stressed neurons may contribute to their loss.
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              Identification of telmisartan as a unique angiotensin II receptor antagonist with selective PPARgamma-modulating activity.

              The metabolic syndrome is a common precursor of cardiovascular disease and type 2 diabetes that is characterized by the clustering of insulin resistance, dyslipidemia, and increased blood pressure. In humans, mutations in the peroxisome proliferator-activated receptor-gamma (PPARgamma) have been reported to cause the full-blown metabolic syndrome, and drugs that activate PPARgamma have proven to be effective agents for the prevention and treatment of insulin resistance and type 2 diabetes. Here we report that telmisartan, a structurally unique angiotensin II receptor antagonist used for the treatment of hypertension, can function as a partial agonist of PPARgamma; influence the expression of PPARgamma target genes involved in carbohydrate and lipid metabolism; and reduce glucose, insulin, and triglyceride levels in rats fed a high-fat, high-carbohydrate diet. None of the other commercially available angiotensin II receptor antagonists appeared to activate PPARgamma when tested at concentrations typically achieved in plasma with conventional oral dosing. In contrast to ordinary antihypertensive and antidiabetic agents, molecules that can simultaneously block the angiotensin II receptor and activate PPARgamma have the potential to treat both hemodynamic and biochemical features of the metabolic syndrome and could provide unique opportunities for the prevention and treatment of diabetes and cardiovascular disease in high-risk populations.
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                Author and article information

                Journal
                J Neuroinflammation
                J Neuroinflammation
                Journal of Neuroinflammation
                BioMed Central
                1742-2094
                2012
                29 May 2012
                : 9
                : 102
                Affiliations
                [1 ]Division of Intramural Research Programs, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Section on Pharmacology, NIMH, NIH, DHHS, 10 Center Drive, Bldg. 10, Room # 2D-57, Bethesda, MD, 20892, USA
                Article
                1742-2094-9-102
                10.1186/1742-2094-9-102
                3410820
                22642771
                f9ad939c-90b7-4706-9b67-13d59894bf9e
                Copyright ©2012 Pang et al.; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 14 December 2011
                : 29 May 2012
                Categories
                Research

                Neurosciences
                sk-n-sh neuroblasts,angiotensin ii at1 receptor blockers,cortical neurons,pge2 release,neuronal inflammation,oxidative stress,neuroprotection,il-1β neurotoxicity,cox-2,jnk activation

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