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Current Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

Review Article

Cross-Talk Between NO Synthase Isoforms in Neuro-Inflammation: Possible Implications in HIV-Associated Neurocognitive Disorders

Author(s): Tiziana Persichini, Sofia Mariotto, Hisanori Suzuki, Elena Butturini, Roberta Mastrantonio, Orazio Cantoni and Marco Colasanti

Volume 23 , Issue 24 , 2016

Page: [2706 - 2714] Pages: 9

DOI: 10.2174/0929867323666160809100452

Price: $65

Abstract

Inducible nitric oxide synthase (iNOS) is expressed in several cell types, particularly in inflammatory cells, in response to diverse proinflammatory stimuli, including viral proteins as HIV Tat and gp120. This response is preceded by an early decline in basal nitric oxide (NO) levels, dependent on a signaling leading to inhibition of the constitutive isoform of NO synthase (cNOS). This process requires critical levels of arachidonic acid (AA), generated by Ca2+-dependent activation of cytosolic phospholipase A2, and is mediated by the downstream tyrosine kinase-dependent phosphorylation of cNOS. Lowering basal NO levels are necessary for the activation of nuclear factor-κB, and thus for the expression of a variety of genes regulated by this transcription factor, which include iNOS. Notably, NO and AA, two small lipid soluble molecules, can trigger the above responses also in distal cells. Thus, AA produced at the very early stages of the inflammatory response is a likely critical signal switching the regulation of the “NO tone” from physiological (i.e., mediated by cNOS) to pathological (i.e., mediated by iNOS). This later phase of the inflammatory response is often accompanied by the onset of deleterious effects in the tissue, in which a critical role is played by iNOS-derived NO (directly or indirectly, i.e., via formation of peroxynitrite) as well as by products of the AA cascade. In this review, the authors discuss the implications of the crosstalk between the NOS isoforms in HIV-associated neuro-pathogenesis highlighting the role of NO and AA as mediators of cytotoxicity.

Keywords: Arachidonic acid, astrocytes, constitutive NOS, cytosolic phospholipase A2, nitric oxide, HAND, HIV, inducible NOS.


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