Pathologic role of glial nitric oxide in adult and pediatric neuroinflammatory diseases

Article ID	Journal	Published Year	Pages	File Type
7303970	Neuroscience & Biobehavioral Reviews	2014	15 Pages	PDF

Abstract

It is well established that glial cells have critical roles in the inflammatory processes in the central nervous system (CNS). These cells can be activated by a variety of endogenous and exogenous stimuli (i.e. gliosis) and can produce high levels of bioactive compounds that are noxious for neuronal cell function. One of the most important molecules released by activated glial cells is the bioactive free radical nitric oxide (NO). Although NO physiologically acts as both neuromodulator and neurotransmitter in the brain, excess production of NO by glial cells has diverse harmful effects on neuronal function, causing neuronal cell injury/death. The production of NO is induced by overexpression of the inducible isoform of NO synthase (iNOS) enzyme in glial cells. In this review, we describe the possible mechanisms that underlie the iNOS-mediated overproduction of glial NO in several pediatric and adult neuropathologic conditions such as periventricular leukomalacia (PVL), Krabbe's disease, X-linked adrenoleukodystrophy (ALD) and multiple sclerosis (MS). We specifically discuss various signaling cascades that activate several transcription factors involved in the iNOS expression in both astrocytes and microglia. We also discuss the consequences of iNOS-mediated NO production in neuroinflammatory diseases including MS. A complete understanding of the regulation of iNOS expression in glial cells and the mechanisms by which iNOS-mediated NO production is involved in neuroinflammation can provide new insights into the identification of novel targets for therapeutic intervention in NO-mediated neurologic diseases.

Keywords

NF-κB LPS COX Jnk MYD88 MBP VLCFA NADPH MAL ERK CRS DEP iNOS PGE2 RNS PPAR eNOS IκB EAE MPTP JAK2 NMDA N-methyl-d-aspartate nNOS AP-1 TLR PKC NMDAR IKK cyclo-oxygenase-2 PARP GSK-3 SAHA SOCS VCAM-1 VLA-4 M-CSF CD154 ISRE Janus Kinase 2 cNOS NG-nitro-l-arginine methyl ester MMP3 IRF-1 nuclear factor κ-light-chain-enhancer of activated B cells X-linked adrenoleukodystrophy ATF-2 ALDP Adrenoleukodystrophy protein L-N6-(1-iminoethyl)-lysine Janus kinase 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine C/EBP Ca2+IκB kinase l-NAME l-NIL MAPK NMDA receptor inducible NO synthase O2−PTpase PTIO Small interfering RNA ROS siRNA ALD Astrocyte experimental allergic encephalomyelitis amyotrophic lateral sclerosis Suberoylanilide hydroxamic acid Very-long-chain fatty acid Neuroinflammation Oligodendrocyte interleukin Alzheimer's disease ALS Huntington's disease Parkinson's disease Neurodegeneration tumor necrosis factor-α TIR Toll-like receptor very late antigen-4 CNS Diesel exhaust particles BBB Blood–brain barrier suppressors of cytokine signaling endothelial nitric oxide synthase neuronal nitric oxide synthase Inducible nitric oxide synthase (iNOS)constitutive nitric oxide synthase Superoxide central nervous system IRAK macrophage colony stimulating factor interferon regulatory factor-1 TNF-α activating transcription factor 2 Periventricular leukomalacia lipopolysaccharide CD40 ligand Matrix metalloproteinase 3 Cerebrospinal fluid CSF PVL inhibitor of NF-κB Multiple sclerosis Vascular cell adhesion molecule 1 Microglia Nitric oxide Nitric oxide (NO)nicotinamide adenine dinucleotide phosphate Src Homology 2 histone acetyl-transferase HIV human immunodeficiency virus myeloid differentiation primary response gene 88 CCAAT/enhancer-binding protein protein tyrosine phosphatases activator protein-1 Myelin basic protein Protein kinase C Prostaglandin E2 Poly(ADP-ribose) polymerase HAT Calcium IL-1 receptor-associated kinase extracellular signal-regulated kinases mitogen-activated protein kinases Gas glycogen synthase kinase-3 reactive nitrogen species Reactive oxygen species Toll/interleukin-1 receptor peroxisome proliferator-activated receptor Cytokine receptors