Chapter 18 Expression of nitric oxide synthase-2 in glia associated with CNS pathology

Loihl, Angela K.; Murphy, Seán

doi:10.1016/s0079-6123(08)63213-6

Cited by 53 publications

(36 citation statements)

References 119 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This regulation of NOS-2 by NO explains why NOS inhibitors cause an accumulation of NOS-2 mRNA (Luss et al, 1994), and points to a potential problem with the therapeutic use of NOS-2 inhibitors namely, a rebound of expression and therefore NO production upon inhibitor withdrawal. In the CNS, this negative feedback by NO could contribute to the very discrete expression of NOS-2 that is observed in various neuropathologies (Loihl and Murphy, 1998). It has also been reported that NO from constitutive NOS-1 tonically suppresses the NOS-2 gene (Togashi et al, 1997).…”

Section: Nos-2 Gene Suppressorsmentioning

confidence: 97%

Production of nitric oxide by glial cells: Regulation and potential roles in the CNS

Murphy

2000

Glia

Self Cite

294

203

View full text Add to dashboard Cite

Roles proposed for nitric oxide (NO) in CNS pathophysiology are increasingly diverse and range from intercellular signaling, through necrotic killing of cells and invading pathogens, to the involvement of NO in apoptosis and tissue remodeling. In vitro evidence and observations from experimental animal models of a variety of human neuropathologies, including stroke, indicate that glial cells can produce NO. Regulation of at least one of the NO synthase genes (NOS‐2) in glia has been well described; however, apart from hints emerging out of co‐culture studies and extrapolation based upon the reactivity of NO, we are a long way from identifying functions for glial‐derived NO in the CNS. Although the assumption is that NO is very often cytotoxic, it is evident that NO production does not always equate with tissue damage, and that both the cellular source of NO and the timing of NO production are important factors in terms of its effects. With the development of strategies to transfer or manipulate expression of the NOS genes in specific cells in situ, the ability to deliver NO into the CNS via long‐lived chemical donors, and the emergence of more selective NOS inhibitors, an appreciation of the significance of glial‐derived NO will change. GLIA 29:1–13, 2000. © 2000 Wiley‐Liss, Inc.

show abstract

Section: Nos-2 Gene Suppressorsmentioning

confidence: 97%

Production of nitric oxide by glial cells: Regulation and potential roles in the CNS

Murphy

2000

Glia

Self Cite

294

203

View full text Add to dashboard Cite

show abstract

“…However, astrocytes are not only a source of trophic factors (NGF, bFGF), but also proinflammatory cytokines (IL-1 , IL-6) and cytotoxic cytokines (Fas L, TNF-, TGF-) [80][81][82][83]. Activated astrocytes also produce toxic molecules such as reactive oxygen species and NO [84][85][86].…”

Section: The Role Of Microglia Activation and Reactive Gliosis In Iscmentioning

confidence: 99%

Molecular mechanisms of neuroprotective action of immunosuppressants ‐ facts and hypotheses

Kamińska

Gawęda-Walerych

Zawadzka

2004

J Cellular Molecular Medi

112

View full text Add to dashboard Cite

Cyclosporin A (CsA) and FK506 (Tacrolimus) are short polypeptides which block the activation of lymphocytes and other immune system cells. Immunosuppressants exert neuroprotective and neurotrophic action in traumatic brain injury, sciatic nerve injury, focal and global ischemia in animals. Their neuroprotective actions are not understood and many hypotheses have been formed to explain such effects. We discuss a role of drug target -calcineurin in neuroprotective action of immunosuppressants. Protein dephosphorylation by calcineurin plays an important role in neuronal signal transduction due to its ability to regulate the activity of ion channels, glutamate release, and synaptic plasticity. In vitro FK506 protects cortex neurons from NMDA-induced death, augments NOS phosphorylation inhibiting its activity and NO synthesis. However, in vivo experiments demonstrated that FK506 in neuroprotective doses did not block excitotoxic cell death nor did it alter NO production during ischemia/reperfusion. Tissue damage in ischemia is the result of a complex pathophysiological cascade, which comprises a variety of distinct pathological events. Resident non-neuronal brain cells respond rapidly to neuronal cell death and may have both deleterious and useful role in neuronal damage. There is increasing evidence that reactive gliosis and post-ischemic inflammation involving microglia contribute to ischemic damage. We have demonstrated that FK506 modulates hypertrophic/proliferative responses and proinflammatory cytokine expression in astrocytes and microglia in vitro and in focal transient brain ischemia. Our findings suggest that astrocytes and microglia are direct targets of FK506 and modulation of glial response and inflammation is a possible mechanism of FK506-mediated neuroprotection in ischemia.

show abstract

“…The residual expression of the disrupted gene challenges the idea that proximal promoter sequences are obligatory for induction. These mice provide a unique opportunity to study the molecular and physiological effects of both a truncated NOS-2 promoter and protein in intact animals following neurodegeneration, trauma, and viral infection, conditions in which the NO from NOS-2 is proposed to play a role (7).…”

Section: Fig 6 Expression Of Markers Of Ischemic Inflammation Inmentioning

confidence: 99%

“…The relatively large amount of NO that can be synthesized by NOS-2 over a sustained period has been implicated in diverse functions associated with inflammation and injury (6). Expression of NOS-2 in the central nervous system has been associated with viral, parasitic, and bacterial infections; in multiple sclerosis and neurodegenerative diseases; and in trauma and ischemia (7). Given the potential involvement of NOS-2 in such pathologies, a clear understanding of the mechanisms of NOS-2 gene regulation in vivo is important.…”

mentioning

confidence: 99%

Transcriptional Activation following Cerebral Ischemia in Mice of a Promoter-deleted Nitric Oxide Synthase-2 Gene

Loihl

Whalen

Campbell

et al. 1999

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Nitric oxide synthase (NOS)-2 is transcriptionally activated in a wide variety of injurious conditions, including cerebral ischemia, and the resulting nitric oxide is implicated both in tissue damage and recovery. Studies in vitro suggest that the proximal region of the NOS-2 promoter is obligatory for gene activation by proinflammatory cytokines. However, following cerebral ischemia in a NOS-2 gene-deficient mouse in which this region and exons 1-4 have been deleted, we find temporal and spatial expression, identical to wild-type, from a previously unidentified promoter region. The resulting protein is predicted to lack the first 113 amino acids and is NOS-2-incompetent. Fortuitously, this gene-deficient mouse presents a unique opportunity to determine more about the mechanisms of NOS-2 gene regulation in vivo.

show abstract

Chapter 18 Expression of nitric oxide synthase-2 in glia associated with CNS pathology

Cited by 53 publications

References 119 publications

Production of nitric oxide by glial cells: Regulation and potential roles in the CNS

Production of nitric oxide by glial cells: Regulation and potential roles in the CNS

Molecular mechanisms of neuroprotective action of immunosuppressants ‐ facts and hypotheses

Transcriptional Activation following Cerebral Ischemia in Mice of a Promoter-deleted Nitric Oxide Synthase-2 Gene

Contact Info

Product

Resources

About