Roles proposed for nitric oxide (NO) in the CNS are increasingly diverse and range from intercellular signalling, through the killing of cells and invading pathogens, to the involvement of NO in programmed cell death and tissue remodelling. In experimental animal models of a variety of human neurophathologies, including stroke, there is evidence for upregulation of the genes coding for the three isoforms of NO synthase (NOS). In some of these neuropathologies it is clear that NO from a specific NOS isoform, expressed in a particular cell type, can contribute to damage. As a result there is increasing interest in deriving NOS isoform-selective inhibitors as potential therapeutic agents. On the other hand, in specific CNS pathologies NO has properties predicted to be beneficial and, therefore, determining and apportioning its role is and imperative. The long-term objective of this program is to determine how the NOS-2 gene is regulated in the CNS and roles for the resulting NO in pathophysiology. The immediate foal is to examine NOS-2 expression following transient and permanent meddle cerebral artery occlusion, models of focal ischemia in which pathological outcomes mirror the cognitive and sensorimotor deficits seen in humans following stroke. Using wildtype mice and NOS-2 gene-deficient littermates, hypotheses will be tested concerning the roles of cytokines and steroids in the regulation of NOS-2 expression, and the contribution of the resulting NO to pathological outcome Specifically, to identify (1) activators and (2) suppressors of the NOS-2 gene following ischemia, and then observe the effects on ischemic pathology of manipulating these proteins. Currently, there is no suitable drug to provide neuroprotection after human stroke. These studies will not only reveal roles for NO in the onset and recovery from damage following ischemia but may also provide the basis for novel and rational therapeutics.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS029226-09
Application #
6529539
Study Section
Special Emphasis Panel (ZRG1-BDCN-3 (01))
Program Officer
Behar, Toby
Project Start
2001-08-01
Project End
2004-07-31
Budget Start
2002-08-01
Budget End
2003-07-31
Support Year
9
Fiscal Year
2002
Total Cost
$150,000
Indirect Cost
Name
University of Nottingham
Department
Type
DUNS #
City
Nottingham
State
Country
United Kingdom
Zip Code
NG7 2-RD
Gibson, Claire L; Bath, Philip M W; Murphy, Sean P (2010) G-CSF administration is neuroprotective following transient cerebral ischemia even in the absence of a functional NOS-2 gene. J Cereb Blood Flow Metab 30:739-43
Coughlan, Teresa; Gibson, Claire; Murphy, Sean (2009) Progesterone, BDNF and neuroprotection in the injured CNS. Int J Neurosci 119:1718-40
Gibson, Claire L; Gray, Laura J; Bath, Philip M W et al. (2008) Progesterone for the treatment of experimental brain injury;a systematic review. Brain 131:318-28
Gibson, Claire L; Gray, Laura J; Murphy, Sean P et al. (2006) Estrogens and experimental ischemic stroke: a systematic review. J Cereb Blood Flow Metab 26:1103-13
Constantinescu, Cris S; Tani, Marie; Ransohoff, Richard M et al. (2005) Astrocytes as antigen-presenting cells: expression of IL-12/IL-23. J Neurochem 95:331-40
Coughlan, Teresa; Gibson, Claire; Murphy, Sean (2005) Modulatory effects of progesterone on inducible nitric oxide synthase expression in vivo and in vitro. J Neurochem 93:932-42
Gibson, Claire L; Constantin, Despina; Prior, Malcolm J W et al. (2005) Progesterone suppresses the inflammatory response and nitric oxide synthase-2 expression following cerebral ischemia. Exp Neurol 193:522-30
Willmot, Mark; Gray, Laura; Gibson, Claire et al. (2005) A systematic review of nitric oxide donors and L-arginine in experimental stroke; effects on infarct size and cerebral blood flow. Nitric Oxide 12:141-9
Gibson, Claire L; Bath, Philip M W; Murphy, Sean P (2005) G-CSF reduces infarct volume and improves functional outcome after transient focal cerebral ischemia in mice. J Cereb Blood Flow Metab 25:431-9
Willmot, Mark; Gibson, Claire; Gray, Laura et al. (2005) Nitric oxide synthase inhibitors in experimental ischemic stroke and their effects on infarct size and cerebral blood flow: a systematic review. Free Radic Biol Med 39:412-25

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