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Glucocorticoid receptor-nitric oxide crosstalk and vulnerability to experimental parkinsonism: pivotal role for glia-neuron interactions

Marchetti, Bianca Maria and Serra, Pier Andrea and Tirolo, Cataldo and L'Episcopo, Francesca and Caniglia, Salvo and Gennuso, Florinda and Testa, Nuccio and Miele, Egidio and Desole, Maria Speranza and Barden, Nicholas and Morale, Maria Concetta (2005) Glucocorticoid receptor-nitric oxide crosstalk and vulnerability to experimental parkinsonism: pivotal role for glia-neuron interactions. Brain Research Reviews, Vol. 48 (2), p. 302-321. ISSN 0165-0173. Article.

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DOI: 10.1016/j.brainresrev.2004.12.030

Abstract

Inflammation and oxidative stress have been closely associated with the pathogenesis of neurodegenerative disorders, including Parkinson's disease (PD). The expression of inducible nitric oxide synthase (iNOS) in astrocytes and microglia and the production of large amounts of nitric oxide (NO) are thought to contribute to dopaminergic neuron demise. Increasing evidence, however, indicates that activated astroglial cells play key roles in neuroprotection and can promote recovery of CNS functions. Endogenous glucocorticoids (GCs) via glucocorticoid receptors (GRs) exert potent anti-inflammatory and immunosuppressive effects and are key players in protecting the brain against stimulation of innate immunity. Here we review our work showing that exposure to a dysfunctional GR from early embryonic life in transgenic (Tg) mice expressing GR antisense RNA represents a key vulnerability factor in the response of nigrostriatal dopaminergic neurons to the neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and further report that exacerbation of dopaminergic neurotoxicity with no recovery is determined by failure of astroglia to exert neuroprotective effects. Aberrant iNOS gene expression and increased glia vulnerability to cell death characterized the response of GR-deficient mice to stimulation of innate immunity. More importantly, GR-deficient glial cells failed to protect fetal dopaminergic neurons against oxidative stress-induces cell death, whereas wild-type glia afforded neuroprotection. Thus, lack of iNOS/NO regulation by GCs can program an aberrant GR–NO crosstalk in turn responsible for loss of astroglia neuroprotective function in response to stimulation of innate immunity, pointing to glia and efficient GR–NO dialogue as pivotal factors orchestrating neuroprotection in experimental parkinsonism.

Item Type:Article
ID Code:1162
Status:Published
Refereed:Yes
Uncontrolled Keywords:Glucocorticoid receptor, neuroinflammation, Parkinson's disease, inducible nitric oxide synthase, neuron-glia interactions, neuroprotection
Subjects:Area 05 - Scienze biologiche > BIO/14 Farmacologia
Divisions:001 Università di Sassari > 01 Dipartimenti > Neuroscienze, scienze materno infantili
Publisher:Elsevier
ISSN:0165-0173
Deposited On:18 Aug 2009 10:04

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