TY - JOUR
T1 - Glucocorticoid receptor-nitric oxide crosstalk and vulnerability to experimental parkinsonism
T2 - Pivotal role for glia-neuron interactions
AU - Marchetti, Bianca
AU - Serra, Pier Andrea
AU - Tirolo, Cataldo
AU - L'Episcopo, Francesca
AU - Caniglia, Salvo
AU - Gennuso, Florinda
AU - Testa, Nuccio
AU - Miele, Egidio
AU - Desole, Speranza
AU - Barden, Nicholas
AU - Morale, Maria Concetta
PY - 2005/4
Y1 - 2005/4
N2 - 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.
AB - 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.
KW - Glucocorticoid receptor
KW - Inducible nitric oxide synthase
KW - Neuroinflammation
KW - Neuron-glia interactions
KW - Neuroprotection
KW - Parkinson's disease
UR - http://www.scopus.com/inward/record.url?scp=20244369883&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=20244369883&partnerID=8YFLogxK
U2 - 10.1016/j.brainresrev.2004.12.030
DO - 10.1016/j.brainresrev.2004.12.030
M3 - Article
C2 - 15850669
AN - SCOPUS:20244369883
VL - 48
SP - 302
EP - 321
JO - Brain Research Reviews
JF - Brain Research Reviews
SN - 0165-0173
IS - 2
ER -