Glucocorticoid receptor-nitric oxide crosstalk and vulnerability to experimental parkinsonism: pivotal role for glia-neuron interactions.
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.
Marchetti
Bianca
B
Neuropharmacology Section, OASI Institute for Research and Care on Mental Retardation and Brain Aging (IRCCS), Troina (EN) Italy. bianca.marchetti@oasi.en.it
Serra
Pier Andrea
PA
Tirolo
Cataldo
C
L'episcopo
Francesca
F
Caniglia
Salvo
S
Gennuso
Florinda
F
Testa
Nuccio
N
Miele
Egidio
E
Desole
Speranza
S
Barden
Nicholas
N
Morale
Maria Concetta
MC
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008954:Models, Biological; D009457:Neuroglia / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009569:Nitric Oxide / Q000502:physiology*; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000503:physiopathology*; D020239:Receptor Cross-Talk / Q000502:physiology*; D011965:Receptors, Glucocorticoid / Q000502:physiology*
D011965:Receptors, Glucocorticoid; D009569:Nitric Oxide; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine