Glucocorticoid receptor deficiency increases vulnerability of the nigrostriatal dopaminergic system: critical role of glial nitric oxide.
Glucocorticoids (GCs) exert via glucocorticoid receptors (GRs) potent anti-inflammatory and immunosuppressive effects. Emerging evidence indicates that an inflammatory process is involved in dopaminergic nigro-striatal neuronal loss in Parkinson's disease. We here report that the GR deficiency of transgenic (Tg) mice expressing GR antisense RNA from early embryonic life has a dramatic impact in "programming" the vulnerability of dopaminergic neurons to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The GR deficiency of Tg mice exacerbates MPTP-induced toxicity to dopaminergic neurons, as revealed by both severe loss of tyrosine hydroxylase positive nigral neurons and sharp decreases in striatal levels of dopamine and its metabolites. In addition, the late increase in dopamine oxidative metabolism and ascorbic acid oxidative status in GR-deficient mice was far greater than in wild-type (Wt) mice. Inducible nitric oxide synthase (iNOS) was sharply increased in activated astrocytes, macrophages/microglia of GR-deficient as compared with Wt mice. Moreover, GR-deficient microglia produced three- to fourfold higher nitrite levels than Wt mice; these increases preceded the loss of dopaminergic function and were resistant to GR the inhibitory effect of GC, pointing to peroxynitrites as candidate neurotoxic effectors. The iNOS inhibitor N6-(1-iminoethyl)-L-lysine normalized vulnerability of Tg mice, thus establishing a novel link between genetic impairment of GR function and vulnerability to MPTP.
Morale
Maria Concetta
MC
OASI Institute for Research and Care on Mental Retardation and Brain Aging (IRCCS), Neuropharmacology Section, 94018 Troina, Italy.
Serra
Pier Andrea
PA
Delogu
Maria Rosaria
MR
Migheli
Rossana
R
Rocchitta
Gaia
G
Tirolo
Cataldo
C
Caniglia
Salvo
S
Testa
Nuccio
N
L'Episcopo
Francesca
F
Gennuso
Florinda
F
Scoto
Giovanna M
GM
Barden
Nicholas
N
Miele
Egidio
E
Desole
Maria Speranza
MS
Marchetti
Bianca
B
D000818:Animals; D003345:Corticosterone / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008239:Lysine / Q000031:analogs & derivatives* / Q000494:pharmacology; D020267:MPTP Poisoning / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D008822:Mice, Transgenic; D017072:Neostriatum / Q000378:metabolism*; D009457:Neuroglia / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D009474:Neurons / Q000201:enzymology / Q000378:metabolism / Q000502:physiology; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D018384:Oxidative Stress; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000502:physiology*; D013378:Substantia Nigra / Q000378:metabolism*; D014446:Tyrosine 3-Monooxygenase / Q000032:analysis
D004791:Enzyme Inhibitors; C090663:N(6)-(1-iminoethyl)lysine; D011965:Receptors, Glucocorticoid; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D014446:Tyrosine 3-Monooxygenase; D008239:Lysine; D004298:Dopamine; D003345:Corticosterone