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C3aR inhibition reduces neurodegeneration in experimental lupus.
- Source :
-
Lupus [Lupus] 2010 Jan; Vol. 19 (1), pp. 73-82. Date of Electronic Publication: 2009 Nov 09. - Publication Year :
- 2010
-
Abstract
- Complement activation is an important aspect of systemic lupus erythematosus. In this study we investigated the role of C3a/C3a receptor (R) signaling in brains of the lupus model, MRL/lpr mice, by treating the mice with C3aR antagonist (a) from 13 to 19 weeks of age. C3aR mRNA (0.2 +/- 0.027 versus 0.56 +/- 0.19) and protein (0.16 +/- 0.09 versus 0.63 +/- 0.19) expression was increased in MRL/lpr brains compared with MRL+/+ controls. Apoptosis, a key feature in lupus brain, was significantly reduced by C3aRa treatment, as assessed by DNA laddering, TUNEL staining and caspase3 activity (48% of MRL/lpr mice). mRNA expression of proinflammatory molecules that cause apoptosis, TNFalpha (0.33 +/- 0.07 versus 0.15 +/- 0.1), MIP2 (3.8 +/- 1.3 versus 1.7 +/- 0.6), and INFgamma (4.8 +/- 1.0 versus 2.07 +/- 1.28) are reduced in MRL/lpr brains with C3aRa treatment. In line with these results, Western blotting demonstrates the significant increase in phosphorylation of survival molecules Akt and Erk, decrease in PTEN and reduced iNOS expression. INFgamma receptor (R) and AMPA-GluR1 co-localized, and concomitant with reduced INFgammaR expression, AMPAGluR1 expression was also decreased by C3aR antagonist. All of these variables that modulate neuronal excitability and regulate synaptic plasticity are C3aR dependent in the MRL/lpr brains and suggest a potential therapeutic role for C3aR inhibition in CNS lupus.
- Subjects :
- Animals
Apoptosis
Complement Activation
Gliosis prevention & control
Interferon-gamma physiology
Lupus Erythematosus, Systemic immunology
Male
Mice
Mice, Inbred MRL lpr
Neurodegenerative Diseases prevention & control
Neurons pathology
Nitric Oxide Synthase Type II genetics
Receptors, AMPA physiology
Receptors, Complement antagonists & inhibitors
Signal Transduction
Lupus Erythematosus, Systemic complications
Neurodegenerative Diseases etiology
Receptors, Complement physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1477-0962
- Volume :
- 19
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Lupus
- Publication Type :
- Academic Journal
- Accession number :
- 19900981
- Full Text :
- https://doi.org/10.1177/0961203309348978