Abstract | BACKGROUND AND PURPOSE: Systemic administration of Toll-like receptor (TLR) 4 and TLR9 agonists before cerebral ischemia have been shown to reduce ischemic injury by reprogramming the response of the brain to stroke. Our goal was to explore the mechanism of TLR-induced neuroprotection by determining whether a TLR7 agonist also protects against stroke injury. METHODS: RESULTS: The results show that GDQ reduces infarct volume as well as functional deficits in mice. GDQ pretreatment provided robust neuroprotection in TNF(-/-) mice, indicating that TNF was not essential. GDQ induced a significant increase in plasma IFNα levels and both IRF7(-/-) and IFNAR(-/-) mice failed to be protected, implicating a role for IFN signaling in TLR7-mediated protection. CONCLUSIONS: Our studies provide the first evidence that TLR7 preconditioning can mediate neuroprotection against ischemic injury. Moreover, we show that the mechanism of protection is unique from other TLR preconditioning ligands in that it is independent of TNF and dependent on IFNAR.
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Authors | Philberta Y Leung, Susan L Stevens, Amy E B Packard, Nikola S Lessov, Tao Yang, Valerie K Conrad, Noortje N A M van den Dungen, Roger P Simon, Mary P Stenzel-Poore |
Journal | Stroke
(Stroke)
Vol. 43
Issue 5
Pg. 1383-9
(May 2012)
ISSN: 1524-4628 [Electronic] United States |
PMID | 22403050
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Aminoquinolines
- Imidazoles
- Interferon Regulatory Factor-7
- Membrane Glycoproteins
- Neuroprotective Agents
- Tlr7 protein, mouse
- Toll-Like Receptor 7
- Tumor Necrosis Factor-alpha
- gardiquimod
- Receptor, Interferon alpha-beta
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Topics |
- Aminoquinolines
(therapeutic use)
- Animals
- Brain
(blood supply)
- Brain Infarction
(pathology)
- Imidazoles
(therapeutic use)
- Interferon Regulatory Factor-7
(deficiency, genetics, physiology)
- Ischemic Preconditioning
(methods)
- Male
- Membrane Glycoproteins
(agonists)
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Models, Animal
- Neuroprotective Agents
(therapeutic use)
- Receptor, Interferon alpha-beta
(deficiency, genetics, physiology)
- Signal Transduction
(physiology)
- Stroke
(physiopathology, prevention & control)
- Toll-Like Receptor 7
(agonists)
- Tumor Necrosis Factor-alpha
(deficiency, genetics, physiology)
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