Toll-like receptor 3 agonist Poly I:C protects against simulated cerebral ischemia in vitro and in vivo |
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Authors: | Lin-na Pan Wei Zhu Cai Li Xu-lin Xu Lian-jun Guo Qing Lu |
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Institution: | 1.Department of Pharmacology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China;2.Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation, Hubei Province, Wuhan 430030, China;3.Department of Emergency Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China |
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Abstract: | Aim:To examine the neuroprotective effects of the Toll-like receptor 3 (TLR3) agonist Poly I:C in acute ischemic models in vitro and in vivo.Methods:Primary astrocyte cultures subjected to oxygen-glucose deprivation (OGD) were used as an in vitro simulated ischemic model. Poly I:C was administrated 2 h before OGD. Cell toxicity was measured using MTT assay and LDH leakage assay. The levels of TNFα, IL-6 and interferon-β (IFNβ) in the media were measured using ELISA. Toll/interleukin receptor domain-containing adaptor-inducing IFNβ (TRIF) protein levels were detected using Western blot analysis. A mouse middle cerebral artery occlusion (MCAO) model was u sed for in vivo study. The animals were administered Poly I:C (0.3 mg/kg, im) 2 h before MCAO, and examined with neurological deficit scoring and TTC staining. The levels of TNFα and IL-6 in ischemic brain were measured using ELISA.Results:Pretreatment with Poly I:C (10 and 20 μg/mL) markedly attenuated OGD-induced astrocyte injury, and significantly raised the cell viability and reduced the LDH leakage. Poly I:C significantly upregulated TRIF expression accompanied by increased downstream IFNβ production. Moreover, Poly I:C significantly suppressed the pro-inflammatory cytokines TNFα and IL-6 production. In mice subjected to MCAO, administration of Poly I:C significantly attenuated the neurological deficits, reduced infarction volume, and suppressed the increased levels of TNFα and IL-6 in the ischemic striatum and cortex.Conclusion:Poly I:C pretreatment exerts neuroprotective and anti-inflammatory effects in the simulated cerebral ischemia models, and the neuroprotection is at least in part due to the activation of the TLR3-TRIF pathway. |
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Keywords: | Toll-like receptor Poly I:C stroke astrocyte oxygen-glucose deprivation middle cerebral artery occlusion inflammation TNFα IL-6 interferon-β Toll/interleukin receptor domain-containing adaptor-inducing interferon β (TRIF) |
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