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Polyinosinic-polycytidylic acid has therapeutic effects against cerebral ischemia/reperfusion injury through the downregulation of TLR4 signaling via TLR3.

Abstract
Recent reports have shown that preconditioning with the TLR3 ligand polyinosinic-polycytidylic acid (poly(I:C)) protects against cerebral ischemia/reperfusion (I/R) injury. However, it is unclear whether poly(I:C) treatment after cerebral I/R injury is also effective. We used mouse/rat middle cerebral artery occlusion and cell oxygen-glucose deprivation models to evaluate the therapeutic effects and mechanisms of poly(I:C) treatment. Poly(I:C) was i.p. injected 3 h after ischemia (treatment group). Cerebral infarct volumes and brain edemas were significantly reduced, and neurologic scores were significantly increased. TNF-α and IL-1β levels were markedly decreased, whereas IFN-β levels were greatly increased, in the ischemic brain tissues, cerebral spinal fluid, and serum. Injuries to hippocampal neurons and mitochondria were greatly reduced. The numbers of TUNEL-positive and Fluoro-Jade B(+) cells also decreased significantly in the ischemic brain tissues. Poly(I:C) treatment increased the levels of Hsp27, Hsp70, and Bcl2 and decreased the level of Bax in the ischemic brain tissues. Moreover, poly(I:C) treatment attenuated the levels of TNF-α and IL-1β in serum and cerebral spinal fluid of mice stimulated by LPS. However, the protective effects of poly(I:C) against cerebral ischemia were abolished in TLR3(-/-) and TLR4(-/-)mice. Poly(I:C) downregulated TLR4 signaling via TLR3. Poly(I:C) treatment exhibited obvious protective effects 14 d after ischemia and was also effective in the rat permanent middle cerebral artery occlusion model. The results suggest that poly(I:C) exerts therapeutic effects against cerebral I/R injury through the downregulation of TLR4 signaling via TLR3. Poly(I:C) is a promising new drug candidate for the treatment of cerebral infarcts.
AuthorsPeng-Fei Wang, Huang Fang, Jing Chen, Sen Lin, Yong Liu, Xiao-Yi Xiong, Yan-Chun Wang, Ren-Ping Xiong, Feng-Lin Lv, Jian Wang, Qing-Wu Yang
JournalJournal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 192 Issue 10 Pg. 4783-94 (May 15 2014) ISSN: 1550-6606 [Electronic] United States
PMID24729619 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antiviral Agents
  • HSP27 Heat-Shock Proteins
  • HSP70 Heat-Shock Proteins
  • Hspb1 protein, rat
  • Hspb2 protein, mouse
  • Interleukin-1beta
  • TLR3 protein, mouse
  • TLR3 protein, rat
  • Tlr4 protein, mouse
  • Tlr4 protein, rat
  • Toll-Like Receptor 3
  • Toll-Like Receptor 4
  • Tumor Necrosis Factor-alpha
  • Poly I-C
Topics
  • Animals
  • Antiviral Agents (pharmacology)
  • Brain Ischemia (drug therapy, genetics, immunology, pathology)
  • Down-Regulation (drug effects, genetics, immunology)
  • HSP27 Heat-Shock Proteins (genetics, immunology)
  • HSP70 Heat-Shock Proteins (genetics, immunology)
  • Interleukin-1beta (genetics, immunology)
  • Male
  • Mice
  • Mice, Knockout
  • Poly I-C (pharmacology)
  • Rats
  • Rats, Sprague-Dawley
  • Reperfusion Injury (drug therapy, genetics, immunology, pathology)
  • Signal Transduction (drug effects, genetics, immunology)
  • Time Factors
  • Toll-Like Receptor 3 (genetics, immunology)
  • Toll-Like Receptor 4 (genetics, immunology)
  • Tumor Necrosis Factor-alpha (genetics, immunology)

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