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

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
  • 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)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research network!

Choose Username:
Verify Password: