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.

• Authors: Peng-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
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 192 Issue 10 Pg. 4783-94 (May 15 2014) ISSN: 1550-6606 [Electronic] United States
• PMID: 24729619 (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)