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.

RETRACTED: Regulatory T cells ameliorate intracerebral hemorrhage-induced inflammatory injury by modulating microglia/macrophage polarization through the IL-10/GSK3β/PTEN axis

“…21,32 After the blood vessels and meninges removed, the cortices of postnatal day 1 mice were digested using 0.25% trypsin-EDTA (Life Technologies, Birmingham, MI) for 5 min and stopped by heat-inactivated FBS. After triturated using a P-1000 plastic tip, the cells suspension was cultured in DMEM containing 10% heatinactivated FBS (Gibco, Life Technologies Corporation), 50 U/ml penicillin and 50 mg/ml streptomycin.…”

Effect of Melatonin and Resveratrol against Memory Impairment and Hippocampal Damage in a Rat Model of Vascular Dementia

“…On the other hand, Bax is a proapoptotic protein which can trigger cell death by transferring to the mitochondrial membrane and inducing cytochrome c release [85] . The Bcl2 family maintains a stabilization of the balance between Bcl-2 and Bax [86][87][88][89] . Therefore, the effects of both melatonin and resveratrol have been examined on the level of Bcl-2 and Bax in the hippocampal CA1 region.…”

The toll-like receptor 3 pathway in homeostasis, responses to injury and wound repair

“…As indicated earlier (see Section 2.3), TLR3 has previously been implicated in mediating loss of BBB integrity and contributing to neuropathology in a mouse model of WNV infection [30]. Nonetheless, recent studies have reported protective effects of poly(IC) treatment in brain I/R injury models [87][88][89]. This was linked to the capacity of TLR3 signalling in human astrocytes to drive expression of anti-inflammatory cytokines, such as Ifn-, which act as neuroprotective factors [87,88].…”

“…For example, in a mouse model, poly(IC) treatment following I/R injury improved recovery of brain function, as assessed by neurological behaviour [89].…”