Poly(I:C) preconditioning ameliorates cognitive dysfunction after cerebral I/R injury by inhibiting TRAF6 signaling

Abstract

Objective: Toll-like receptor (TLR) activation plays an important role in cerebral ischemia-reperfusion injury. In addition, increasing evidence suggests that TLRs may affect cognitive behavior through TLR-mediated signaling. Here, we explored the protective effects of TLR3 on cognitive dysfunction after ischemia in the context of poly(I:C) preconditioning.Materials and Methods : Mice (n=84) were randomly divided into the sham group, AAV (vector) group, middle cerebral artery occlusion (MCAO) model group, poly(I:C) (pre) + MCAO model group, and AAV (TRAF6) + poly(I:C) (pre) + MCAO model group. The mice were injected i.p. with poly(I:C) (1.25 mg/g) 24 h prior to cerebral ischemia. Then, neurological scores were assessed, and the infarct volume was measured after cerebral ischemia-reperfusion. We evaluated the poly(I:C) preconditioning-induced attenuation of neuronal damage using Nissl and TUNEL staining. We assessed the poly(I:C) preconditioning-mediated inhibition of I/R-induced glial activation, inflammatory factor levels and TRAF6 expression. We also assessed whether TRAF6 affects poly(I:C) preconditioning to improve cognitive dysfunction and neuroprotection.Results: The results showed that compared with those of the sham group and AAV (vector) group, the functional neurological scores and focal infarct volume of the MCAO group and poly(I:C) preconditioning group were significantly increased. The results also showed that compared with those of the MCAO group, the functional neurological scores and focal infarct volume of the poly(I:C) preconditioning group were significantly reduced. Our results indicated that poly(I:C) preconditioning significantly attenuated neuronal apoptosis and cell loss. Poly(I:C) preconditioning also inhibited I/R-induced glial cell activation and reduced NF-κB, TNF-α and IL-β levels. Our findings showed that poly(I:C) preconditioning affected cognitive dysfunction following cerebral I/R. Here, we observed that poly(I:C) preconditioning affected the expression and distribution of TRAF6 following cerebral I/R. TRAF6 overexpression abolished poly(I:C)-induced neuroprotection and worsened cognitive dysfunction in cerebral I/R injury.Significance: Our findings suggested that poly(I:C) preconditioning ameliorates cognitive dysfunction after cerebral I/R injury by inhibiting TRAF6 signaling, which is a potential therapeutic target for the treatment of cognitive dysfunction after stroke.

Pre‐ and post‐conditioning with poly I:C exerts neuroprotective effect against cerebral ischemia injury in animal models: A systematic review and meta‐analysis

“…Sensitivity analysis revealed that cell death results are single-study driven. 34 After removal of Wang et al, 34 we observed that poly I:C administration significantly reduces cell death (I 2 = 0.00%; p = 0.00). Again, the wider CIs of Wang et al 34 in cell death might be the reason for this heterogeneity.…”

“…The four studies were from the USA 21,25,32,33 and China, 19,22,23,34 while one study was from Canada 24 and Sweden, 26 respectively. Eight studies used an intraperitoneal injection of poly I:C, 21–24,26,32–34 one used intramuscular 19 and subcutaneous 25 each. Various concentrations of the poly I:C ranging from 0.3 to 4 mg/kg were used in the included studies.…”

“…meta-analysis with poly I:C and CI consist of five studies. 19,22,23,25,34 Using a random-effects model, we found that poly I:C reduces the N.S., which is an indicator of better functional recovery [I 2 = 95.63%; SMD = -2.50; CIs (−4.76, −0.24); p = 0.03] (Figure 5A). The effects of poly I:C on cell death were assessed from three studies.…”

“…showed a high level of heterogeneity and species-wise subgroup analysis showed that high heterogeneity is associated with the mice group while rats showed moderate heterogeneity (I 2 = 55.45). Furthermore, sensitivity analysis showed that removing reference 34 The Wang et al 34 has high wider CIs in N.S., which is usually associated with the uncertainty of results and might be the reason for this heterogeneity.…”

“…Eight studies used mice, 19,21,[24][25][26][32][33][34] only one study used rats 23 and both mice and rats were used in one study. 22 The four studies were from the USA 21,25,32,33 and China, 19,22,23,34 while one study was from Canada 24 and Sweden, 26 respectively.…”