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. 2017 Sep 7;8(46):80315-80324.
doi: 10.18632/oncotarget.20699. eCollection 2017 Oct 6.

Vinpocetine alleviate cerebral ischemia/reperfusion injury by down-regulating TLR4/MyD88/NF-κB signaling

Li-Rong Wu  1 , Liang Liu  1 , Xiao-Yi Xiong  1 , Qin Zhang  1 , Fa-Xiang Wang  1 , Chang-Xiong Gong  1 , Qi Zhong  1 , Yuan-Rui Yang  1 , Zhao-You Meng  1 , Qing-Wu Yang  1
Affiliations

Vinpocetine alleviate cerebral ischemia/reperfusion injury by down-regulating TLR4/MyD88/NF-κB signaling

Li-Rong Wu et al. Oncotarget. .

Abstract

Inflammatory responses play crucial roles in cerebral ischemia/reperfusion injury. Toll-like receptor 4 (TLR4) is an important mediator of the neuroinflammatory response to cerebral ischemia/reperfusion injury. Vinpocetine is a derivative of the alkaloid vincamine and exerts an anti-inflammatory effect by inhibiting NF-κB activation. However, the effects of vinpocetine on pathways upstream of NF-κB signaling, such as TLR4, have not been fully elucidated. Here, we used mouse middle cerebral artery occlusion (MCAO) and cell-based oxygen-glucose deprivation (OGD) models to evaluate the therapeutic effects and mechanisms of vinpocetine treatment. The vinpocetine treatment significantly reduced mice cerebral infarct volumes and neurological scores. Moreover, the numbers of TUNEL+ and Fluoro-Jade B+ cells were significantly decreased in the ischemic brain tissues after vinpocetine treatment. In the OGD model, the vinpocetine treatment also increased the viability of cultured cortical neurons. Interestingly, vinpocetine exerted a neuroprotective effect on the mouse MCAO model and cell-based OGD model by inhibiting TLR4-mediated inflammatory responses and decreasing proinflammatory cytokine release through the MyD88-dependent signaling pathway, independent of TRIF signaling pathway. In conclusion, vinpocetine exerts anti-inflammatory effects to ameliorate cerebral ischemia/reperfusion injury in vitro and in vivo. Vinpocetine may inhibit inflammatory responses through the TLR4/MyD88/NF-κB signaling pathway, independent of TRIF-mediated inflammatory responses. Thus, vinpocetine may be an attractive therapeutic candidate for the treatment of ischemic cerebral injury or other inflammatory diseases.

Keywords: cerebral ischemia/reperfusion; ischemic stroke; middle cerebral artery occlusion; toll-like receptor 4; vinpocetine.

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Conflict of interest statement

CONFLICTS OF INTEREST The authors have no competing interests to declare.

Figures

Figure 1
Figure 1. Vinpocetine reduced cerebral ischemia reperfusion injury
After cerebral ischemia/reperfusion injury, Vinpocetine (10 mg/kg) or vehicle was i.p. injected into mice. A. TTC staining and quantification of the infarct volumes (n = 5). B. The vinpocetine treatment significantly decreased the neurological scores (n = 7) and numbers of TUNEL-positive C. and FJB-positive cells D. (n = 5). Data are presented as means±SEM (**p < 0.01).
Figure 2
Figure 2. Vinpocetine increased the viability and LDH levels in primary cortical neurons and reduced neuronal apoptosis in the OGD model
Primary cortical neurons and microglial cells were used for the OGD model, and the viability of primary cortical neurons and microglial cells was significantly decreased in response to OGD. However, we did not observe any significant effects of the vinpocetine treatment on primary cortical neuron viability A., LDH release B. or cell apoptosis C., D. after the OGD treatment. After microglial cells were subjected to OGD, their supernatants were added to primary cortical neurons and the effects of different concentrations (5, 20, and 50 μmol/L) of vinpocetine on primary cortical neurons viability E., LDH release F. and apoptosis G., H. were examined. Data are presented as means±SEM (*p < 0.05, **p < 0.01).
Figure 3
Figure 3. Vinpocetine inhibited the activation of the TLR4/MyD88 /NF-κB pathway in mice with cerebral ischemia reperfusion injury
A. After cerebral ischemia/reperfusion injury, TLR4 expression was increased significantly in the infarcted area 24 h after the induction of ischemia and reperfusion. B. The levels of TLR4, MyD88, TRIF, and total and nuclear NF-kB p65 proteins were examined by Western blotting. The vinpocetine treatment inhibited the increase in TLR4 C. and MyD88 D. expression, but not TRIF E. (n = 5). Total NF-κB p65 F. and nuclear NF-κB p65 G., H. expression are shown. Data are presented as means±SEM (**p < 0.01).
Figure 4
Figure 4. Vinpocetine inhibited the activation of the TLR4/MyD88 /NF-κB pathway in the microglia OGD model
A. Effects of the 50 μmol/L vinpocetine treatment on the levels of the TLR4, total and nuclear NF-κB p65 proteins were examined by Western blotting. The vinpocetine treatment inhibited the increase in TLR4 B. Total NF-κB p65 C. and nuclear NF-κB p65 D. expression are shown. E.-G. The vinpocetine treatment inhibited the increase in MyD88 but not TRIF. Data are presented as means±SEM (**p < 0.01).
Figure 5
Figure 5. Vinpocetine attenuated inflammatory cytokine release in mice with cerebral ischemia-reperfusion injuries and the cell-based OGD model
Effects of vinpocetine on the secretion of IL-1β A. and TNF-α B. in the mouse cerebral ischemia-reperfusion injury model are shown. Effects of vinpocetine on the secretion of IL-1β C. and TNF-α D. in the microglia OGD model are shown. Data are presented as means±SEM (**p < 0.01).
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