Tocilizumab inhibits neuronal cell apoptosis and activates STAT3 in cerebral infarction rat model

Abstract

Cerebral infarction is a severe hypoxic ischemic necrosis with accelerated neuronal cell apoptosis in the brain. As a monoclonal antibody against interleukin 6, tocilizumab (TCZ) is widely used in immune diseases, whose function in cerebral infarction has not been studied. This study aims to reveal the role of TCZ in regulating neuronal cell apoptosis in cerebral infarction. The cerebral infarction rat model was constructed by middle cerebral artery occlusion and treated with TCZ. Cell apoptosis in hippocampus and cortex of the brain was examined with TUNEL method. Rat neuronal cells cultured in oxygen-glucose deprivation (OGD) conditions and treated with TCZ were used to compare cell viability and apoptosis. Apoptosis-related factors including B-cell lymphoma extra large (Bcl-xL) and Caspase 3, as well as the phosphorylated signal transducer and activator of transcription 3 (p-STAT3) in brain cortex were analyzed from the protein level. Results indicated that TCZ treatment could significantly prevent the promoted cell apoptosis caused by cerebral infarction or OGD (P < 0.05 or P < 0.01). In brain cortex of the rat model, TCZ up-regulated Bcl-xL and down-regulated Caspase 3, consistent with the inhibited cell apoptosis. It also promoted tyrosine 705 phosphorylation of STAT3, which might be the potential regulatory mechanism of TCZ in neuronal cells. This study provided evidence for the protective role of TCZ against neuronal cell apoptosis in cerebral infarction. Based on these fundamental data, TCZ is a promising option for treating cerebral infarction, but further investigations on related mechanisms are still necessary.

IL6 receptor blockade preserves articular cartilage and increases bone volume following ischemic osteonecrosis in immature mice

“…In addition, tocilizumab treatment rescued the loss of Safranin O staining, which reflects glycosaminoglycan content in the articular cartilage matrix 30 . Consistent with these findings, tocilizumab treatment has been shown to reduce neural cell apoptosis in a rat model of cerebral infarction and in oxygen-glucose deprived culture conditions 31 . Similarly, tocilizumab treatment significantly inhibited apoptosis and increased proliferation viability of human cardiac myocytes in culture conditions simulating ischemic reperfusion injury 32 .…”

RBPJ polymorphisms associated with cerebral infarction diseases in Chinese Han population

“…Certain diseases or genetic factors can change the characteristics of the cerebral vascular systems and contribute to cerebral infarction or other CSVDs. [ 18 , 42 ] In the blood vessel development, the Notch signaling pathway regulates the expression of many genes involved in the cell proliferation, differentiation, apoptosis, and cell fate decision, [ 26 ] and coordinates arterial differentiation of endothelial cells. [ 43 – 46 ] Targeted mutations of the Notch target genes could result in embryonic lethality due to severe defects in the angiogenic vascular remodeling.…”

“…The risk factors so far documented include smoking, obesity, dyslipidemia, high blood pressure, diabetes and aging, [ 14 , 15 ] and the pathogenesis involves neuronal cell apoptosis. [ 16 , 17 ] Blockage of the brain blood vessels is the direct cause of the disease, resulting from embolism or thrombosis and leading to cerebral ischemia, [ 18 ] which may induce immune responses and inflammation. [ 15 , 19 – 23 ]…”

Potentially Common Therapeutic Targets for Multiple Sclerosis and Ischemic Stroke

“…However, we have to remain cautious and more data are necessary on the impact of TNF-α inhibitors on IS as it has been observed that TNF-α inhibition was associated with increased ischemic damage following a decrease in innate immune response from the brain ( Pires et al, 2014 ). Considering IL6, it has been reported that pre-treatment with tocilizumab, a monoclonal antibody against IL6 in a rat model of ischemic stroke, prevents neuronal cell apoptosis ( Wang et al, 2016 ).…”