Tissue kallikrein protects against ischemic stroke by suppressing TLR4/NF-κB and activating Nrf2 signaling pathway in rats

Abstract

Abstract. Brain damage following cerebral ischemia-reperfusion (I/R) is a complicated pathophysiological course, in which inflammation and oxidative stress have been suggested to serve an important role. Toll-like receptor 4 (TLR4) has been suggested to be involved in secondary inflammatory process in cerebral ischemia. Nuclear factor erythroid 2-related factor 2 (Nrf2), an important regulator of the antioxidant host defense, maintains the cellular redox homeostasis. Tissue kallikrein (TK) has been proven to elicit a variety of biological effects in ischemic stroke through its anti-inflammatory and anti-oxidant properties. However, the mechanisms underlying its beneficial effects remain poorly defined. The present study examined the hypothesis that TK attenuates ischemic cerebral injury via the TLR4/nuclear factor-κB (NF-κB) and Nrf2 signaling pathways. Using a transient rat middle cerebral artery occlusion (MCAO) model, the effects of immediate and delayed TK treatment subsequent to reperfusion were investigated. The neurological deficits, infarct size, and the expression of TLR4/NF-κB and Nrf2 pathway in ischemic brain tissues were measured at 24 following MCAO. The results indicated that TK immediate treatment significantly improved neurological deficits and reduced the infarct size, accompanied by the inhibition of TLR4 and NF-κB levels, and the activation of Nrf2 pathway. Furthermore, TK delayed treatment also exerted neuroprotection against I/R injury. However, the neuroprotective effect of TK immediate treatment was better compared with that of TK delayed treatment. In conclusion, the results indicated that TK protected the brain against ischemic injury in rats after MCAO through its anti-oxidative and anti-inflammatory effects. Suppression of TLR4/NF-κB and activation of the Nrf2 pathway contributed to the neuroprotective effects induced by TK in cerebral ischemia. Therefore, TK may provide an effective intervention with a wider therapeutic window for ischemic stroke.

Homocysteine-induced oxidative stress through TLR4/NF-κB/DNMT1-mediated LOX-1 DNA methylation in endothelial cells

“…It is also involved in the pro-inflammatory response, a first line of defense against infectious diseases, whereas TLR4 is involved in the induction of innate immune and inflammatory responses. A previous study has demonstrated that TLR4-mediated signaling pathways mainly stimulate the activation of NF-κB (35) and the present study showed that Hcy promoted the mRNA and protein expression of TLR4. According to previous studies and the present study, TLR4/NF-κB/DNMT1 may be involved in Hcy-induced LOX-1 DNA hypomethylation.…”

Therapeutic Values of Human Urinary Kallidinogenase on Cerebrovascular Diseases

“…Yang et al found that HUK improves neurological deficits, reduces the infarct volume, and decreases inflammatory responses in rats following cerebral ischemia. Meanwhile, they also found that the levels of TLR4 and NF-kB in ischemic brains increased following MCAO by western blot analysis, and this effect was significantly inhibited by immediate treatment of HUK ( 30 ). It concluded that tissue kallikrein protects against ischemic stroke through antioxidation and anti-inflammation by suppressing TLR4/NF-κB signaling pathway in rats.…”

Anti-Neuroinflammatory Effect of Alantolactone through the Suppression of the NF-κB and MAPK Signaling Pathways

“…It has been reported that the TLR4/NF-κB signaling pathway accelerates the inflammatory process in neuroinflammatory injury [39][40][41]. NF-κB is a nuclear transcription factor that regulates the expression of numerous genes that are responsible for regulating apoptosis, tumorigenesis, inflammation, and various autoimmune diseases [42].…”