Ribonuclease attenuates hepatic ischemia reperfusion induced cognitive impairment through the inhibition of inflammatory cytokines in aged mice
Introduction
Postoperative cognitive dysfunction (POCD), which is caused by brain impairment, is a frequent complication following major surgery in elderly people. This dysfunction is characterized by a progressive deterioration of cognitive function, reduction in self-care, increased hospitalization and delayed recovery. With advances in surgical and anesthetic techniques and in combination with increased life expectancy, POCD is becoming an area of focus in hospitals. Nevertheless, the definite mechanism of POCD remains unclear, and no optimum treatment yet exists for this postoperative complication. Increasing evidence has indicated that neuroinflammation plays an essential role in the pathogenesis of POCD [1]. High level of proinflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β), in serum and brain tissue are associated with the occurrence of POCD [2], [3]. The effects of inflammation on cognition function may be mediated by different mechanisms; for example, direct effects on memory processes through cytokine-dependent signaling, alterations in neurogenesis, or epigenetic modifications [4].
A previous study demonstrated that extracellular RNA (exRNA) is enriched at sites of tissue damage and acts as a proinflammatory mediator [5]. In accordance with the damaging nature of exRNA, several proinflammatory cytokines (including TNF-α, IL-1β, and IL-6) are upregulated in macrophages [5]. Ribonuclease (RNase), the counterpart of exRNA, has mostly been reported as of potential use in anticancer therapy; however, recent studies have demonstrated that it can also exert potent organ-protective effects in several pathological conditions due to its mediation of an anti-inflammatory effect [6], [7], [8]. During cardiac ischemia reperfusion (IR) injury, RNase performs cardiac protection through the attenuation of myocardial cytokine production, leukocyte infiltration and apoptosis [8]; it also exhibits neuroprotective properties by reducing vessel occlusion, infarct volume [9], and preventing brain edema formation [6]. Our previous study demonstrated that RNase protects the liver against IR injury through the inhibition of inflammatory cytokines and apoptosis in mice (data not published). However, it is unknown whether RNase treatment can attenuate POCD that is induced by hepatic IR.
Therefore, based on the previous results and the contribution of the exRNA/RNase system to inflammation, we hypothesized that exRNA plays an important role in the IR-induced inflammation response and that POCD and RNase can protect against exRNA-mediated injury. Thus, in the present study, we aimed to evaluate the effect of RNase treatment on cognitive function and the expression of proinflammatory cytokines in a mouse hepatic IR model.
Section snippets
Animals
Male wild type C57BL/6J mice (aged 15 months, 25–35 g) were used in the study. All animal experiments followed the guidelines published by the Ministry of Science and Technology of China. Care was taken to minimize discomfort, distress, and pain in the animals. The study protocol was approved by Animal Ethics Committee of West China Hospital of Sichuan University (Chengdu, China).
Experimental design
The mice were divided into four groups: vehicle-treated sham operation (Sham); RNase-treated sham operation (Sham +
RNase treatment attenuated hepatic IR-induced cognitive dysfunction
All groups had similar swimming speeds pre and postoperatively (Fig. 2B), implying that the surgical operation performed in this study had no impact on exercise capacity. The probe test conducted at day 3 after surgery demonstrated a statistically significant reduction in memory retrieval in the IR group compared to that in the sham group as evidenced by a decreased percentage of time spent in the old target quadrant (Fig. 2A), suggesting that liver IR induced a significant cognitive impairment
Discussion
In the present study, we found that hepatic IR induced cognitive impairment in aged mice and increased the expression of inflammatory cytokines in the serum and hippocampus. Most importantly, RNase treatment exerted protective effects against learning and memory impairment by decreasing the expression of proinflammatory cytokines both in the serum and hippocampus.
We used a well-established mouse model of hepatic IR (which mimics a common procedure during liver surgery) to carry out our studies
Description of research support
This work was supported by the National Natural Science Foundation of China (No. 81671062, to Dr. Tao Zhu), and the National Natural Science Foundation of China (No. 81500937, to Dr. Chan Chen).
Conflict of interest
The authors do not have any conflict of interest.
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2020, CytokineCitation Excerpt :RNase has also demonstrated cardiac protection by reducing myocardial leukocyte infiltration and suppressing apoptosis in cardiac I/R injury [12]. Our previous studies suggested that RNase attenuated postoperative cognitive injuries by alleviating hippocampal apoptosis and inflammation in old mice [13,14], and reduced acute lung I/R injury [11]. However, the exact mechanism by which RNase induces organ protection remains to be elucidated, and the effect of RNase on liver I/R injury remains unclear.
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2020, International ImmunopharmacologyRibonuclease attenuates acute intestinal injury induced by intestinal ischemia reperfusion in mice
2020, International ImmunopharmacologyCitation Excerpt :This may be the reason why the administration protocol of RNase in our study just alleviate the intestinal injury and increase survival rate in the early phase post-I/R. In line with previous studies [9,12,15,24], we propose that the exRNAs/RNase system is involved in the development of intestinal I/R injury, and the activation of TLR3 contributes to intestinal I/R injury, but the relationship between exRNAs and TLR3 is unknown, which warrants further study to understand how intestinal epithelial cells can sense and respond to exRNAs. The increased exRNAs levels may contribute to ischemic intestine injury, and perioperative RNase treatment is an encouraging approach to protect against intestinal I/R injury.
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They contributed equally to this article and share first authorship.