Dai Yutong, Wu Hao, Chen Ying, Gu Xiaoping, Xia Tianjiao
1. Jiangsu Key Laboratory of medical molecular technology, Nanjing University 210008; 2. Department of Anesthesiology, Gulou Hospital, Nanjing University School of medicine 210008
International Journal of Anesthesiology and resuscitation, 2020,41 (02): 196-199
DOI：10.3760/cma.j.issn.1673-4378.2020.02.015
Fund projects
National Natural Science Foundation of China (8173003381701371);
Jiangsu Natural Science Foundation (bk20170654)
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[summary]
Postoperative cognitive dysfunction (POCD) [in 2018, six journals including BJA suggested that POCD be renamed as perioperative neurocognitive disorders (PND) to describe preoperative and postoperative neurocognitive disorders [1]. In order to accurately describe the research scope of the subject, POCD is still used in this paper, which refers to the changes of personality, social and cognitive functions after surgery, with the decline of learning and memory functions as the main feature. The pathophysiological mechanism of POCD is not clear, but it is generally believed that inflammation plays an important role. Now we summarize and explore the inflammatory mechanism of POCD.
The occurrence of central inflammatory response induced by operation
Operation can cause systemic inflammation, over activation of WBC and cascade of cytokines. The levels of IL-1, IL-6 and TNF - α in plasma were increased. These inflammatory factors can enter the brain through various ways (directly through the blood brain barrier (BBB) or destroy BBB) or transmit signals to the brain. The increase of pro-inflammatory cytokines in the brain will over activate the microglia, induce more inflammatory substances to release in the brain, lead to nerve cell damage, and produce a vicious cycle. There are several ways of central inflammatory response induced by operation.
1.1 directly through BBB
The peripheral inflammatory factors produced by the body during the operation can enter the brain directly through a variety of ways, including infiltration, passive diffusion, transporter transport and so on. For example, in a highly inflammatory environment, the monocytes expressing chemokine receptor 2 can enter the brain directly through BBB, and the infiltrated monocytes will further promote the development of central inflammation [2]; in the place without continuous BBB (such as periventricular area), because of the greater permeability of BBB, the peripheral inflammatory factors can passively diffuse into the center along the gradient of concentration; in the complete BBB area, they can also pass through specific transporters ATP is consumed and actively transported into the brain. In general, the incidence of similar inflammatory factors directly entering the brain is relatively low, while the systemic inflammatory response and cytokine cascade reaction induced by surgery increase the possibility of these inflammatory factors directly entering the brain.
1.2 enter the center after damaging BBB
In fact, there are only a few inflammatory factors that can directly pass through BBB. In more cases, surgery causes the increase of BBB permeability, leading to a large number of inflammatory factors entering the center. For example, NF - κ B protein exists in all cell types and regulates the activation of immune cells, which is an important target for amplifying inflammatory signals. Inflammatory factors can activate NF - κ B pathway and increase BBB permeability through positive feedback loop [3]; at the same time, Hu et al. [4] showed that when using 1.5 In the orthopaedic operation of MAC sevoflurane anesthetized rats, anesthetics can enhance the destruction of BBB, and further enhance the destruction effect of sevoflurane on BBB due to the decrease of closure protein expression and the increase of matrix metalloproteinase 2 and matrix metalloproteinase 9 expression. Terrando et al [5] proved that the operation can destroy BBB by releasing TNF α, promote macrophage migration to hippocampus and damage cognitive function. He et al. [6] showed that the content of central nervous specific protein (S100 β) in serum of patients after operation increased significantly, and S100 β is one of the peripheral markers of BBB injury [7], which indirectly proved that operation may cause BBB injury. To sum up, BBB injury was induced by operation, and the permeability was enhanced, so that inflammatory factors could enter the center and induce central inflammatory response.
1.3 the inflammatory signal is transmitted to the center through various signaling pathways
The central inflammatory response induced by surgery, in addition to the inflammatory factors directly into the central induction, may also be the peripheral inflammatory factors through multiple signal pathways to the central inflammatory signal. For example, the peripheral inflammatory factor signal IL? 1 induced by surgery can directly bind to some special parts of intracranial microvascular with its homologous receptor, stimulate BBB endothelial cells, activate astrocytes and microglia, make them secrete a variety of immune active molecules, and induce central immune response [8]. It has also been shown that the peripheral inflammatory stimulation induced by surgery can activate the primary vagus nerve through paracrine pathway, then transmit the signal to the center, activate the central microglia, further produce proinflammatory factors, complement, oxygen free radicals, etc., and induce the central inflammatory response. In addition, TNF family cytokines and other inflammatory stimulation can activate extracellular signal regulated protein kinase, and its signal stimulation BBB will lead to the structural coordination cascade reaction of adjacent nerve vessels, amplifying the signal, while there are a large number of related receptors on the surface and in the nucleus of microglia cells in the brain, which can bind and be activated with a large number of blood-derived extracellular signal regulated protein kinase, In this way, a series of downstream molecules can be activated to induce central inflammation [9]. Therefore, it is one of the important ways to induce the central inflammatory response that the peripheral inflammatory factors transmit the inflammatory signals to the center through many ways.
Central inflammation and cognitive dysfunction
2.1 neuritis subsides slowly
In recent years, many studies have shown that brain and immune system have two-way interaction. Under normal circumstances, the immune system can protect and promote the central system. Learning and memory process depends on the hippocampus, which is a brain area with a large number of pro-inflammatory cytokines receptors. In inflammatory conditions, a large number of inflammatory factors will have adverse effects on cognitive function. However, not all inflammatory reactions in the central system can induce POCD, vacas et al. [10] proposed that this may be because postoperative neuroinflammation includes pro-inflammatory and anti-inflammatory phases, and short-term inflammation is a necessary process of tissue repair, while POCD is prone to occur when neuritis subsides slowly. In other words, short-term neuroinflammation or inflammatory factors in the center under normal state do not induce POCD, but in the context of systemic inflammatory environment, due to the central inflammation subsides slowly, POCD is easy to be caused.
2.2 direct role of neuroinflammation through inflammatory mediators
Inflammatory factors can also directly affect the brain, resulting in cognitive decline. Take high mobility group box? 1 (HMGB1) as an example. HMGB1 is a kind of cytokine with late pro-inflammatory effect, which can be released at the site of inflammation and / or tissue damage, and promote the production of cytokines and cell migration. It is considered to be the key inflammatory mediator in surgical stress [11]. In the central system, inflammation activated microglia release HMGB1 and combine with macrophage antigen complex 1 and NADPH oxidase of microglia to promote the progress of inflammation and stimulate the production of neurotoxic factors. In the clinical experiment, compared with the control group, the serum HMGB1 level of POCD patients increased significantly [12]. Many evidences show that the increase of HMGB1 level is related to the impairment of cognitive function. Among them, a single injection of HMGB1 can reproduce the defects in the hippocampal memory test after similar operations, which confirms that HMGB1 plays a relatively independent role in the damage of cognitive function [13]. In addition, the experiment proved that the injection of IL-1 β into the lateral ventricle could lead to the excitotoxic injury; some studies confirmed that the expression of IL-1 β mRNA in the hippocampus of the mice after operation was significantly higher than that of the control group, and the spatial memory ability of the mice decreased significantly. At the same time of directly mediating nerve injury, IL? 1 β can also promote the release of secondary inflammatory mediators, further aggravating nerve injury; the increase of TNF? α level also plays an important role in neuron degeneration and loss, which can cause swelling and degeneration of nerve and glial cells, release various neurotoxic factors, and reduce cognitive function [14]; excessive activation of glial cells can also produce excitatory toxicity At this time, its nutritional effect on neurons is reversed to damage, affecting brain function and causing cognitive impairment. In conclusion, a variety of inflammatory factors can directly affect brain function.
2.3 indirect effects of neuroinflammation through non inflammatory mediators
In addition to the direct effects of inflammatory mediators, neuritis also has other indirect effects on cognitive function. One possible hypothesis is that neuroinflammation indirectly affects the function of neurons necessary for learning and memory by regulating the neurointimal pathway. Take brain derived neurotrophic factor (BDNF) as an example. In animal experiments, BDNF level in hippocampus and neuroinflammation decreased, but BDNF level in prefrontal cortex remained intact, and the cognitive function mediated by these brain regions also remained normal. This may be due to the fact that the BDNF pathway in the hippocampus is particularly susceptible to neuroinflammation, and cognitive impairment occurs only when the BDNF pathway is significantly affected. This also explains the fact that the hippocampal dependent function of rats is impaired, while the prefrontal cortex is not affected by neuroinflammation [15]. Therefore, it can be concluded that neuritis can indirectly affect cognitive function through BDNF pathway. In addition, inflammatory stimulation can stimulate the endogenous cannabinoid system of old mice,
Further activation of phosphoinositide 3-kinase (PI3K) / protein kinase B (Akt) / mammalian rapamycin, MTOR) signaling pathway, i.e. inflammatory signal is amplified by PI3K / Akt / mTOR signaling pathway in a cascade, in which mTOR can lead to decreased synaptic plasticity and cognitive dysfunction such as learning and memory [16? 18]; inflammatory factors can also activate NF? κ B, thereby activating Wnt signaling pathway, making β? Catenin unable to be phosphorylated and degraded, inhibiting cAMP response element binding protein, and affecting neuron process Touch plasticity, resulting in cognitive decline [19]. In addition, inflammation can increase the secretion of glucocorticoid receptor in the systemic circulation, and then cause the disorder of acetylcholine, 5-hydroxytryptamine, noradrenaline and other neurotransmitter systems in the central nervous system, and then induce mental disorder and cognitive decline [20]. In fact, there are many other signaling pathways that can be activated by inflammatory factors and thus affect the cognitive function of the center.
The relationship between central inflammation and risk factors and prevention of POCD
3.1 POCD risk factors
Many risk factors of POCD are related to the neuroinflammatory mechanism. For example, as an independent risk factor of POCD, old age has an important relationship with central inflammatory susceptibility. Inflammatory mechanism plays an important role in the occurrence and development of POCD. In the animal experiment, the activation of microglia in the hippocampus of young rats increased at the first week after operation and returned to the control level at the first week [21], while in the old rats, the increased activation trend of microglia at the second week after operation can be observed, indicating that age has an effect on the activation of microglia in the hippocampus. Another study showed that IL? 1 β in the aged rats increased significantly on the 1st and 4th day after operation, and returned to normal on the 12th day, but not in the young adult rats, which was consistent with the time course of spatial memory disorder [22]. It is concluded that the elderly are more likely to have neuroinflammatory reaction, so the probability of POCD caused by central inflammatory reaction is higher in the elderly patients. Preoperative cognitive impairment (such as vascular dementia, Alzheimer's disease