April 18, 2024

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Protective mechanism of propofol on ischemic brain injury

Research progress on the protective mechanism of propofol on ischemic brain injury

Protective mechanism of propofol on ischemic brain injury.  The mechanism through which propofol exerts brain protection, the dosage of propofol, and the time window for using propofol need to be further explored, but its anti-inflammatory, anti-oxidant, and anti-apoptotic effects are expected to become targets for the treatment of IBI. 


Research progress on the protective mechanism of propofol on ischemic brain injury



Ischemic brain injury (IBI) is one of the main causes of death and disability worldwide, and currently its treatment methods are limited. The degree of brain injury when IBI occurs is determined by the severity of the primary injury and the intensity of the secondary injury cascade, which is often irreversible. At present, reperfusion of ischemic occluded vessels as soon as possible is the standard treatment for IBI patients, but reperfusion may aggravate brain damage, namely ischemia reperfusion injury (IRI), causing neuronal and cerebrovascular dysfunction, threatening the survival of IBI patients .

It has been reported that propofol has neuroprotective and anti-neuroinflammatory effects, and it has shown a protective effect on ischemic brain tissue neurons in a variety of in vivo and in vitro brain injury models. The role of propofol in IBI is reviewed.

1. Overview of Propofol

Propofol exerts sedative and hypnotic effects by activating the central inhibitory neurotransmitter γ-aminobutyric acid. It is a common general intravenous anesthetic in clinical practice. It is widely used because of its rapid onset, fast metabolism and low incidence of postoperative nausea and vomiting. It is used in the induction and maintenance of general anesthesia, as well as in the anesthesia of short day surgery and sedation of patients in the intensive care unit. In recent years, studies have pointed out that in addition to its sedative and hypnotic effects, propofol also has protective effects on all tissues and organs of the body.

Propofol can protect astrocytes from oxidative stress and activate astrocyte-mediated neuron protection; in a mouse model of acute lung injury induced by lipopolysaccharide, propofol can alleviate the alveoli Wall rupture, pulmonary edema and neutrophil infiltration; in diabetic cardiomyocyte hypoxia-reoxygenation model, post-treatment with propofol can reduce myocardial damage; propofol can regulate miR-290-5p/CCL-2 pathway improvement Kidney damage induced by sepsis. Propofol plays a protective role in damaged tissues and organs through different mechanisms. The mechanism of using propofol to improve the function of various tissues and organs has become a research hotspot in recent years.


2.1 Overview of IBI

IBI is mostly caused by thromboembolism in the cerebral aorta or its branch vessels or abnormal structures of cerebral blood vessels. Thrombus obstruction of blood vessels causes tissue ischemia and hypoxia energy loss, resulting in a series of ischemic cascades, causing irreversible tissue damage. The body’s function and metabolic abnormalities during ischemia depend on the occluded artery, and the occluded artery determines the ischemic area the size of. In addition, increased intracranial pressure, intracerebral hypoperfusion, painful stimulation, or surgery-related injury can lead to cerebral edema, stroke and other diseases that cause secondary IBI.

2.2 IBI pathophysiology

2.2.1 Inflammation

Inflammation is one of the important pathophysiological mechanisms of IBI. In the early stage of IBI injury, damaged neuronal cells stimulate pro-inflammatory immune responses, and activated microglia produce interleukin (IL)-1 and tumor necrosis factor (TNF) -α and other cytokines, leading to impaired balance between pro-inflammatory and anti-inflammatory cytokines, causing inflammation in the brain parenchyma and peripheral immune system, and mediating secondary neuronal death. Acetylated high-mobility group proteins are released from immune cells into the extracellular space and activate the inflammatory response mediated by Toll-like receptor 4 (TLR4) signaling. In addition, the blood-brain barrier is destroyed during cerebral ischemia, the permeability of cerebral blood vessels increases, blood components extravasate into the brain, brain cell metabolism disorders cause the expression of inflammatory factors to increase, and inflammatory factors destroy the blood vessel wall, which further leads to cerebral blood flow Reduce, make brain tissue ischemia worse.

2.2.2 Oxidative stress

Oxidative stress is part of the pathological process of IBI. Under ischemic conditions, compared to other organs, the brain is more susceptible to the effects of reactive oxygen species due to its low antioxidant capacity, high oxygen consumption, and high levels of polyunsaturated fatty acids. Zhao et al. showed that the use of the active oxygen scavenger EUK-134 can reduce IBI in rats, and when the active oxygen inhibitor R(+) PPX is used, the cerebral infarct area of ​​ischemic rats is significantly reduced 6h after reperfusion. Ischemic acidosis activates reduced nicotinamide adenine nucleotide phosphate oxidase-2 to induce the production of oxygen free radicals in neurons. It suggests that oxidative stress plays an important role in IBI.

2.2.3 Calcium overload

Calcium overload plays a key role in the continuous neuronal death after cerebral ischemia and reperfusion. Neurons and glia are depolarized and release large amounts of glutamate, leading to glutamate receptors, especially N-methyl- D-aspartate (NMDA) receptors are over-stimulated, and ischemia causes the level of NMDA receptors to increase, causing a large amount of calcium influx in the early stage after ischemia. In addition, excessive intracellular calcium ions can cause calcium overload in the mitochondrial matrix, which affects mitochondrial function, resulting in a decrease in ATP production and an increase in the release of reactive oxygen species, thereby further aggravating brain damage.

2.2.4 Apoptosis

Apoptosis plays an important role in neuronal death after acute cerebral ischemia. Energy deficiency after cerebral ischemia causes intraneuronal calcium overload, oxygen free radical production, excitatory glutamate accumulation, etc., which cause mitochondrial damage, and it also causes apoptosis. The key element of death. Cerebral ischemia causes changes in the expression of apoptosis-related proteins in the ischemic cerebral hemisphere, such as increased caspase-3 levels, decreased expression of anti-apoptotic subfamily members Bcl-2, and pro-apoptotic members Bcl-2 related x Increased protein Bax level, etc., promote apoptosis. Microglia and astrocytes can remove broken apoptotic cells, reduce neuron loss during IBI and reduce infarct volume.

3. The possible mechanism of propofol’s brain protection on IBI

Propofol can protect the ischemic brain by reducing cerebral blood flow, lowering intracranial pressure and cerebral metabolic rate. Its protective effect is related to its anti-inflammatory and anti-oxidative stress properties. In addition, propofol has also been proven to be very effective. It regulates the apoptotic protein well, inhibits apoptosis, and enables the survival of neurons in the area around the infarction.

3.1 Anti-inflammatory effect

3.1.1 PI3K/Akt pathway

Phosphoinositide 3-kinase (PI3K) is a type of lipid kinase. Phosphorylated PI3K activates its downstream protein serine-threonine protein kinase (Akt) to play a role. PI3K/Akt pathway regulation includes apoptosis, transcription, and translation. It is widely involved in the physiology of normal cells and the pathological process of tumors. The PI3K/Akt pathway is also an important survival pathway for neurons, and it plays a key role in promoting neuron survival in IBI and other traumatic brain injuries.

In the rat IBI model treated with propofol, the degree of cerebral edema was reduced, the area of ​​cerebral infarction was reduced, and the expression of inflammatory factors such as TNF-α and IL-1β decreased, and the expression of phosphorylated Akt was up-regulated. After using the Akt inhibitor LY294002, the anti-inflammatory effect of propofol and the effect of up-regulating Akt expression were inhibited. In subarachnoid hemorrhage and the early brain damage caused by it, propofol can inhibit inflammation through the PI3K/Akt pathway, significantly improve the permeability of the blood-brain barrier, neurological dysfunction, and brain edema so as to protect neurons effect. The PI3K/Akt pathway has a neuroprotective effect, and propofol can activate the PI3K/Akt pathway to improve brain damage.

3.1.2 TLR4/nuclear transcription factor (NF)-κB pathway

TLR4 is mainly expressed in the microglia of the central nervous system. It plays an important role in the pro-inflammatory response mediated by a variety of microglia. If the TLR4 pathway is incorrectly activated or the signal is uncontrollably amplified, it will affect the nervous system. The TLR4 gene knockout mice showed improved neurological and/or behavioral results in various cerebral infarction models.

TLR4 activates its downstream NF-κB to participate in the transcription of a variety of pro-inflammatory genes after activation. Propofol treatment can inhibit the activation of the TLR4 pathway and the production of pro-inflammatory factors, and propofol can be inhibited in pretreatment and post-treatment NF-κB activity. In the brain injury model using microglia hypoxia and reoxygenation, it was found that the use of propofol pretreatment can significantly reduce microglia damage, and inhibit the up-regulation of TLR4 and NF-κB expression to play a neuroprotective effect. The inhibitory effect of propofol on the TLR4/NF-κB pathway may become an effective target for the treatment of IBI.

3.1.3 Other anti-inflammatory effects

Propofol has shown neuroprotective effects in the neuroinflammatory response of various brain injury models. The endogenous non-coding RNA molecule miR-155 is an important therapeutic target for central nervous system injury. In a mouse model of cerebral ischemia with middle cerebral artery occlusion, the expression of miR-155 was up-regulated by 25 times, and propofol was used After treatment, the expression of miR-155 was significantly inhibited, and the expression of inflammatory factors TNF-α and IL-6 was reduced. In addition, propofol can reduce inflammation and brain damage by inhibiting NOD-like receptor protein 3 inflammasome activation and pro-inflammatory cytokine maturation. Therefore, using propofol as an anti-inflammatory treatment to reduce the damage of inflammatory response to neurons during cerebral ischemia and improve neurological function is a feasible therapeutic intervention policy.

3.2 Anti-oxidant stress

Propofol can exert antioxidant effects in many ways. First of all, propofol is structurally similar to vitamin E, and can act as an antioxidant by reacting with free radicals to form phenoxy groups. Second, a large number of oxygen free radicals are produced during IBI. The endogenous antioxidant enzyme superoxide dismutase (SOD) can protect cells from active oxygen damage by scavenging free radicals. SOD expression is down-regulated in the acute cerebral ischemia model, and propofol can reduce the spinal cord injury during ischemia-reperfusion by enhancing the activity of different subtypes of SOD.

In addition, propofol can inhibit the production of reactive oxygen species induced by hydrogen peroxide, and weaken its inhibitory effect on SOD and glutathione. In addition to its integrated detoxification effect, glutathione also has an antioxidant effect. Recent studies have shown that alpha-synuclein, a soluble monomer that is abundant in the central nervous system, can specifically participate in the regulation of oxidative phosphorylation and mitochondrial function. Its oligomers increase the level of neuronal oxidative stress and acute cerebral ischemia. When α-synuclein accumulates, it exacerbates neuronal damage.

Propofol can reduce the level of alpha-synuclein fibrils after cerebral ischemia and attenuate the aggregation of alpha-synuclein induced by ischemia in the early stage of cerebral ischemia. It can be seen from this that propofol can protect the brain by resisting oxidative stress during cerebral ischemia.

3.3 Inhibition of calcium overload

Intracellular calcium ions are an important signaling molecule involved in all aspects of neuron physiology, but excessive calcium ions will cause nerve cells to excessively release excitatory transmitters, resulting in excitotoxicity and neurological dysfunction. In Li et al. studies, it was found that propofol can protect hippocampal neurons through the calcineurin/FKBP12.6-RyR/calcium overload pathway, and calcineurin (CaN) affects FK506 binding protein 12.6 (FKBP12.6). ) Regulate the calcium ion channel RyR to change the intracellular calcium ion concentration. When subjected to special stimuli, the up-regulation of CaN activity promotes the opening of RyR channels and causes calcium overload. Propofol can reduce the activity of CaN in hypoxia-reoxygenated hippocampal neurons, separate FKBP12.6 from RyR, close calcium channels and reduce intracellular calcium overload.

3.4 Anti-apoptotic effect

It has been reported that high-dose propofol post-treatment can significantly reduce the number of apoptotic cells, reduce the area of ​​cerebral infarction, and can up-regulate Bcl-2 by weakening the activity of the apoptotic factors caspase 3, 8, 9, 12 induced by hydrogen peroxide The /Bax ratio exerts an anti-apoptotic effect. In the IRI model using primary hippocampal cells treated with high glucose, hypoxia and reoxygenation, propofol reduced the expression of cytochrome C and mitochondrial fission protein Fsi1 and inhibited apoptosis.

In the study by Li et al., another pathway for propofol to protect hippocampal neurons from injury in the ischemia-reperfusion model is the RhoA/Lats1/YAP/Bcl-2 pathway. YAP protects hippocampal neurons from propofol. Apoptotic damage plays an important role. Propofol activates YAP by dephosphorylating YAP and promoting nuclear translocation of YAP, which in turn activates its downstream anti-apoptotic member Bcl-2. At the same time, activated YAP acts as a synergistic transcriptional activator to promote stem cells Self-renewal thereby inhibits cell apoptosis.

In IBI, due to the sudden and continuous interruption of local cerebral blood flow, the brain is in a state of ischemia and hypoxia, and then neurological dysfunction and other brain tissue damage and even necrosis occur. As a commonly used intravenous anesthetic, propofol not only has sedative and hypnotic effects, but also has neuroprotective effects on IBI. The mechanism through which propofol exerts brain protection, the dosage of propofol, and the time window for using propofol need to be further explored, but its anti-inflammatory, anti-oxidant, and anti-apoptotic effects are expected to become targets for the treatment of IBI. 

(source:internet, reference only)

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