|Year : 2022 | Volume
| Issue : 2 | Page : 210-217
Effects of ferulic acid on regulating the neurovascular unit: Implications for ischemic stroke treatment
Xiang Wang1, Xin-Ran Liu2, Ke-Xin Li1, Xiang Fan3, Yang Liu4
1 Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China
2 School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, China
3 Zhejiang Chinese Medical University, Zhejiang, China
4 Chinese Medical College, Tianjin University of Traditional Chinese Medicine, Tianjin, China
|Date of Submission||03-Aug-2020|
|Date of Acceptance||30-Apr-2021|
|Date of Web Publication||30-Jun-2022|
548, Binwen Road, Binjiang District, Hangzhou, Zhejiang 310000
Source of Support: None, Conflict of Interest: None
Ferulic acid (FA) is a phenolic phytochemical with antioxidant and anti-inflammatory pharmacological effects. In recent years, the neuroprotective effects of FA have been studied extensively. Many researchers have attempted to use FA to prevent and treat neurological diseases and have made some progress. This paper mainly collated the study of the protective effect of FA on stroke and summarized the protective effect of FA on ischemic stroke and the potential protective effects of FA on neurovascular units.
Keywords: Ferulic acid, ischemic stroke, neuroprotective effects, neurovascular unit
|How to cite this article:|
Wang X, Liu XR, Li KX, Fan X, Liu Y. Effects of ferulic acid on regulating the neurovascular unit: Implications for ischemic stroke treatment. World J Tradit Chin Med 2022;8:210-7
|How to cite this URL:|
Wang X, Liu XR, Li KX, Fan X, Liu Y. Effects of ferulic acid on regulating the neurovascular unit: Implications for ischemic stroke treatment. World J Tradit Chin Med [serial online] 2022 [cited 2022 Aug 8];8:210-7. Available from: https://www.wjtcm.net/text.asp?2022/8/2/210/349268
| Introduction|| |
Stroke is an acute cerebrovascular injury. It is the second leading cause of death and is also the leading cause of disability worldwide. Stroke refers to a group of diseases that cause damage to brain tissue due to a sudden rupture of brain blood vessels or a blockage that prevents blood from flowing to the brain. Stroke is classified into two types: hemorrhagic and ischemic; approximately 80% of strokes are ischemic. Cerebral ischemia can induce excessive oxidative stress, destroy energy metabolism, and cause severe brain damage., Moreover, patients who survive an ischemic stroke will face a higher recurrence rate and the occurrence of other ischemic events. Therefore, many national and foreign researchers have conducted an increasing number of studies on ischemic stroke. Some progress has been made by studying certain aspects of the pathogenesis of ischemic stroke, such as anti-oxidative stress and anti-apoptosis. However, clinically effective ischemic stroke treatments and methods for improving prognosis remain lacking. In the past, studies on ischemic injury were limited to single cells or divided into different cell groups and structures in the brain, ignoring the integrity of the brain and the interaction between different structures. Subsequently, researchers realized that any brain disease resulted from the interaction of many cells and tissues. Therefore, strategies must jump out of the scope of a single cell and find a more comprehensive treatment plan for ischemic brain injury.
The proposal of the neurovascular unit brought researchers a conceptual model composed of brain endothelial cells, astrocytes, microglia, neurons, and the extracellular matrix. Based on the understanding of blood vessels and various cells in the brain tissue, the concept of the neurovascular unit was formed. Due to this concept, nerve cell damage caused by different reasons is regarded as a tissue damage process in which all cells and matrix components of the brain are involved. Neurovascular units maintain the integrity of the brain tissue and are a new target for clinical stroke treatments. These mainly include glial cells, which support the nerve cell system; neuronal axons, which act as signal transducers; and microvessels that provide energy to nerve tissue. The introduction of this concept includes closely related cells such as cerebral microvascular endothelial cells, astrocytes, and neurons in the brain as a whole and improves the protection of single neurons. It also includes reperfusion therapy of cerebral ischemia injury to the level of neurovascular unit protection and repair and has brought a new direction and opportunity for the treatment of ischemic stroke.
Ferulic acid (4-hydroxy-3-methoxycinnamic acid, FA) [Figure 1]a and [Figure 1]b is mainly distributed in the seeds and leaves of plants and often exists in free form or in combination with cell wall polysaccharides. Hence, plant cell walls are the main source of FA. Studies have shown that some medicinal plants contain FA, such as Angelica sinensis (Oliv.) Diels, Ligusticum chuanxiong Hort., Cimicifuga foetida L., Notopterygium incisum Ting ex H. T. Chang, and Allium cepa Linn. The FA content in Allium cepa was determined to be as high as 1.65% via high-performance liquid chromatography.,
|Figure 1: (a) Ferulic acid (4-hydroxy-3-methoxycinnamic acid, FA). (b) Three-dimensional conformation of ferulic acid|
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Since ancient times, Chinese herbal medicine has been used to treat neurological diseases. FA can reduce the damage to nerve cells, improve the repair of damaged cells, and is an effective free radical scavenger. FA has a neuroprotective effect on cerebral ischemia–reperfusion injury (I/R) by regulating Bcl-2/Bax-mediated apoptosis in the ischemic area. FA in A. sinensis was found to decrease the expression levels of peroxidase-2 and thioredoxin in a rat model of ischemic brain injury induced by MACO. It also maintains a balanced interaction between thioredoxin and apoptosis signal-regulating kinase 1, thereby inhibiting apoptosis. An anti-Alzheimer's disease study has shown that FA in A. sinensis inhibits polyamyloid β-protein (Aβ)-induced damage in differentiated PC-12 cells and can effectively inhibit and reduce cytotoxicity. In this study, Ginkgo biloba extract, as a positive control, inhibited Aβ aggregation and fibrillary formation, thereby reducing AGGAβ neurotoxicity.
Numerous studies have demonstrated that FA has neuroprotective effects and therapeutic effects on neurological diseases such as ischemic stroke. This article aims to provide some ideas and references for future therapies and ischemic stroke research on FA by reviewing its protective effect on ischemic stroke and its potential protective effect on the neurovascular unit.
| Protective Effects of Ferulic Acid on Ischemic Stroke|| |
Ferulic acid has neuroprotective effects. An increasing number of studies have shown that FA plays a protective role against nerve injury after ischemic stroke by promoting the growth of new blood vessels. Furthermore, it has antioxidant, anti-inflammatory, and anti-apoptotic properties. It can also modulate three isomers, modulate hippocampal protein expression and intracellular calcium levels, and modulate the expression of specific enzymes and several proteins.
Ferulic acid promotes the growth of new blood vessels
Currently, the efficacy of drugs that dissolve thrombin and improve cerebral flow in the treatment of ischemic stroke is not ideal, so more research focuses on the field of new angiogenesis. Angiogenesis refers to the growth of new vessels from the existing vessels. After ischemic stroke, neovascularization can not only restore blood flow in the ischemic border region but also promote endogenous neurogenesis and improve nerve function. Studies have shown that FA can promote angiogenesis. Specifically, it has been shown that FA can induce angiogenesis in human umbilical vein endothelial cell (HUVEC) blood vessels without cytotoxicity by promoting the expression of vascular endothelial growth factor (VEGF) and platelet-derived growth factor in HUVECs.
Antioxidant stress and anti-inflammatory functions of ferulic acid
Parvalbumin is mainly expressed in brain tissue. It can combine with calcium and play a calcium-buffering role, preventing neurons from being damaged by cytotoxic Ca2+ overload. Parvalbumin expression is decreased in animals with ischemic brains, but FA treatment counteracted the reduction in parvalbumin levels caused by ischemic injury. In addition, FA treatment in hippocampal cells can inhibit the increase in Ca2+ levels induced by glutamate toxicity.
γ-enolase is a neuron-specific enolase with a neuroprotective effect. Cerebral ischemic injury causes a decrease in the expression of γ-enolase in neuronal cells; however, FA treatment can attenuate the decline of γ-enolase expression and exert a neuroprotective effect.
Peroxiredoxin-2 is highly expressed in the brain and is a neuron-specific protein., It has been demonstrated that peroxiredoxin-2 plays a role in reducing brain damage after transient cerebral ischemia., Thioredoxin has neuroprotective and cytoprotective effects. Thioredoxin can attenuate oxidative stress and prevent caspase-3 expression, thereby reducing the volume of infarction and neuronal apoptosis after cerebral ischemia injury., During middle cerebral artery occlusion (MCAO), cerebral ischemic injury leads to decreased expression levels of peroxiredoxin-2 and thioredoxin. FA treatment can inhibit the decrease in the protein levels of peroxiredoxin-2 and thioredoxin and exert neuroprotective effects. In addition, FA has an anti-inflammatory effect and can attenuate inflammation-induced oxidative stress by downregulating the activation of microglia and macrophages in striatal injury areas.
Ferulic acid promotes the production of erythropoietin in the brain and peripheral blood
Erythropoietin (EPO) is the main regulator of erythropoiesis in mammals. It can stimulate the hematopoietic function of the bone marrow, increase the number of red blood cells in a timely and effective manner, and enhance the body's ability to combine, transport, and supply oxygen, thereby improving the state of hypoxia. It has been demonstrated that FA can reduce hippocampal nerve injury in ischemic rats, improve nerve function defects, and increase EPO expression in hippocampal and peripheral blood, suggesting that promoting EPO production in the brain and peripheral blood may be a neuroprotective mechanism of FA. It has also been shown that FA can increase EPO expression in the ischemic brain, increase EPO expression in peripheral blood, and enter the brain from the blood through the blood − brain barrier (BBB). This evidence suggests that promoting EPO production in the brain and peripheral blood may be a neuroprotective mechanism of FA.
Ferulic acid modulates the expression of three nitric oxide synthase isomers
Nitric oxide (NO) production is mediated by three different NO synthase (NOS) isomers: endothelial NOS (eNOS), inducible NOS (iNOS), and neuronal NOS (nNOS). It has been reported that eNOS can produce protective NO, whereas iNOS produces neurotoxic NO. In comparative experiments, eNOS levels decreased during MCAO; FA attenuated this decrease. However, the expression levels of iNOS and nNOS increased in MCAO-operated animals, and FA treatment prevented the injury-induced increase in the levels of these isoforms. These results suggest that FA may exert neuroprotective effects by upregulating or downregulating the expression of the three NOS isomers.
Anti-apoptotic effects of ferulic acid
FA can activate or inhibit multiple signal transduction pathways; hence, it might play an anti-apoptotic role. [Figure 2] shows the anti-apoptotic signaling pathway regulated by FA.,,,,,
|Figure 2: The anti-apoptotic signaling pathway regulated by ferulic acid. Astrocyte 15 (PEA-15) is highly expressed in the CNS. It is rich in phosphorylated proteins and can regulate apoptosis. PEA-15 plays a neuroprotective role by binding to FADD, inhibiting the activation of the caspase cascade, and mediating and blocking TNF-α-induced apoptotic cell death. After a cerebral ischemic injury occurs, the expression of TNF-α increases, and the level of PEA-15 decreases. FA treatment can inhibit the decrease of PEA-15 levels induced by cerebral ischemic injury. Experiments have shown that after pretreatment with FA, the signaling pathway mediated by HSP70/Bcl-2 is upregulated, the integrity of the outer membrane of the mitochondria is protected, and the apoptosis pathway is suppressed, which is induced by Bax, Cytochrome c/Smac/DIABLO/XIAP/caspase-3, and AIF. PEA-15: Phosphoprotein enriched in astrocytes, CNS: Central nervous system, FA: Ferulic acid, TNF-α: Tumor necrosis factor-alpha|
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Apoptosis is an important factor that exacerbates cerebral infarction during cerebral ischemia. Heat-shock proteins (HSPs) are functionally related proteins, and their related functions are usually induced by heat, heavy metals, ischemic injury, and other stress stimuli. The 70-kDa HSP (HSP70) has neuroprotective effects. Its overexpression can activate the anti-apoptotic pathway in the ischemic area and protect against ischemic injury. There are two ways for mitochondria to regulate apoptosis: the caspase-dependent pathway or the independent pathway. The integrity of the mitochondrial membrane also has a significant effect on mitochondrial-mediated apoptosis, and its absence indirectly leads to caspase-dependent apoptosis. FA protects the integrity of the mitochondrial membrane and prevents caspase-dependent apoptosis.
Cerebral ischemic injury causes a decrease in the levels of phospho-PKD1, phospho-Akt, and phospho-bad. FA treatment can inhibit the reduction in the levels of these proteins, greatly reducing the infarct volume caused by the injury. The 14-3-3 protein and Bcl-xl can interact with phospho-Bad and exert anti-apoptotic effects. Cerebral ischemia-induced injury weakens the interaction between phospho-Bad and 14-3-3 proteins. Pretreatment with FA not only does not affect the expression of 14-3-3 protein and Bcl-xl but also prevents damage-induced interaction levels from decreasing. Further research has shown that FA can also inhibit the decrease in mTOR, p70S6 kinase, and S6 phosphorylation levels induced by cerebral ischemic injury, so the neuroprotective effect against focal cerebral ischemia can be exerted.
Cerebral I/R injury model experiments have shown that FA can inhibit apoptosis, Ca2+ influx, and the production of the superoxide anion (O2−), malondialdehyde, and glutathione peroxidase. This protects against oxidative stress and apoptosis induced by I/R injury.
Mitogen-activated protein (MAP) kinase can regulate many cell functions, including cell proliferation, differentiation, and death. FA, which activates the MAP kinase signaling pathway, prevents the reduction of phosphor-AF1, phosphor-MEK1/2, phosphor-ERK1/2, phosphor-p90RSK, and phosphor-Bad levels due to MCAO injury, thereby reducing apoptosis after focal cerebral ischemia. FA can also activate the p38 MAPK/p90RSK/CREB/Bcl-2 signaling pathway, regulate apoptosis induced by Bax, inhibit the cortical penumbral cytochrome c-mediated caspase-3-dependent apoptosis pathway, and play a neuroprotective role in cerebral infarction.
FA has neuroprotective effects on p38 MAP kinase-mediated NO-induced apoptosis at 24 h of reperfusion by significantly increasing GABAB1 receptor expression.
Ferulic acid modulates hippocampal protein expression and intracellular calcium levels
FA can reduce the increase of hippocampal calcium caused by injury and weaken the increase of intracellular calcium level to play a neuroprotective role.
Ischemic brain injury disturbs the balance of intracellular calcium levels, induces an increase in intracellular calcium concentration, and activates the caspase cascade, leading to apoptosis and necrotic cell death. Hippocalcin is a calcium-buffering protein. It can be combined with Ca2+ and then released into the cytoplasm, thereby maintaining a steady state of Ca2+ ions in the central nervous system (CNS). In neuronal cells, the excitatory toxicity of excessive calcium induces apoptosis, leading to disorders of the CNS., Hippocalcin can remove excessive intracellular calcium and play a neuroprotective role. After a focal cerebral ischemic injury, FA treatment exerts a neuroprotective effect by regulating intracellular calcium levels and hippocampal protein expression. FA can also maintain the expression level of hippocampal proteins in neuronal cells during focal cerebral ischemia, thereby regulating the balance of intracellular calcium and exerting neuroprotective effects.
Ferulic acid modulates the expression of specific proteins
Protein phosphatase 2A (PP2A) is an important serine and threonine phosphatase that regulates cell differentiation, apoptosis, signal transduction,,,, and normal brain function. PP2A contains multiple subunits: A, B, and C. The A and C subunits are highly expressed in most tissues, and the B subunits are abundant in the brain. Therefore, the B subunit can regulate the function of PP2A in the nervous system, and regulating the expression of the B subunit can make PP2A play a different role in the nervous system. Related studies have shown that the B subunit of PP2A has a reduced expression due to MCAO and glutamate-induced damage. FA treatment can inhibit the downregulation of the B subunit due to cerebral ischemic injury, thereby protecting neuronal cells and reducing neuronal cell death. This result suggests that FA may play a neuroprotective role by maintaining the PP2A subunit in MCAO.
Adenosine homocysteine is a catabolic enzyme abundant in the cerebral cortex, hippocampus, and cerebellum; NAD+-dependent isocitrate dehydrogenase participates in energy metabolism, and GAPDH is a glycolytic enzyme that catalyzes glycolysis. These three enzymes are all involved in energy metabolism. Cerebral ischemia can alter the energy metabolism of cells, resulting in a decrease in the concentration and expression of these three enzymes, resulting in a weakened neuroprotective effect. FA treatment can prevent the concentration of these three enzymes from decreasing, thereby helping regulate energy metabolism due to cerebral ischemic injury and ultimately playing a neuroprotective role.
| Potential Protective Effect of Ferulic Acid on Neurovascular Units|| |
The concept of a neurovascular unit regarded brain diseases as lesions that occurred in the brain as a whole, rather than as a result of a single cell or tissue. At present, there is no research on the effect of FA on the neurovascular unit. However, studies have demonstrated that FA has a protective effect on cerebral endothelial cells, astrocytes, and neurons. Therefore, this article mainly reviews the protective mechanism of FA on cerebral microvascular endothelial cells, astrocytes, microglia, and neurons. Based on the protective effect of FA on several major cells in the neurovascular unit, it is speculated that FA has a potential protective effect on the whole neurovascular unit.
Protective effect of ferulic acid on cerebral microvascular endothelial cells
FA alleviates oxidative damage in brain microvascular endothelial cells (BMECs), the core components of the BBB, through punctate mitochondria-dependent mitophagy. The BBB has a selective barrier function that plays a vital role in many cerebrovascular diseases.
Mitochondria are the primary sites in which cells produce energy. In the oxygen-glucose deprivation (OGD) state, the rapid increase in cellular reactive oxygen species (ROS) hinders mitochondrial energy metabolism and destroys the structure of the mitochondrial network. Currently, researchers found that damaged mitochondria may be degraded by a special autophagy process called mitochondrial phagocytosis, which alleviates cellular oxidative stress caused by mitochondrial dysfunction. Previous research has shown that FA treatment alleviates BMEC damage caused by OGD via punctate mitochondria-dependent mitophagy and attenuates the oxidative damage in mitochondria caused by OGD by upregulating the expression of LC3-II, promoting autophagy.
Protective effect of ferulic acid on astrocytes
The most widely distributed cell types in the mammalian brain are the astrocytes, the largest glial cells. They fill the gaps between the cell body and the processes of nerve cells, supporting and separating neurons. FA mainly protects astrocytes by inhibiting the expression of iNOS and increasing NO levels.
Astrocytes play an important role in inflammation and neurodegenerative diseases of the CNS.,, When brain lesions occur in astrocytes, some neurotoxic peptides induce the overexpression of iNOS and other inflammatory factors through the nuclear transcription factor-κB (NF-κB) pathway, resulting in the death of astrocytes. FA pretreatment protects astrocytes by inhibiting the NF-κB pathway, inhibiting the expression of iNOS, and increasing intracellular NO levels.,,
Protective effect of ferulic acid on microglia
Microglia are glial cells in the brain that clear damaged nerves in the CNS. The activation of microglia plays a very important role in the pathogenesis of neurodegenerative diseases, but excessive activation can cause neurotoxicity and inflammation. Studies have shown that FA may act on ROS and NLRP3 inflammasomes to resist various inflammatory factors and inhibit the inflammatory response mediated by excessive activation of microglia.
Some researchers have also proved that FA targets toll-like receptor 4 in the hippocampi of mice, inhibiting the activation of glial cells and its downstream inflammatory factors such as COX2, tumor necrosis factor-alpha, and interleukin-1β, among others. These results show that FA exerts a neuroprotective effect by acting directly or indirectly on glial cells.
Protective effect of ferulic acid on neurons
The basic structure of the nervous system is the neuron, which is also a functional unit of the nervous system. Neurons have the function of receiving sensory information and integrating sensory information, distributing it to skeletal muscle, and controlling movement.
FA promotes the proliferation of neural stem progenitor cells, such as neural stem cells (NSCs) and neural precursor cells (NPCs) and promotes the survival of nerve cells, the formation of neurospheres, the growth of neurites, and the excitability of neural networks in vitro. FA also inhibits endoplasmic reticulum (ER) stress and other effects, playing a protective role in neurons.
Ferulic acid can promote the differentiation and proliferation of neural stem cell/neural precursor cell
NSCs are neurogenic pluripotent cells with self-renewal and proliferation ability, while NPCs are pluripotent cells that can differentiate into neurons and glial cells in the nervous system. Neurons activate NSCs after injury, allowing NSCs to gather at the injury site to replace dead neurons., NSCs can also be derived form human embryonic stem cells, and can proliferate to form neurospheres containing neuros.
FA treatment can significantly promote the proliferation of NSC/NPCs, increasing the number and size of neurospheres formed, promoting the differentiation of NSCs into mature neurons,, increasing the number of neurons, and indirectly protecting them.
Ferulic acid can inhibit endoplasmic reticulum stress
ER stress can cause neuronal cell death. Transcription of the ER chaperone protein-encoding genes GRP78/Bip, GRP94, and protein disulfide isomerase can be induced by the ER to promote protein folding. This induction system is called the unfolded protein response.,,,
The mRNA expression level of GPR78/Bip was increased and the induction of CHOP caused by ER stress was decreased upon pretreatment with FA in mouse neuroblastoma cell line, Neuro2a (N2a). In addition, FA can also inhibit the activation of caspase-4 by affecting the UPOR after ER stress, thereby inhibiting ER stress-induced neuronal death.
| Mechanisms of Neurovascular Unit Protection|| |
With the recent deepening of the understanding and emphasis on the neurovascular unit, the protection and repair of the neurovascular unit are gradually taken as the main treatment measures when an ischemic stroke occurs. Many current studies have proven that some marker proteins that act on the core components of neurovascular units, such as VEGF, glial fibrillary acidic protein, neuronal nuclear antigen (neuronal nuclei antigen, NeuN), and Wnt/β-catenin signaling pathway key proteins β-catenin and the scaffold protein Axin2, have certain therapeutic and repair effects on ischemic stroke. For example, activating brain endothelial microvascular growth factors can promote the formation of new blood vessels, promote endogenous neurogenesis, and improve nerve function. After an ischemic stroke, activating the Wnt/β-catenin signaling pathway can promote the differentiation of NSCs, promote nerve regeneration, reduce the size of cerebral infarctions, and accelerate the recovery of nerve function., However, there are still many unknown neurovascular unit-related proteins and the relationship between ischemic stroke is unclear. Hence, researchers need to conduct more comprehensive mechanistic studies, but current reports still suggest that improving the treatment for neurovascular units in an ischemic brain is an important measure for stroke prevention.
| Conclusions|| |
FA is a phenolic compound abundant in plants. It is included in the active ingredients of many Chinese herbal medicines, such as A. sinensis, Cimicifuga heracleifo Komar, and Lycium barbarum. It has antioxidant, anti-apoptotic, free radical scavenging, neuroprotective, and other pharmacological effects. According to the current research results, FA has a protective effect on brain tissue damage after the onset of ischemic stroke. The specific mechanisms of action of FA on the different units of the CNS have been clearly explained, suggesting that it has the potential to be a new therapeutic or prognostic agent for ischemic stroke.
Neurovascular units are composed of many cells and elements, such as circulating blood elements, astrocytes, endothelial cells, extracellular matrix, and adjacent neurons. The neurovascular unit maintains the normal physiological function of neurons and ameliorates neuronal damage. The purpose of this concept was to emphasize the importance of the interaction and interrelation between these units, by clustering them together as one unit. After the onset of nervous system diseases, neurovascular functional integrity is disrupted, causing multiple cascade injuries. It can be seen from the data presented that FA has a protective effect on brain endothelial cells, astrocytes, microglia, and neurons. However, this report is not yet exhaustive, and many other protection mechanisms are still awaiting discovery. Based on this, it is speculated that FA has a potential protective effect on neurovascular units composed mainly composed of brain endothelial cells, astrocytes, and neurons. Although the mechanisms of protection are yet unclear, further research is needed, but this provides a new direction and reference for the study of the neuroprotective effects of FA.
The treatment of ischemic stroke with FA can be linked to the neurovascular unit to provide a new, multi-target, holistic treatment method in the future. This will help in the full development of FA as a rich medicinal natural medicine resource.
The authors are thankful to the Tianjin University of Traditional Chinese Medicine for their help in conducting this study.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest to declare.
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