• Users Online: 1975
  • Print this page
  • Email this page

 
Table of Contents
REVIEW ARTICLE
Year : 2022  |  Volume : 8  |  Issue : 2  |  Page : 210-217

Effects of ferulic acid on regulating the neurovascular unit: Implications for ischemic stroke treatment


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 Submission03-Aug-2020
Date of Acceptance30-Apr-2021
Date of Web Publication30-Jun-2022

Correspondence Address:
Xiang Fan
548, Binwen Road, Binjiang District, Hangzhou, Zhejiang 310000
China
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/wjtcm.wjtcm_76_21

Rights and Permissions
  Abstract 


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 Top


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.[1] Cerebral ischemia can induce excessive oxidative stress, destroy energy metabolism, and cause severe brain damage.[2],[3] 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.[4]

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.[5] 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.[6],[7]
Figure 1: (a) Ferulic acid (4-hydroxy-3-methoxycinnamic acid, FA). (b) Three-dimensional conformation of ferulic acid

Click here to view


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,[8] 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.[9] 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.[10] It also maintains a balanced interaction between thioredoxin and apoptosis signal-regulating kinase 1, thereby inhibiting apoptosis.[10] 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.[11] In this study, Ginkgo biloba extract, as a positive control, inhibited Aβ aggregation and fibrillary formation, thereby reducing AGGAβ neurotoxicity.[11]

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 Top


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.[12]

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.[13]

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.[14]

Peroxiredoxin-2 is highly expressed in the brain and is a neuron-specific protein.[15],[16] It has been demonstrated that peroxiredoxin-2 plays a role in reducing brain damage after transient cerebral ischemia.[17],[18] Thioredoxin has neuroprotective and cytoprotective effects.[19] Thioredoxin can attenuate oxidative stress and prevent caspase-3 expression, thereby reducing the volume of infarction and neuronal apoptosis after cerebral ischemia injury.[20],[21] 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.[10] 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.[22]

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.[23]

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.[24] 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.[25]

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.[26],[27],[28],[29],[30],[31]
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.[9] PEA-15: Phosphoprotein enriched in astrocytes, CNS: Central nervous system, FA: Ferulic acid, TNF-α: Tumor necrosis factor-alpha

Click here to view


Apoptosis is an important factor that exacerbates cerebral infarction during cerebral ischemia.[32] 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.[33] The 70-kDa HSP (HSP70) has neuroprotective effects.[34] Its overexpression can activate the anti-apoptotic pathway in the ischemic area and protect against ischemic injury.[35] There are two ways for mitochondria to regulate apoptosis: the caspase-dependent pathway or the independent pathway.[36] The integrity of the mitochondrial membrane also has a significant effect on mitochondrial-mediated apoptosis, and its absence indirectly leads to caspase-dependent apoptosis.[37] FA protects the integrity of the mitochondrial membrane and prevents caspase-dependent apoptosis.[9]

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.[38] 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.[39]

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.[40]

Mitogen-activated protein (MAP) kinase can regulate many cell functions, including cell proliferation, differentiation, and death.[41] 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.[42] 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.[43]

FA has neuroprotective effects on p38 MAP kinase-mediated NO-induced apoptosis at 24 h of reperfusion by significantly increasing GABAB1 receptor expression.[44]

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.[45]

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.[46] 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).[47] In neuronal cells, the excitatory toxicity of excessive calcium induces apoptosis, leading to disorders of the CNS.[47],[48] 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.[45]

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,[49],[50],[51],[52] and normal brain function.[53] 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.[54] 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.[55] 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.[56]

Adenosine homocysteine is a catabolic enzyme abundant in the cerebral cortex, hippocampus, and cerebellum;[57] NAD+-dependent isocitrate dehydrogenase participates in energy metabolism,[58] 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.[59]


  Potential Protective Effect of Ferulic Acid on Neurovascular Units Top


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.[60]

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.[61] 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.[62] 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.[63]

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.[64],[65],[66] 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.[67],[68],[69]

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.[70]

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.[71] 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,[72] 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.[73],[74] NSCs can also be derived form human embryonic stem cells, and can proliferate to form neurospheres containing neuros.[75]

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,[76],[77] 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.[78],[79],[80],[81]

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.[82]


  Mechanisms of Neurovascular Unit Protection Top


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.[83] For example, activating brain endothelial microvascular growth factors can promote the formation of new blood vessels, promote endogenous neurogenesis, and improve nerve function.[12] 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.[84],[85] 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 Top


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.[4] 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.

Acknowledgments

The authors are thankful to the Tianjin University of Traditional Chinese Medicine for their help in conducting this study.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest to declare.



 
  References Top

1.
Thrift AG, Dewey HM, Macdonell RA, McNeil JJ, Donnan GA. Incidence of the major stroke subtypes: Initial findings from the North East Melbourne stroke incidence study (NEMESIS). Stroke 2001;32:1732-8.  Back to cited text no. 1
    
2.
Blomgren K, Hagberg H. Free radicals, mitochondria, and hypoxia-ischemia in the developing brain. Free Radic Biol Med 2006;40:388-97.  Back to cited text no. 2
    
3.
Allen CL, Bayraktutan U. Oxidative stress and its role in the pathogenesis of ischaemic stroke. Int J Stroke 2009;4:461-70.  Back to cited text no. 3
    
4.
Lo EH, Dalkara T, Moskowitz MA. Mechanisms, challenges and opportunities in stroke. Nat Rev Neurosci 2003;4:399-415.  Back to cited text no. 4
    
5.
Kumar N, Pruthi V. Potential applications of ferulic acid from natural sources. Biotechnol Rep (Amst) 2014;4:86-93.  Back to cited text no. 5
    
6.
Zhang X, Gao ZP. Research progress in ferulic acid. Mod Chin Med 2020;22:138-47.  Back to cited text no. 6
    
7.
Mancuso C, Santangelo R. Ferulic acid: Pharmacological and toxicological aspects. Food Chem Toxicol 2014;65:185-95.  Back to cited text no. 7
    
8.
Zduńska K, Dana A, Kolodziejczak A, Rotsztejn H. Antioxidant properties of ferulic acid and its possible application. Skin Pharmacol Physiol 2018;31:332-6.  Back to cited text no. 8
    
9.
Cheng CY, Kao ST, Lee YC. Ferulic acid exerts anti-apoptotic effects against ischemic injury by activating HSP70/Bcl-2- and HSP70/autophagy-mediated signaling after permanent focal cerebral ischemia in rats. Am J Chin Med 2019;47:39-61.  Back to cited text no. 9
    
10.
Sung JH, Gim SA, Koh PO. Ferulic acid attenuates the cerebral ischemic injury-induced decrease in peroxiredoxin-2 and thioredoxin expression. Neurosci Lett 2014;566:88-92.  Back to cited text no. 10
    
11.
Wei WL, Zeng R, Gu CM, Qu Y, Huang LF. Angelica sinensis in China – A review of botanical profile, ethnopharmacology, phytochemistry and chemical analysis. J Ethnopharmacol 2016;190:116-41.  Back to cited text no. 11
    
12.
Zhang Q, Zhao YH. Therapeutic angiogenesis after ischemic stroke: Chinese medicines, bone marrow stromal cells (BMSCs) and their combinational treatment. Am J Chin Med 2014;42:61-77.  Back to cited text no. 12
    
13.
Sung JH, Kim MO, Koh PO. Ferulic acid attenuates the focal cerebral ischemic injury-induced decrease in parvalbumin expression. Neurosci Lett 2012;516:146-50.  Back to cited text no. 13
    
14.
Gim SA, Koh PO. Ferulic acid prevents the injury-induced decrease of γ-enolase expression in brain tissue and HT22 cells. Lab Anim Res 2014;30:8-13.  Back to cited text no. 14
    
15.
Sarafian TA, Verity MA, Vinters HV, Shih CC, Shi L, Ji XD, et al. Differential expression of peroxiredoxin subtypes in human brain cell types. J Neurosci Res 1999;56:206-12.  Back to cited text no. 15
    
16.
Jin MH, Lee YH, Kim JM, Sun HN, Moon EY, Shong MH, et al. Characterization of neural cell types expressing peroxiredoxins in mouse brain. Neurosci Lett 2005;381:252-7.  Back to cited text no. 16
    
17.
Boulos S, Meloni BP, Arthur PG, Bojarski C, Knuckey NW. Peroxiredoxin 2 overexpression protects cortical neuronal cultures from ischemic and oxidative injury but not glutamate excitotoxicity, whereas Cu/Zn superoxide dismutase 1 overexpression protects only against oxidative injury. J Neurosci Res 2007;85:3089-97.  Back to cited text no. 17
    
18.
Gan Y, Ji X, Hu X, Luo Y, Zhang L, Li P, et al. Transgenic overexpression of peroxiredoxin-2 attenuates ischemic neuronal injury via suppression of a redox-sensitive pro-death signaling pathway. Antioxid Redox Signal 2012;17:719-32.  Back to cited text no. 18
    
19.
Masutani H, Bai J, Kim YC, Yodoi J. Thioredoxin as a neurotrophic cofactor and an important regulator of neuroprotection. Mol Neurobiol 2004;29:229-42.  Back to cited text no. 19
    
20.
Zhou F, Gomi M, Fujimoto M, Hayase M, Marumo T, Masutani H, et al. Attenuation of neuronal degeneration in thioredoxin-1 overexpressing mice after mild focal ischemia. Brain Res 2009;1272:62-70.  Back to cited text no. 20
    
21.
Ma YH, Su N, Chao XD, Zhang YQ, Zhang L, Han F, et al. Thioredoxin-1 attenuates post-ischemic neuronal apoptosis via reducing oxidative/nitrative stress. Neurochem Int 2012;60:475-83.  Back to cited text no. 21
    
22.
Cheng CY, Su SY, Tang NY, Ho TY, Chiang SY, Hsieh CL. Ferulic acid provides neuroprotection against oxidative stress-related apoptosis after cerebral ischemia/reperfusion injury by inhibiting ICAM-1 mRNA expression in rats. Brain Res 2008;1209:136-50.  Back to cited text no. 22
    
23.
Zhang L, Wang H, Wang T, Jiang N, Yu P, Chong Y, et al. Ferulic acid ameliorates nerve injury induced by cerebral ischemia in rats. Exp Ther Med 2015;9:972-6.  Back to cited text no. 23
    
24.
Wynia-Smith SL, Smith BC. Nitrosothiol formation and S-nitrosation signaling through nitric oxide synthases. Nitric Oxide 2017;63:52-60.  Back to cited text no. 24
    
25.
Koh PO. Ferulic acid modulates nitric oxide synthase expression in focal cerebral ischemia. Lab Anim Res 2012;28:273-8.  Back to cited text no. 25
    
26.
Krueger J, Chou FL, Glading A, Schaefer E, Ginsberg MH. Phosphorylation of phosphoprotein enriched in astrocytes (PEA-15) regulates extracellular signal-regulated kinase-dependent transcription and cell proliferation. Mol Biol Cell 2005;16:3552-61.  Back to cited text no. 26
    
27.
Renault F, Formstecher E, Callebaut I, Junier MP, Chneiweiss H. The multifunctional protein PEA-15 is involved in the control of apoptosis and cell cycle in astrocytes. Biochem Pharmacol 2003;66:1581-8.  Back to cited text no. 27
    
28.
Sharif A, Canton B, Junier MP, Chneiweiss H. PEA-15 modulates TNFalpha intracellular signaling in astrocytes. Ann N Y Acad Sci 2003;1010:43-50.  Back to cited text no. 28
    
29.
Kitsberg D, Formstecher E, Fauquet M, Kubes M, Cordier J, Canton B, et al. Knock-out of the neural death effector domain protein PEA-15 demonstrates that its expression protects astrocytes from TNFalpha-induced apoptosis. J Neurosci 1999;19:8244-51.  Back to cited text no. 29
    
30.
Dawson DA, Martin D, Hallenbeck JM. Inhibition of tumor necrosis factor-alpha reduces focal cerebral ischemic injury in the spontaneously hypertensive rat. Neurosci Lett 1996;218:41-4.  Back to cited text no. 30
    
31.
Koh PO. Ferulic acid prevents the cerebral ischemic injury-induced decreases of astrocytic phosphoprotein PEA-15 and its two phosphorylated forms. Neurosci Lett 2012;511:101-5.  Back to cited text no. 31
    
32.
Tsuchiya D, Hong S, Matsumori Y, Shiina H, Kayama T, Swanson RA, et al. Overexpression of rat heat shock protein 70 is associated with reduction of early mitochondrial cytochrome C release and subsequent DNA fragmentation after permanent focal ischemia. J Cereb Blood Flow Metab 2003;23:718-27.  Back to cited text no. 32
    
33.
Kwon HM, Kim Y, Yang SI, Kim YJ, Lee SH, Yoon BW. Geldanamycin protects rat brain through overexpression of HSP70 and reducing brain edema after cerebral focal ischemia. Neurol Res 2008;30:740-5.  Back to cited text no. 33
    
34.
Kang L, Zhang G, Yan Y, Ke K, Wu X, Gao Y, et al. The role of HSPA12B in regulating neuronal apoptosis. Neurochem Res 2013;38:311-20.  Back to cited text no. 34
    
35.
Hishiya A, Takayama S. Molecular chaperones as regulators of cell death. Oncogene 2008;27:6489-506.  Back to cited text no. 35
    
36.
Obrenovitch TP. Molecular physiology of preconditioning-induced brain tolerance to ischemia. Physiol Rev 2008;88:211-47.  Back to cited text no. 36
    
37.
Uren RT, Dewson G, Bonzon C, Lithgow T, Newmeyer DD, Kluck RM. Mitochondrial release of pro-apoptotic proteins: Electrostatic interactions can hold cytochrome c but not Smac/DIABLO to mitochondrial membranes. J Biol Chem 2005;280:2266-74.  Back to cited text no. 37
    
38.
Koh PO. Ferulic acid prevents the cerebral ischemic injury-induced decrease of Akt and Bad phosphorylation. Neurosci Lett 2012;507:156-60.  Back to cited text no. 38
    
39.
Koh PO. Ferulic acid attenuates focal cerebral ischemia-induced decreases in p70S6 kinase and S6 phosphorylation. Neurosci Lett 2013;555:7-11.  Back to cited text no. 39
    
40.
Ren Z, Zhang R, Li Y, Li Y, Yang Z, Yang H. Ferulic acid exerts neuroprotective effects against cerebral ischemia/reperfusion-induced injury via antioxidant and anti-apoptotic mechanisms in vitro and in vivo. Int J Mol Med 2017;40:1444-56.  Back to cited text no. 40
    
41.
Noshita N, Sugawara T, Hayashi T, Lewén A, Omar G, Chan PH. Copper/zinc superoxide dismutase attenuates neuronal cell death by preventing extracellular signal-regulated kinase activation after transient focal cerebral ischemia in mice. J Neurosci 2002;22:7923-30.  Back to cited text no. 41
    
42.
Shin TJ, Cho D, Ham J, Choi DH, Kim S, Jeong S, et al. Changes in thalamo-frontal interaction under different levels of anesthesia in rats. Neurosci Lett 2016;627:18-23.  Back to cited text no. 42
    
43.
Cheng CY, Tang NY, Kao ST, Hsieh CL. Ferulic acid administered at various time points protects against cerebral infarction by activating p38 MAPK/p90RSK/CREB/Bcl-2 anti-apoptotic signaling in the subacute phase of cerebral ischemia-reperfusion injury in rats. PLoS One 2016;11:e0155748.  Back to cited text no. 43
    
44.
Cheng CY, Su SY, Tang NY, Ho TY, Lo WY, Hsieh CL. Ferulic acid inhibits nitric oxide-induced apoptosis by enhancing GABA (B1) receptor expression in transient focal cerebral ischemia in rats. Acta Pharmacol Sin 2010;31:889-99.  Back to cited text no. 44
    
45.
Koh PO. Ferulic acid prevents cerebral ischemic injury-induced reduction of hippocalcin expression. Synapse 2013;67:390-8.  Back to cited text no. 45
    
46.
Hayashi T, Abe K. Ischemic neuronal cell death and organellae damage. Neurol Res 2004;26:827-34.  Back to cited text no. 46
    
47.
Baimbridge KG, Celio MR, Rogers JH. Calcium-binding proteins in the nervous system. Trends Neurosci 1992;15:303-8.  Back to cited text no. 47
    
48.
Bleakman D, Roback JD, Wainer BH, Miller RJ, Harrison NL. Calcium homeostasis in rat septal neurons in tissue culture. Brain Res 1993;600:257-67.  Back to cited text no. 48
    
49.
Millward TA, Zolnierowicz S, Hemmings BA. Regulation of protein kinase cascades by protein phosphatase 2A. Trends Biochem Sci 1999;24:186-91.  Back to cited text no. 49
    
50.
Zolnierowicz S. Type 2A protein phosphatase, the complex regulator of numerous signaling pathways. Biochem Pharmacol 2000;60:1225-35.  Back to cited text no. 50
    
51.
Janssens V, Goris J. Protein phosphatase 2A: A highly regulated family of serine/threonine phosphatases implicated in cell growth and signalling. Biochem J 2001;353:417-39.  Back to cited text no. 51
    
52.
Sontag E, Nunbhakdi-Craig V, Lee G, Bloom GS, Mumby MC. Regulation of the phosphorylation state and microtubule-binding activity of Tau by protein phosphatase 2A. Neuron 1996;17:1201-7.  Back to cited text no. 52
    
53.
Gong CX, Lidsky T, Wegiel J, Zuck L, Grundke-Iqbal I, Iqbal K. Phosphorylation of microtubule-associated protein tau is regulated by protein phosphatase 2A in mammalian brain. Implications for neurofibrillary degeneration in Alzheimer's disease. J Biol Chem 2000;275:5535-44.  Back to cited text no. 53
    
54.
Strack S, Zaucha JA, Ebner FF, Colbran RJ, Wadzinski BE. Brain protein phosphatase 2A: Developmental regulation and distinct cellular and subcellular localization by B subunits. J Comp Neurol 1998;392:515-27.  Back to cited text no. 54
    
55.
Sim AT. The regulation and function of protein phosphatases in the brain. Mol Neurobiol 1991;5:229-46.  Back to cited text no. 55
    
56.
Koh PO. Ferulic acid attenuates the injury-induced decrease of protein phosphatase 2A subunit B in ischemic brain injury. PLoS One 2013;8:e54217.  Back to cited text no. 56
    
57.
Patel BT, Tudball N. Localization of S-adenosylhomocysteine hydrolase and adenosine deaminase immunoreactivities in rat brain. Brain Res 1986;370:250-64.  Back to cited text no. 57
    
58.
Barnes LD, Kuehn GD, Atkinson DE. Yeast diphosphopyridine nucleotide specific isocitrate dehydrogenase. Purification and some properties. Biochemistry 1971;10:3939-44.  Back to cited text no. 58
    
59.
Sung JH, Cho EH, Cho JH, Won CK, Kim MO, Koh PO. Identification of proteins regulated by ferulic acid in a middle cerebral artery occlusion animal model-a proteomics approach. J Vet Med Sci 2012;74:1401-7.  Back to cited text no. 59
    
60.
Wardlaw JM. Blood-brain barrier and cerebral small vessel disease. J Neurol Sci 2010;299:66-71.  Back to cited text no. 60
    
61.
Fischer TD, Hylin MJ, Zhao J, Moore AN, Waxham MN, Dash PK. Altered mitochondrial dynamics and TBI pathophysiology. Front Syst Neurosci 2016;10:29.  Back to cited text no. 61
    
62.
Scherz-Shouval R, Elazar Z. ROS, mitochondria and the regulation of autophagy. Trends Cell Biol 2007;17:422-7.  Back to cited text no. 62
    
63.
Chen JL, Duan WJ, Luo S, Li S, Ma XH, Hou BN, et al. Ferulic acid attenuates brain microvascular endothelial cells damage caused by oxygen-glucose deprivation via punctate-mitochondria-dependent mitophagy. Brain Res 2017;1666:17-26.  Back to cited text no. 63
    
64.
Heneka MT, Rodríguez JJ, Verkhratsky A. Neuroglia in neurodegeneration. Brain Res Rev 2010;63:189-211.  Back to cited text no. 64
    
65.
Hamby ME, Sofroniew MV. Reactive astrocytes as therapeutic targets for CNS disorders. Neurotherapeutics 2010;7:494-506.  Back to cited text no. 65
    
66.
Moncada S, Bolaños JP. Nitric oxide, cell bioenergetics and neurodegeneration. J Neurochem 2006;97:1676-89.  Back to cited text no. 66
    
67.
Nomura Y. NF-kappaB activation and IkappaB alpha dynamism involved in iNOS and chemokine induction in astroglial cells. Life Sci 2001;68:1695-701.  Back to cited text no. 67
    
68.
Saha RN, Pahan K. Regulation of inducible nitric oxide synthase gene in glial cells. Antioxid Redox Signal 2006;8:929-47.  Back to cited text no. 68
    
69.
Kikugawa M, Ida T, Ihara H, Sakamoto T. Ferulic acid and its water-soluble derivatives inhibit nitric oxide production and inducible nitric oxide synthase expression in rat primary astrocytes. Biosci Biotechnol Biochem 2017;81:1607-11.  Back to cited text no. 69
    
70.
Bao Y, Chen Q, Xie Y, Tao Z, Jin K, Chen S, et al. Ferulic acid attenuates oxidative DNA damage and inflammatory responses in microglia induced by benzo(a)pyrene. Int Immunopharmacol 2019;77:105980.  Back to cited text no. 70
    
71.
Rehman SU, Ali T, Alam SI, Ullah R, Zeb A, Lee KW, et al. Ferulic acid rescues LPS-induced neurotoxicity via modulation of the TLR4 receptor in the mouse hippocampus. Mol Neurobiol 2019;56:2774-90.  Back to cited text no. 71
    
72.
Gage FH. Mammalian neural stem cells. Science 2000;287:1433-8.  Back to cited text no. 72
    
73.
Nakatomi H, Kuriu T, Okabe S, Yamamoto S, Hatano O, Kawahara N, et al. Regeneration of hippocampal pyramidal neurons after ischemic brain injury by recruitment of endogenous neural progenitors. Cell 2002;110:429-41.  Back to cited text no. 73
    
74.
Russo I, Barlati S, Bosetti F. Effects of neuroinflammation on the regenerative capacity of brain stem cells. J Neurochem 2011;116:947-56.  Back to cited text no. 74
    
75.
Chaddah R, Arntfield M, Runciman S, Clarke L, van der Kooy D. Clonal neural stem cells from human embryonic stem cell colonies. J Neurosci 2012;32:7771-81.  Back to cited text no. 75
    
76.
Gu L, Cui X, Wei W, Yang J, Li X. Ferulic acid promotes survival and differentiation of neural stem cells to prevent gentamicin-induced neuronal hearing loss. Exp Cell Res 2017;360:257-63.  Back to cited text no. 76
    
77.
Yabe T, Hirahara H, Harada N, Ito N, Nagai T, Sanagi T, et al. Ferulic acid induces neural progenitor cell proliferation in vitro and in vivo. Neuroscience 2010;165:515-24.  Back to cited text no. 77
    
78.
Sidrauski C, Chapman R, Walter P. The unfolded protein response: An intracellular signalling pathway with many surprising features. Trends Cell Biol 1998;8:245-9.  Back to cited text no. 78
    
79.
Tirasophon W, Welihinda AA, Kaufman RJ. A stress response pathway from the endoplasmic reticulum to the nucleus requires a novel bifunctional protein kinase/endoribonuclease (Ire1p) in mammalian cells. Genes Dev 1998;12:1812-24.  Back to cited text no. 79
    
80.
Kozutsumi Y, Segal M, Normington K, Gething MJ, Sambrook J. The presence of malfolded proteins in the endoplasmic reticulum signals the induction of glucose-regulated proteins. Nature 1988;332:462-4.  Back to cited text no. 80
    
81.
Oyadomari S, Araki E, Mori M. Endoplasmic reticulum stress-mediated apoptosis in pancreatic beta-cells. Apoptosis 2002;7:335-45.  Back to cited text no. 81
    
82.
Hiratsuka T, Matsuzaki S, Miyata S, Kinoshita M, Kakehi K, Nishida S, et al. Yokukansan inhibits neuronal death during ER stress by regulating the unfolded protein response. PLoS One 2010;5:e13280.  Back to cited text no. 82
    
83.
Li GD, Li XX, Dong JJ, Wu Y, Han YS. Effect of electroacupuncture on neurovascular unit and Wnt/β-catenin signaling in rats with cerebral ischemia. Zhen Ci Yan Jiu 2021;46:87-94.  Back to cited text no. 83
    
84.
Qiu CW, Liu ZY, Hou K, Liu SY, Hu YX, Zhang L, et al. Wip1 knockout inhibits neurogenesis by affecting the Wnt/β-catenin signaling pathway in focal cerebral ischemia in mice. Exp Neurol 2018;309:44-53.  Back to cited text no. 84
    
85.
Wang J, Chen T, Shan G. miR-148b regulates proliferation and differentiation of neural stem cells via Wnt/β-catenin signaling in rat ischemic stroke model. Front Cell Neurosci 2017;11:329.  Back to cited text no. 85
    


    Figures

  [Figure 1], [Figure 2]



 

Top
 
  Search
 
    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

 
  In this article
Abstract
Introduction
Protective Effec...
Potential Protec...
Mechanisms of Ne...
Conclusions
References
Article Figures

 Article Access Statistics
    Viewed453    
    Printed36    
    Emailed0    
    PDF Downloaded47    
    Comments [Add]    

Recommend this journal