Biomedicine & Pharmacotherapy 170 (2024) 115847

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Biomedicine & Pharmacotherapy

journal homepage: www.elsevier.com/locate/biopha

Review

Flavonoids and ischemic stroke-induced neuroinflammation: Focus on the

glial cells
Weizhuo Lu b, Zhiwu Chen a, *, Jiyue Wen a, *
a
Department of Pharmacology, School of Basic Medical Sciences, Anhui Medical University, Hefei, China
b
Medical Branch, Hefei Technology College, Hefei, China

A R T I C L E I N F O A B S T R A C T

Keywords: Ischemic stroke is one of the most cases worldwide, with high rate of morbidity and mortality. In the pathological
Microglia process of ischemic stroke, neuroinflammation is an essential process that defines the functional prognosis. After
Astrocyte stroke onset, microglia, astrocytes and the infiltrating immune cells contribute to a complicated neuro­
Neuroinflammation
inflammation cascade and play the complicated roles in the pathophysiological variations of ischemic stroke.
Ischemic stroke
Both microglia and astrocytes undergo both morphological and functional changes, thereby deeply participate in
Flavonoids
the neuronal inflammation via releasing pro-inflammatory or anti-inflammatory factors. Flavonoids are plant-
specific secondary metabolites and can protect against cerebral ischemia injury via modulating the inflamma­
tory responses. For instances, quercetin can inhibit the expression and release of pro-inflammatory cytokines,
such as tumor necrosis factor (TNF)-α, IL-6 and IL-1β, in the cerebral nervous system (CNS). Apigenin and rutin
can promote the polarization of microglia to anti-inflammatory genotype and then inhibit neuroinflammation. In
this review, we focused on the dual roles of activated microglia and reactive astrocyte in the neuroinflammation
following ischemic stroke and discussed the anti-neuroinflammation of some flavonoids. Importantly, we aimed
to reveal the new strategies for alleviating the cerebral ischemic stroke.

1. Introduction neuroinflammation is an essential process in ischemic stroke that defines

the functional prognosis [7]. After stroke onset, both astrocyte and
Stroke is known as a leading cause of death worldwide [1,2], a half of microglia are activated and release the pro-inflammatory or
stroke survivors are left with chronic disabilities. Ischemic stroke is anti-inflammatory factors, thereby result in a complicated neuro­
induced by cerebral vascular stenosis or occlusion and occupies inflammation cascade. Especially, microglia are rapidly activated by
approximately 80% of the stroke population [3]. The acute phase of ischemic insults and undergo both morphological and functional
ischemic stroke determines the dynamic changes and the evolution of changes. Activated microglia produce the inflammatory factors, such as
the brain lesion and is closely associated with neuronal deficits [4]. Until tumor necrosis factor alpha (TNF-α), interleukin (IL)− 23, IL-1β and
now, acute treatments of ischemic stroke include mechanical throm­ IL-12, or release the anti-inflammatory mediators, containing trans­
bectomy and the thrombolytic therapy with recombinant tissue plas­ forming growth factor beta (TGF-β), IL-4 and IL-10 [8]. Similarly, as­
minogen activator (rt-PA). However, rt-PA treatment cannot be trocytes likewise undergo morphological and translational changes and
performed on majority of patients for the limited therapeutic time then release the pro-inflammatory or anti-inflammatory factors. There­
windows and the secondary brain injury after reperfusion [5]. There­ fore, both activated astrocytes and microglia have the double-edged
fore, it is of great urgency to explore the therapeutic targets and find the sword effect on the neuroinflammation following the ischemic stroke
possible drugs for ischemic stroke. [9].
As reported in the literature, the neuronal death in the acute brain Flavonoids, plant-specific secondary metabolites, have many phar­
injury after ischemic stroke is directly caused by severe ischemia within macological effects against ischemic stroke [10], such as
minutes after stroke onset. In the pathological process of delayed brain anti-inflammation and antioxidation [11], and regulating the function
injury, neuronal injury is mainly induced by neuroinflammation and the of key cellular enzymes [12,13]. Furthermore, flavonoids like nar­
brain edema, which occurs several days following stroke onset [6]. Thus, ingenin, (-)-epigallocatechin-3-gallate (EGCG), quercetin, rutin,

* Corresponding authors.
E-mail addresses: chpharmzw@163.com (Z. Chen), wenjiyue139@aliyun.com (J. Wen).

https://doi.org/10.1016/j.biopha.2023.115847
Received 8 September 2023; Received in revised form 27 October 2023; Accepted 5 November 2023
Available online 27 November 2023
0753-3322/© 2023 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
W. Lu et al. Biomedicine & Pharmacotherapy 170 (2024) 115847

apigenin and baicalein have been proven to counteract the neuro­ the ischemic hemisphere [32]. Depletion of IL-1α or IL-1β could reduce
inflammatory responses following ischemic stroke. Accumulating study the ischemic stroke injury and restrain the BBB disruption in experi­
has revealed the neuroprotective efficacy of these flavonoids against mental stroke [33]. Further study has revealed that IL-1α-mediated
cerebral ischemic injury via anti-neuroinflammation [14]. This review neurovascular inflammation and BBB injury could cause the infiltration
aimed to discuss complicated roles of microglia and astrocytes on the of neutrophils to ischemic lesions [34], which played a major role in
ischemic stroke-induced neuroinflammation and revealed the thera­ ischemic brain pathobiology [35]. Besides, IL-1β likewise deteriorated
peutic potential of flavonoids on ischemic brain injury. neurons, glial cells and the vasculature after ischemic stroke [36].
Furthermore, the deteriorated role of IL-1 family on stroke pathology
2. Neuroinflammation following ischemic stroke was evidenced by decreased infarct volumes in experimental ischemic
stroke in IL-1 (α/β) knockout (IL-1-/-) mice [37].
Neuroinflammation has been implicated in the initiation and pro­ IL-6 also belongs to pro-inflammatory interleukins and is secreted by
gression of several CNS diseases, including ischemic stroke [15]. Among glial cells, monocytes and neurons [38]. The IL-6 signaling pathway
all of the damage factors involved in cerebral ischemia-induced brain contains classic and trans-signaling mechanisms [39]. In classic
injury, neuroinflammation is critical one that defines the functional signaling, IL-6 stimulates target cells via membrane-bound IL-6 receptor
prognosis of both stoke patients and experimental stroke of animals (IL-6R), which upon ligand binding associates with the signaling re­
[16]. After stroke onset, microglia and astrocytes rapidly recognize and ceptor protein gp130 [40]. Whereas trans-signaling requires prior
react to the ischemia stimuli and the neuronal damage. Activated binding of IL-6 to the soluble IL-6R (sIL-6R) [41]. In trans-signaling,
microglia and astrocytes participate in neuroinflammation via releasing binding of IL-6 thesIL-6R activates effector cells via gp130 regardless
the pro-inflammatory or anti-inflammatory factors. Pro-inflammatory of whether the cells express the IL-6R itself. The trans-signaling of IL-6is
factors amplify the neuronal damage and deteriorate the brain func­ regarded to be accounted for the pro-inflammatory property of IL-6
tion. In contrast, the anti-inflammatory factors can restrain the neuro­ [42].
inflammation and promote neuronal repair [17,18]. Thus, microglia and Contrary to the role of pro-inflammatory cytokines in neuro­
astrocytes are major players in the inflammation response following inflammation, IL-10 is regarded as an anti-inflammatory cytokine, for it
ischemic stroke. Exploration of the dual roles of microglia and astrocytes can reduce inflammation and limit the cellular apoptosis [43]. In
could have important implications for ischemic stroke treatment by experimental ischemic stroke models of mice, upregulation of IL-10
informing the neuroinflammatory interventions. using transgenic technology could reduce the brain infarct volume and
inhibit the cellular apoptosis [44]. Likewise, low-level of IL-10 is found
2.1. Microglia in neuroinflammation (Fig. 1) to be correlated with poor outcome of experimental ischemic stroke,
evidenced by significantly inflammatory reactions and worse neuro­
Microglia make up 4–11% of the CNS cell population and are in logical deficits [45]. In a murine model of experimental stroke, Piepke
“resting stage” in a normal CNS environment [19]. Microglia in “resting et al. [46,47] confirmed the neuroprotective effects of IL-10 on the
stage” can monitor their surrounding environment through extending functional outcome post-ischemia, the researchers found that IL-10
and contracting their parapodium. This housekeeping function of deficient exhibit obviously increased infarct sizes and impaired neuro­
microglia can clear the metabolic products and eliminate the deterio­ logical outcome and enlarged brain atrophy of mice following cerebral
rated tissue components after brain injury [20]. Importantly, microglia ischemia. Therefore, we proposed that the anti-inflammatory properties
are the first response cells that are recruited to infarct lesions following of IL-10 can be used as a potential clue for the diagnosis and prognosis of
ischemic stroke, and function in the occurrence and progression of ischemic stroke.
neuroinflammation [21]. Afterwards, microglia are activated and
polarize to two phenotypic subtypes, M1 and M2 [22], M1 and M2 2.1.3. The phenotypic change of microglia and neuroinflammation
microglia respectively secrete pro-inflammatory cytokines, such as As aforementioned, microglia are the first responders in response to
IL-1α, IL-1β, IL-6 and TNF-α, and anti-inflammatory cytokines, including the ischemia insult and undergo both morphological and functional
IL-10 and IL-1R antagonist (IL-1Ra) [23–25]. These cytokines together transformation during the pathological process of ischemic stroke,
form a complex signaling network in neuroinflammatory response after which is known as activation of microglia. Activated microglia become a
ischemic stroke. double sword, with phenotypic transformation to deleterious M1 and
neuroprotective M2 types [48]. M1 microglia can be identified by
2.1.1. Microglia-released TNF-α and neuroinflammation testing the expression of inducible nitric oxide synthase (iNOS), CD16,
TNF-αcontains a secreted form (solTNF) and a transmembrane form CD32, CD86, etc. Microglial polarization of the M1 subtype is charac­
(tmTNF) and is the most studied cytokine in ischemic stroke [26]. The terized by high expression of IL-12 and IL-23 and low expression of IL-10
signal of TNF-α is transferred via two TNF receptors (TNFRs): [49]. The polarization of M2 microglia is characterized by releasing
TNFR-1and TNFR-2 [27]. The solTNF-TNFR-1 signal is mainly respon­ cytokine IL-10, TGF-β, IL-1R agonists, CD302, CD163, etc [49].
sible for pro-inflammatory effects. Conversely, TNFR-2 is only activated M1 microglia can damage the BBB integrity and further promote the
by mtTNF, and mediates the beneficial effects, such as neuronal injury via releasing pro-inflammatory mediators, such as IL-1α,
anti-inflammation and promoting the remyelination and improving the IL-1β, IL-6,TNF-α and chemokine-chemokine ligand 2 (CCL2), and
cell survival [28]. Not surprisingly, removal of solTNF had been re­ through deteriorating the neuroinflammation [50,51]. The deteriorated
ported to alleviate the pathology and symptoms of cerebral ischemia in roles of IL-1α, IL-1β, IL-6, TNF-α on the neuroinflammation have been
mice [29]. Huang et al. likewise revealed the importantly regulatory discussed previously. CCL2 and its corresponding receptor CCR2 have
roles of TNF-α-TNFR-1 signal in ischemic stroke-induced neuro­ been found to up-regulate the inflammatory response in cerebral
inflammation [30]. Therefore, removal of solTNF and retention of ischemia [52]. Guo et al. have found that CCL2/CCR2 expression was
tmTNF can protect against brain injury in experimental stroke. positively related with infarct area and enlargement of lesion, upregu­
lation of CCL2 expression further aggravated the cerebral ischemia [53].
2.1.2. Microglia-released interleukins and neuroinflammation All these findings suggested that microglia -released CCL2 played a
The IL-1 family is closely involved in regulating immune cells and detrimental role in ischemic stroke.
inflammatory processes during ischemic stroke [31]. The roles of IL-1α, Conversely, M2 microglia produce the anti-inflammatory factors,
IL-1β, and IL-1 receptor antagonist (IL-1Rα) in IL-1 family members in such as TGF-β, IL-10 and glucocorticoids [54,55] to maintain BBB
ischemic stroke have been explored in plenty of studies. It has been integrity, promote the proliferation and differentiation of neural cells
reported in literature that IL-1α and IL-1β are dramatically elevated in and tissue repair [56]. Importantly, anti-inflammatory effect of M2

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W. Lu et al. Biomedicine & Pharmacotherapy 170 (2024) 115847

microglia is found to be related with activating peroxisome infiltrating macrophages but also activated microglia can induce further
proliferator-activated receptor-γ (PPARγ), which is known as a tran­ brain damage [85].
scription factor with anti-inflammatory properties [57]. These findings In addition, infiltration of T cells from blood into CNS likewise plays
revealed that the dichotomous roles of activated microglia in inflam­ important and different roles in the neuronal inflammatory response.
matory responses contribute to the phenotypic transformation [58,59]. The T regulatory (Treg) cells are the famous peripheral cells and are
Without a doubt, attenuating M1 activation and enhancing M2 response involved in the resolution of ischemic injury [86]. For instance, Treg
of microglia represent promising therapeutic targets in ischemic stroke. cells have been found to release anti-inflammatory cytokines IL-10 and
TGF-β, and protect against brain injury. In contrast, CD4+, CD8+ and
2.2. Astrocyte in neuroinflammation (Fig. 1) gamma delta T (γδ) cells could deteriorate the brain injury via producing
pro-inflammatory cytokines IFN-g and IL-17 [87].
Astrocytes provide the supportive roles in the CNS under physio­ Moreover, peripheral lymphocytes in CNS likewise interact with ol­
logical condition through various ways, such as promoting BBB forma­ igodendrocytes and oligodendrocyte progenitor cells (OPCs). Briefly,
tion and participating in neuronal metabolic activity and structural the leakage of oligodendrocyte antigens, such as myelin basic protein
supports. Besides, astrocytes participate in regulating cerebral blood (MBP) and myelin oligodendrocyte glycoprotein (MOG), into the pe­
flow and adjust the neurotransmitter release through “tripartite syn­ riphery through broken BBB can promote the infiltration of peripheral
apse” [60,61]. The term ’tripartite synapse’ is a concept in synaptic immune cells into CNS [88], this action is more significant in the core
physiology between astrocytes and neurons based on the demonstration lesion than that in the peri-infarct lesion [89]. Taken together, the
of the existence of bidirectional communication, which is the classic infiltration of peripheral immune cells likewise has at least a dual role on
’bipartite’ information flow between the pre- and postsynaptic neurons inflammatory reaction following ischemic stroke.
[62]. Astrocytes likewise play vital roles in maintaining CNS homeo­
stasis [63] and pruning synapses through phagocytosis and promoting 3. Anti-neuroinflammation of flavonoids (Fig. 3)
the formation synapses [64].
Under the ischemia stimuli, astrocytes undergo morphological and Flavonoids have attracted more attention in recent years because of
functional changes [65], first as reactive astrocytes and then as potential benefits in stroke treatment. The basic structure of flavonoids
scar-forming astrocytes. After that, reactive astrocytes form the astro­ contains a skeleton of two phenyl (A and B) rings and a heterocyclic ring
cytic scars around the lesion epicenter [63] and release the chondroitin (C ring, a chain of three carbon atoms). Flavonoids are classified into
sulfate proteoglycans (CSPGs), which can inhibit the remyelination and following subclasses, flavanones, flavanols, flavonols, flavones, antho­
axonal regeneration [66]. Many studies have revealed two subtypes of cyanins, isoflavones, chalcones and dihydrochalcones, which can be
reactive astrocyte, A1 and A2. The polarization of A1 (pro-in­ found in the website, http://phenol-explorer.eu/compounds/
flammatory) astrocytes are stimulated by neuroinflammatory mediators classification.
from activated microglia, containing IL-1α, C1q and TNF-α. A2 astro­ Accumulating studies have revealed that flavonoids could protect
cytes are activated by ischemia stimuli. A1 astrocytes possess the against cerebral ischemia injury via decreasing inflammatory responses
neurotoxicity due to exacerbating the neuroinflammation [67] through [90]. For instance, quercetin has been found to reduce the neuro­
releasing TNF-α, IL-6 and IL-1β [68,69]. Besides, A1 astrocytes phago­ inflammation through inhibiting the release of cytokines [91] and che­
cytize the surviving neurons [61,70] and Furthermore, up-regulation of mokines [92], as well as decreasing leukocyte infiltration and cerebral
complement component 3 (C3) has been found in A1 astrocytes [71,72]. edema [93]. Besides, apigenin [94], rutin [95] and the other flavonoids,
C3 is harmful to both neurons and oligodendrocytes via activating C3 have been found to possess the anti-neuroinflammatory effect via
receptor [73,74]. reducing the release of pro-inflammatory factors. Figs. 1–3.
By contrast, A2 (anti-inflammatory) astrocytes are characterized as
neuroprotective subtype for producing neurotrophic factors [75]. In 3.1. Flavanones and neuroinflammation
addition, A2 astrocytes acquire the phagocytosis ability to clear the
myelin debris, this action results in reduction of neuroinflammation [72, Naringenin is one of flavanones and widely distributed in oranges,
76]. Moreover, A2 astrocytes can upregulate the expression of anti-in­ grapefruits, citrus and tomatoes. Multiple therapeutic applications of
flammatory cytokine TGF-β, which has neuroprotective effect against naringenin have been found in neurological disorders for its neuro­
cerebral ischemia injury via promoting the synapse formation [77]. protective roles via anti-inflammatory effect [96]. For instance, nar­
Therefore, the complicated (neuroprotective or neurotoxic) roles of ingenin could inhibit the inflammatory signaling in glial cells and
reactive astrocytes on the brain injury due to the phenotypic trans­ protect against neuroinflammation-mediated brain injury. Briefly, nar­
formation. Together, shifting A1 to A2 astrocytic transformation might ingenin attenuated lipopolysaccharide (LPS)-induced inflammatory re­
be potential mechanisms of restraining the neuroinflammation and sponses in vitro via regulating the NF-κB and MAPK signaling pathways
promoting the neuronal repair after ischemic stroke. [97,98]. Besides, the biological activities of naringenin have been pro­
posed to reduce the expression of proinflammatory markers in microglia
2.3. Peripheral immune cells in neuroinflammation (Fig. 2) and astrocytes, containing iNOS and COX-2, through lowering the NF-κB
activity.
As aforementioned, neuronal inflammation is a key pathological Moreover, Vafeiadou et al. have reported that naringenin could
process during ischemic stroke. The pro-inflammatory cytokines- effectively reduce LPS/IFN-c-induced activation of microglia and as­
induced damages of endothelial cells and pericytes result in BBB disin­ trocytes, and lower the related neuronal injury [98,99]. Similarly, Raza
tegration and BBB leakage [78,79], which can further lead to cerebral et al. have revealed that the neuroprotective effect of naringenin against
edema and increased expression of astrocytic aquaporin 4 (AQP4) [80]. experimental stroke was related with inhibiting the NF-κB pathway, as
The BBB breakdown and AQP4 facilitate the infiltration of peripheral evidenced by the reduced nuclear translocation of the NF-κB subunit p65
immune cells into the CNS, containing macrophages and peripheral B in brain tissues of rats after cerebral ischemia/reperfusion [97].
cells and T cells [81,82]. The infiltration of peripheral immune cells Furthermore, Zhang et al. [99] have revealed that
further activates host immune cells, including microglia, and then de­ anti-neuroinflammation of naringenin was related with promoting the
teriorates the neuronal inflammation in CNS via releasing chemokines, phenotypic transformation of microglia to the M2 subtype. The mech­
cytokines and the other molecules [83]. Furthermore, Kristian et al. anism of naringenin-induced microglial polarization was dependent on
have revealed that infiltration of B lymphocytes induced the chronic inactivation of MAPK signaling, particularly relied on the inactivation of
inflammation and the delay cognitive dysfunction [84]. Not only c-Jun N-terminal kinase (JNK). Because the selective activator of JNK

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Fig. 1. Summarized the changes of glial cells and peripheral immune cells in the neuroinflammation following ischemic stroke.

Fig. 2. Summarized the relationship of peripheral immune cells and BBB integration in the neuroinflammation following ischemic stroke.

could inhibit the naringenin-mediated polarization of M2 microglia. previous studies [102]. EGCG is the most abundant and biologically
active polyphenol in green tea [103]. Lee et al. have found that EGCG
could inhibit the inflammation through restraining the expressions of
3.2. Flavanols and neuroinflammation iNOS and COX-2 s, as well as through reducing the production of in­
flammatory cytokines. These actions were found both in culture astro­
Flavanols belong to the Flavan-3-ols of flavonoid family because of cytes and in the mice brain. Particularly, the researchers revealed that
the attachment of a hydroxyl group at position 3 on the C ring. Flavanols upregulated COX-2 and iNOS expressions were responsible for the
lack ketone group at position 4 of the C ring and a double bond between astrocyte activation [102]. In addition, Wu et al. have confirmed the
C-2 and C-3 [100]. The main representatives of flavanols are epi­ anti-neuroinflammatory effects of EGCG and EGCG enriched green tea
catechins, (-) epigallocatechin (EGC), (-)-epicatechin-3-gallate (ECG), extract in the rat cerebral ischemic stroke model [104]. The authors
(-)-epicatechin (EC), (+)-catechin (C),(-)-epigallocatechin-3-gallate revealed that the anti-inflammatory effects of EGCG in BV-2 microglia
(EGCG), (+)-gallocatechin-3-gallate (GCG), (+)-gallocatechin (GC), and cells in vitro was related to inhibiting the iNOS/NO and COX-2 [104].
so on [101]. Moreover, the inhibitory effect of EGCG has been found in
The anti-inflammatory properties of EGCG have been reported in

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Fig. 3. Summarized the role of flavonoids in the neuroinflammation following ischemic stroke.

hypoxia-induced inflammation and oxidative stress in microglia, the anti-inflammation of quercetin is through inhibiting the microglial in­
mechanisms were via activating the Nrf-2/HO-1 pathway as well as flammatory activation [115]. Furthermore, Tsai et al. have revealed that
abrogating the NF-κB pathway [105]. quercetin significantly lowered the expressions of M1 microglia
Furthermore, EGCG treatment could significantly increase the pro­ markers, including IL-6, TNF-α and IL-1β, and increased the expression
liferation of neural progenitor cells (NPCs), which were isolated from of M2 microglia marker IL-10. The researchers have reported that
ipsilateral subventricular zone (SVZ) of cerebral I/R mice. Strikingly, quercetin restrained M1 polarization-mediated neuroinflammatory re­
EGCG could promote the phenotypic transformation of activated sponses, and enhanced the M2 microglial polarization [90]. Together,
microglia to M2 subtype at 28d after mice cerebral ischemia, which were these findings provided valuable information that quercetin may act as a
evidenced by lowering the expression of M1 markers, including CD32, potential drug for the treatment of ischemic stroke via
CD11b, CD16, iNOS and TNF-α, and increasing the expression of M2 anti-inflammatory effect.
markers, containing arginase-1 (Arg-1), YM1, IL-10 and TGF-β [106]. Rutin, another representative of flavonols, is also known as quercetin
Therefore, we declared that EGCG-mediated anti-inflammatory effect 3-O-rutinoside. Rutin can be extracted from many medicinal plants
might be related with promoting the phenotypic transformation of [116]. Similar to the action of quercetin, rutin likewise has the neuro­
microglia to M2 subtype. protective effect against cerebral I/R injury [117]. For instance, rutin
administration can attenuate the expression and activity of
3.3. Flavonols and neuroprotection metalloproteinase-9 (MMP-9) and promotes the BBB function in focal
cerebral ischemia rats [118]. Further research has showed that rutin
Quercetin, a 3,3′,4′,5,7-pentahydroxyflavone, is the major represen­ obviously improved the spatial memory of cerebral ischemia animals
tative of flavonols and rich in fruits, tea, onion, leafy vegetables and and inhibited the repeated cerebral ischemia-induced neuronal death in
herbs [107]. The research about the pharmacokinetics of quercetin has the hippocampal CA1 area [119].
revealed that quercetin administration at a dose of 1.5 g per day resulted Importantly, rutin has been found to increase the expression of
in stable concentration of quercetin in humans plasma [108]. The phagocytic receptors of microglia and enhance the clearance capability
average terminal half-life of quercetin is 3.5 h in healthy humans [108]. of microglia [120,121]. In addition, rutin facilitated the phenotypic
These findings suggested that quercetin may be a candidate drug for transformation of microglia to an M2 subtype and inhibited M1
clinical application. microglia-mediated neuroinflammation via restraining NO-dependent
The anti-inflammatory effect of quercetin has been widely investi­ mechanism [122]. Similarly, Lang et al. have confirmed that rutin
gated in animal model of cerebral I/R [109–111]. Quercetin adminis­ could promote the transformation of microglia from M1 to M2 state and
tration following cerebral I/R in rats significantly reduced the might be a potential candidate for treating the neurological disorders. In
proinflammatory cytokines (IL-1β and IL-6) and increased the addition, the authors found that rutin-mediated M2 microglial polari­
anti-inflammatory cytokines (IL-4, IL-10 and TGFβ1) [112]. Further­ zation was via inhibiting the TLR4/NF-κB signaling pathway [123].
more, quercetin-induced reduction of IL-6 has been found to be related Therefore, rutin targeting microglial cells could be a promising strategy
with inhibiting the activation of astrocytes [113]. A quercetin-enriched to prevent inflammatory factors-mediated cerebral ischemia injury and
diet enhanced the neuronal activity in the medial prefrontal cortex and promote outcome for ischemic stroke treatment.
in the hippocampus after stress by inhibiting the activation of astrocytes
and microglia [114]. Han et al. have also provided strong evidences that

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3.4. Flavones and neuroinflammation 3.6. Isoflavones and the other flavonoids

Apigenin, 4’,5,7-trihydroxyflavone, represents one of flavones [124] Genistein (4’,5,7-trihydroxyisofavone) is a natural isoflavone com­
and can be obtained from vegetables and fruits [125]. The potential pound, with neuroprotective activity [140], and the antioxidant and
biological effects of apigenin, including anti-inflammatory, anti­ anti-inflammatory effects [141]. Studies have revealed that genistein
oxidative stress and anti-apoptotic activities, have been found in pre­ could protect against the chronic or acute brain damage via inhibiting
vious study [126]. Besides, the preventive and therapeutic effects of the inflammatory responses [142]. Moreover, genistein has been found
apigenin have been found in ischemic stroke, and the ability of apigenin to suppress the polarization of M1 microglia and promote the trans­
across the BBB has been confirmed [127]. Importantly, it has been found formation of activated microglia to M2 subtype in rat hippocampus after
that apigenin could increase the proportion of M2 microglia and then stimulation with isoflurane. Besides, genistein could inhibit the ex­
inhibit inflammation [128,129]. Moreover, apigenin could decrease the pressions of TNF-α, IL-1β, IL-6 and IL-8 at mRNA level in
release of proinflammatory cytokines, containing IL-6 and TNF-α. isoflurane-treated BV2 cells. Importantly, genistein promoted the
Further studies have confirmed that apigenin promoted the trans­ transformation of microglia to M2 subtype [142]. These data suggested
formation of activated microglia to M2 subtype and inhibited the acti­ that genistein-mediated anti-neuroinflammation might be related with
vation of M1 microglia [57,130]. Jiang et al. have reported that promoting the phenotypic transformation of microglia to M2 subtype.
apigenin increased the release of anti-inflammatory cytokine IL-10 and Furthermore, chalcones and dihydrochalcones likewise have the
reduced the inflammatory response via promoting the expression of ability to modulate the neuroinflammation. The chalcone (2,20,50-tri­
PPARγ [128,129]. hydroxychalcone) has been reported to modulate neuroinflammatory
Baicalein, another flavone, has been found to ameliorate the activation in BV2 microglial cells and promote a shift from an M1
neurological deficit of cerebral I/R rats, as well as reduce the infarct phenotype to a downregulated microglial profile [143]. The 2’-hy­
sizes and inhibit the brain edema [131]. Liang et al. have confirmed that droxy-4,3’,4’,6’-tetramethoxychalcone has also been found to inhibit
baicalein could be used to treat the cerebral I/R injury when adminis­ the inflammatory responses in BV2 microglial cells induced by LPS
tered in the acute phase of ischemic stroke [132]. Rats treated with [144].
baicalein after cerebral I/R showed the decreased brain infarct volume
and reduced neurobehavioral deficits [133]. Moreover, the researchers 4. Conclusion
have revealed that baicalein could inhibit cerebral ischemia-induced
neuroinflammation via promoting the M2 transformation and inhibit­ After stroke onset, the glial cells and the infiltrating immune cells
ing M1 transformation, and suggested that baicalein exerted neuro­ contribute to a complicated neuroinflammation cascade, thereby un­
protective effects by reducing neuroinflammation, apoptosis and derpin the ischemic stroke injury. Flavonoids are rich in our daily diet (e.
autophagy [133]. Thus, baicalein possesses the potential for develop­ g., vegetables and fruits) and possess the respectable therapeutic effects
ment of therapies for the cerebral ischemia-induced neuroinflammation on cerebral ischemia injury via inhibiting the neuroinflammation. For
and the neuronal injury. instance, naringenin, EGCG, quercetin, rutin, apigenin, baicalein, an­
thocyanins and the other flavonoids, have been found to inhibit and
3.5. Anthocyanins and neuroinflammation limit neuroinflammation following ischemic stroke via affecting the
activation of microglia and/or astrocytes. These flavonoids might be
Anthocyanins (pentunidin-3-O-rutinoside (p-coumaroyl)− 5-O- potential candidates for treating the ischemic stroke.
glucoside) likewise possess the ability to reduce the damage to neuro­
vascular unit in middle cerebral artery occlusion (MCAO) rats [134]. Author contributions
Shin et al. have found that anthocyanins reduced the focal cerebral
ischemia-induced neuronal damage through blocking the JNK and p53 WZL and JYW: conceptualized the project, performed the literature
signaling pathway [135]. In addition, anthocyanins prevented the search, and wrote the manuscript. JYW and ZWC: critically revised the
infiltration of peripheral immune cells in the hippocampus following work.
cerebral ischemia, reduced the release of proinflammatory cytokines
and decreased the activity of myeloperoxidase in cortex and hippo­ Funding
campus. These actions suggested the anti-inflammation of anthocyanins.
Importantly, anthocyanins could strikingly reduce the activation of This study is supported by the Natural Science Research Project of
microglia and astrocyte in brain of mice exposed to LPS [136]. Colleges and Universities in Anhui Province (No. 2023AH052541 and
Furthermore, the effect of anthocyanins on the microglial M1/M2 2023AH050672).
phenotypes has also been demonstrated in the previous reports by using
cyanidin‑3–O‑Glucoside (C3G), an anthocyanin. C3G could enhance the CRediT authorship contribution statement
expressions of CD206 and CD16, which are known as M2-specifc
markers [137]. The anti-inflammatory effect of C3G has been found in Weizhuo Lu: Writing. Zhiwu Chen: Reviewing and editing. Jiyue
LPS-stimulated BV2 microglia activation. The authors found that pre­ Wen: Conceptualization, Supervision, reviewing and editing.
treatment with C3G significantly inhibited the activation of NF-κB and
p38 MAPK signaling pathways in LPS-activated BV2 cells, and then Declaration of Competing Interest
reduced the production of pro-inflammatory cytokines IL-1β and IL-6
[138]. Moreover, Meireles et al. have explored the role of anthocya­ The authors declare that they have no conflict of interest.
nins on the change of microglial phenotype by using N9 microglia cell
line. They revealed that cyanidin, C3G and the amethylated form of C3G Data availability
inhibited the polarization of M1 microglia after LPS/IL-4 stimulation
[139]. These findings suggested that the consumption of anthocyanins No data was used for the research described in the article.
has the possibility of anti-neuroinflammation and against neuronal
injury following brain ischemia.

6
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