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. 2025 Jun 4;15(6):e70551. doi: 10.1002/brb3.70551

The Role of Astrocytes in Poststroke Rehabilitation

Ying Han 1, Li Huang 1, Jiaojiao Wu 1, Guiling Wan 1, Linhong Mo 1,✉, Aixian Liu 1,✉
PMCID: PMC12134494  PMID: 40462588

ABSTRACT

Introduction

Ischemic stroke is a leading cause of death and chronic disability worldwide. Therapeutic options to reduce stroke‐related disability are still limited. Resident astrocytes are the most abundant glial cells in the brain and respond to the pathophysiological changes induced by ischemic stroke.

Methods

Comprehensive literature search and narrative review to summarize the current field of astrocytes in poststroke rehabilitation using the PubMed database.

Results

This review first presents that astrocyte activation is critical for scar formation, synaptogenesis, synaptic remodeling, inflammation limitation, and metabolic regulation. Next, we summarize the contributions of astrocytes to neural repair after stroke with a focus on their effects on exercise, transcranial magnetic stimulation (TMS), transcranial electrical stimulation (tES), music therapy, acupuncture, hyperbaric oxygen therapy (HBOT), and enriched environment (EE).

Conclusions

In this review, we comprehensively analyze the role and possible mechanisms of astrocytes in various rehabilitative treatments and suggest that targeting astrocytes may be an effective strategy for the development of innovative therapeutic strategies for ischemic stroke.

Keywords: astrocyte, ischemic stroke, neuron, rehabilitation

Contributions of astrocytes to neuroprotection in different types of rehabilitation after ischemic stroke.

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1. Introduction

Stroke is the second leading cause of death and the leading cause of disability in adults worldwide. Survivors suffer long‐term disability and require extensive rehabilitation (Barthels and Das 2020). Ischemic stroke, the most common type of cerebrovascular disorder, is caused by an abrupt blockage of an artery that restricts blood flow (Campbell et al. 2019). Ischemic stroke can cause a range of pathophysiological changes in nerve cells, including neuronal death (Tuo et al. 2022). Restoring central nervous system (CNS) function after stroke has long been a major goal of neuroscience research. Astrocytes, the most abundant cells in the CNS, represent approximately 20%–40% of brain cells. On the basis of morphology and specific protein markers, there are two major types of astrocytes in the adult brain: fibrous astrocytes, which are found in white matter tracts, and protoplasmic astrocytes, which are found in gray matter. Glial fibrillary acidic protein (GFAP) is the hallmark intermediate filament protein of astrocytes and is considered a “pan‐astrocyte” marker (Baba et al. 1997; Hol and Pekny 2015). Aldehyde dehydrogenase 1 family, member L1 (Aldh1L1) protein is highly expressed in the cell body and extensive processes of an astrocyte, making it a new “pan‐astrocyte” marker (Y. Yang et al. 2011). Astrocytes play a critical role in maintaining control and homeostasis in both health and disease. Astrocytes are supportive glial cell components in neural tissues and play critical roles in neural conduction, regulation of blood flow, synaptic transmission, modulation of metabolism, and formation of the blood–brain barrier (BBB) (Bonvento and Bolaños 2021; Song et al. 2021{Song, 2021 #46}; Stogsdill et al. 2017). Thus, astrocytes are promising targets for neural repair and remodeling after ischemic stroke.

2. Methods

References for this review were identified through a systematic search of PubMed up to May 2024, supplemented by backward citation tracking. The search strategy combined terms related to stroke rehabilitation (e.g., “stroke”) and therapeutic interventions targeting astrocyte‐mediated mechanisms, including exercise, repetitive transcranial magnetic stimulation (rTMS), transcranial electrical stimulation (tES), music therapy, acupuncture, hyperbaric oxygen therapy (HBOT), and enriched environment (EE). Specific search terms were structured as follows: (1) “stroke” AND “astrocyte” AND “exercise”; (2) “stroke” AND “astrocyte” AND “repetitive transcranial magnetic stimulation (rTMS)”; (3) “stroke” AND “astrocyte” AND “transcranial electrical stimulation (tES)”; (4) “stroke” AND “music”; (5) “stroke” AND “astrocyte” AND “acupuncture”; (6) “stroke” AND “astrocyte” AND “hyperbaric oxygen therapy”; and (7) “stroke” AND “astrocyte” AND “enriched environment.” This narrative review included articles published between 1983 and May 1, 2024, with a total of 111 references. Of these, 51 articles (45.9%) were published in the last 5 years (2020–2024), including the most recent publication on May 1, 2024. The retrieved literature included different formats: original articles, reviews, randomized controlled trials (RCTs), meta‐analyses, and clinical trials. Studies involving both clinical populations (e.g., patients with diagnosed stroke) and nonclinical controls were included, as well as preclinical research using animal models (e.g., mice and rats). All selected articles were peer‐reviewed and published in English.

3. Astrocyte Activation and Its Role in Ischemic Stroke

Under pathological conditions, astrocytes undergo a variety of phenotypic and functional changes, known as reactive astrogliosis. Reactive astrocytes can be identified by increased expression of GFAP and many other proteins as well as dramatic morphological changes. Morphologically, reactive astrocytes become hypertrophic with large processes. After prolonged ischemic stroke, the morphology of reactive astrocytes remains stable, resulting in the formation of a glial scar. Reactive astrogliosis and glial scar formation eventually lead to significant tissue remodeling and permanent structural changes in the penumbra. Recent data suggest that astrocyte activation after ischemic stroke has both beneficial and detrimental effects. For many years, severe reactive astrogliosis and glial scarring at sites of CNS trauma were thought to be barriers to axon regeneration and not conducive to recovery from nerve injury (Silver and Miller 2004). However, recent studies have shown that glial scar formation may gradually reduce the spread of inflammation and lesion volume to prevent brain injury after stroke (Clain et al. 2024; R. Zhang et al. 2018). Reactive astrocytes are heterogeneous, and astrocyte polarization is a new concept in which astrocytes are classified as A1 (neurotoxic) or A2 (neuroprotective) (Escartin et al. 2021; Y. X. Liu et al. 2022). A1 astrocytes can be induced by microglia, and complement component 3 (C3) is a specific marker of A1 astrocytes (Fei et al. 2022). A1 astrocytes lose their normal functional properties and secrete unknown neurotoxins, and activation of the NF‐κB pathway in A1 astrocytes contributes to inflammatory responses and exerts deleterious effects (X. Xu et al. 2018). A2 astrocytes are predominantly induced in ischemic stroke patients and animal models and play a crucial role in synaptic plasticity and brain repair by secreting neuroprotective substances. The JAK/signal transducer and activator of transcription 3 (STAT3) pathway mediates A2 astrocyte activation, including glial scar formation, reduction of leukocyte infiltration, and secretion of cytokines (Z. B. Ding et al. 2021; Justicia et al. 2000).

Ischemic stroke causes changes in the morphology, metabolism, and gene expression of reactive astrocytes. Reactive astrocytes can be identified by morphological changes, becoming hypertrophic with enlarged processes that can be visualized by GFAP staining. Following stroke, astrocytes can provide essential metabolic support to neurons during focal cerebral ischemia, and ATP can be released from activated astrocytes (Cho et al. 2022). In addition, the astrocyte–neuron lactate shuttle and the expression of functional transporters for glutamate and GABA uptake are altered in reactive astrocytes. Reactive astrocytes can also secrete mediators relevant to the protective functions of astrocytes, including neurotrophic, growth, and anti‐inflammatory factors (Caglayan et al. 2023). In addition, astrocyte‐derived metalloproteinases (MMPs) (Y. Zhang et al. 2013), metabolites (Bonvento and Bolaños 2021), and extracellular matrix (ECM) (Johnson et al. 2015) proteins can promote neuronal plasticity following CNS insult. Thus, understanding the regenerative potential of astrocytes is fundamental for the development of strategies to restore neurological function after ischemic stroke.

4. Roles of Astrocytes in Stroke Rehabilitation

4.1. Astrocytes in Exercise

Exercise has been shown to be neuroprotective in both clinical and animal studies, reducing infarct volume, improving cerebral edema, mitigating BBB dysfunction, and increasing survival rates (Ahn et al. 2017; Di Raimondo et al. 2020; Y. H. Ding et al. 2006). Exercise can increase the expression of GFAP, a prototypical marker for the immunohistochemical identification of astrocytes, as well as the density of astrocytes in the brain (Dutra et al. 2012; Saur et al. 2014). Furthermore, morphological changes in astrocytes are associated with increased brain‐derived neurotrophic factor (BDNF) and postsynaptic density protein‐95 (PSD‐95) in astrocytes after exercise (Belaya et al. 2020). In addition, exercise induces changes in astrocyte polarization in healthy animals. Exercise alters astrocytic morphology by increasing the degree and length of ramification and inducing polarization of astrocyte endfeet, thereby affecting the area of contact with capillaries (Saur et al. 2014). Astrocyte endfeet envelop the cerebral capillaries that form the BBB, and astrocytes can take up glucose from the blood (Magistretti 2006).

Glial metabolic plasticity is associated with synaptic plasticity. Exercise can promote plasma glucose uptake via 17β‐estradiol (E2), kinases, and glucose transporter type 4 (GLUT4) expression (Oosthuyse et al. 2023). E2 can be produced by neurons and astrocytes in the brain, and astrocyte‐derived E2 is induced after brain injury/ischemia and plays a key role in reactive gliosis (Brann et al. 2022). Furthermore, astrocyte‐derived E2 has been shown to be critical for induction of the A2 astrocyte phenotype and activation of the JAK‐STAT3 pathway in a mouse model of ischemic stroke (J. Wang et al. 2020). The evidence from these studies suggests that astrocyte‐derived E2 plays a critical role in the metabolism and neuroprotection of exercise training in patients with ischemic stroke.

Exercise preconditioning protects the brain against ischemic injury by regulating a number of molecules within astrocytes, such as glutamate transporter 1 (GLT‐1), heat shock protein 20 (HSP20), and aquaporin‐4 (AQP4). The expression of GLT‐1, a glutamate transporter, is significantly reduced after ischemic stroke (Yeh et al. 2005). Research has shown that pre‐ischemic exercise increases GLT‐1 levels (X. Yang et al. 2012) and regulates glutamate receptors (F. Zhang et al. 2010). Increased astrocytic GLT‐1 is associated with promoting the reuptake of glutamate, thus exerting a neuroprotective effect in ischemic stroke. In addition, HSP20 belongs to the small HSP family and has multiple functions. Upregulation of HSP20 expression in the heart has been shown to protect against cardiac ischemia/reperfusion (I/R) injury (Qian et al. 2009). Research has shown that exercise preconditioning improves outcome in ischemic stroke and attenuates both neuronal and glial apoptosis by promoting HSP20 expression in neurons and glial cells (Lin et al. 2015). AQP4 is the most abundant water channel protein in the brain. Increased expression of AQP4 in the brain results from infarction, which may be related to the development of cerebral edema (Murata et al. 2020). Exercise reduces astrocytic AQP4 expression in the ischemic core by attenuating the decrease in IL‐1 receptor antagonist (IL‐1RA) expression, an anti‐inflammatory cytokine that suppresses brain edema, following ischemic stroke (Gono et al. 2023).

Exercise increases the interaction between astrocytes and other neural cells (such as neurons, microglia, and endothelial cells [ECs]) (Li et al. 2021). Astrocytes release several neurotrophic factors (NTFs) and gliotransmitters that act at nerve synapses, including IGF‐1, BDNF, glutamate, acetylcholine, ATP, and lactate, which are involved in the remodeling of astrocyte–neuron crosstalk (Durkee and Araque 2019; Stogsdill et al. 2017). Exercise mediates crosstalk between astrocytes and microglia via their secreted molecules, such as glial cell line‐derived neurotrophic factor (GDNF), cerebral dopamine neurotrophic factor (CDNF), and BDNF, which are secreted by astrocytes and are involved in modulating microglial activation (Rocha et al. 2012). In addition, a number of studies have shown that astrocytes maintain the integrity of the neurovascular unit (NVU) and mediate BBB permeability by influencing ECs (Benz and Liebner 2022). Thus, astrocyte–neuron–microglia–EC interactions may be induced by exercise and contribute to neuroplasticity.

4.2. Astrocytes in Physical Therapies

4.2.1. Astrocytes in Transcranial Magnetic Stimulation (TMS)

TMS is widely used in clinical rehabilitation and has a direct effect on neuronal excitability; glial cells can also respond directly or indirectly to electrical activity. Astrocytes are important regulatory cells and are likely to be critical mediators of TMS‐induced neural plasticity. TMS affects astrocytes, and 10 Hz magnetic stimulation of cultured astrocytes induces a transient increase in the expression of GFAP (Chan et al. 1999). Another study showed that 1 Hz repetitive magnetic stimulation (rMS) increases intracellular calcium in primary astrocytes and that calcium can respond to different stimuli. In addition, rMS can affect astrocyte physiology by promoting migration and proliferation of primary astrocytes in vitro (Clarke et al. 2017).

Astrocytes are likely to influence synapse formation and spine shape in response to TMS. Neurotransmitter release from neurons is sensed by astrocytes and the subsequent release of gliotransmitters; thus, astrocytes may be the cellular effectors of TMS. rTMS can modulate astrocytes, increase axonal density, and promote neural plasticity after oxygen and glucose deprivation followed by reperfusion (OGD/R) injury, and the expression of synaptic markers, such as PSD‐95, calcium/calmodulin‐dependent protein kinase II (CaMKII), synapsin I, and synaptophysin, could be upregulated (Hong et al. 2020). In addition, high‐frequency rMS (HF‐rMS) directly stimulates the release of several trophic factors by astrocytes, and GDNF is one of the released factors that contributes to neuronal protection. The presence of astrocytes helps maintain the number and length of neurites and increases the number of neurons, and GDNF plays a critical role in the beneficial effects induced by HF‐rMS (Gava‐Junior et al. 2023; Roque et al. 2021). In cortical neuron‐glia cultures exposed to OGD/R, the application of HF‐rMS increases the number of cells expressing extracellular signal‐regulated kinase‐1/2 (ERK‐1/2) and c‐Fos, which are thought to be associated with neuronal proliferation and differentiation and the inhibition of apoptosis (Cruz‐Mendoza et al. 2022; Sahu et al. 2021).

Moreover, rTMS improves functional recovery by modulating astrocytic polarization in ischemic stroke (Zong, Li, et al. 2020). Continuous rTMS has been shown to effectively induce an A1 to A2 shift in vascular‐associated astrocytes and increase the levels of platelet‐derived growth factor receptor beta (PDGFRβ) levels associated with A2 astrocytes in a rat photothrombotic (PT) stroke model (Zong, Li, et al. 2020). The potential beneficial effects of rTMS are associated with robust suppression of reactive micro/astrogliosis, proinflammatory cytokines, oxidative stress, and oxidative neuronal damage. Recent work has shown that rTMS treatment suppresses the production of proinflammatory cytokines such as interleukin‐1β (IL‐1β), interleukin‐3 (IL‐3), interleukin‐6 (IL‐6), interleukin‐17 (IL‐17), and tumor necrosis factor alpha (TNF‐α) in an experimental PT rat model of ischemic stroke (Zong, Dong et al. 2020). rTMS inhibits astrocytic secretion of TNF‐α but promotes the ability of interleukin‐10 (IL‐10) to alleviate neuronal death in the context of OGD/R injury (Hong et al. 2020). These findings provide strong evidence for the promising therapeutic effect of rTMS on astrocytes against ischemic neuronal injury following stroke.

4.2.2. Astrocytes in Transcranial Electrical Stimulation

tES, including transcranial direct and alternating current stimulation (tDCS, tACS), is a noninvasive brain modulation technique. tES has been proven to exert beneficial effects on various neuropsychiatric and neurological conditions. tDCS has a neuroprotective effect on the brain after ischemic stroke (L. C. Wang et al. 2021; K. Y. Zhang et al. 2020), and glial cells play a more important role than neurons do in tDCS‐induced brain activity (Ruohonen and Karhu 2012; Saidi and Firoozabadi 2021).

tES can directly modulate gene expression in astrocytes. Research has shown that tDCS increases selenoprotein P (SEPP1) levels in astrocytes and provides neuroprotection by subsequently activating the SEPP1/vesicle‐associated membrane protein 2 (VAMP2)/syntaxin‐4 (STX4) signaling pathway in neurons following cerebral I/R injury in rats (H. Wang et al. 2024). tDCS treatment increases BDNF levels in different regions of the CNS (Filho et al. 2016), and the synthesis of BDNF by astrocytes is well established (Jurič et al. 2008).

Increased levels of astrocytic Ca2+ induced by tDCS have been observed in association with cortical plasticity (Monai and Hirase 2016). tDCS‐induced Ca2+ increases, which are dependent on the alpha‐1 adrenergic receptor and are diminished by the ablation of noradrenergic neurons, have been identified as being of astrocytic origin. Under tDCS, astrocyte calcium signaling occurs (Monai et al. 2016). tDCS modulates the clearance of metabolic waste in the brain through astrocytic IP3/Ca2+ signaling, leading to the modification of delta waves in the mouse brain (Y. Wang and Monai 2024). Additionally, potassium ion (K+) flow is independent of neuronal activity and occurs predominantly through astrocytes, which have a high K+ conductance at rest (Seifert et al. 2018). K+ redistribution may occur via DCS (Gardner‐Medwin and Nicholson 1983), which affects the excitability of neurons and their axon terminals and dendrites. Thus, astrocytes may play an essential role in tDCS‐induced synaptic plasticity via K+ and Ca2+ in ischemic stroke.

4.2.3. Astrocytes in Music Therapy

Music therapy is a valuable, innovative intervention for stroke recovery, effectively improving motor function (e.g., gait and coordination (Collimore et al. 2023; Y. Wang et al. 2021)), speech rehabilitation (e.g., aphasia recovery (Grau‐Sánchez et al. 2018; Sihvonen et al. 2020, 2021; X. Zhang et al. 2023)), and cognitive‐emotional well‐being (e.g., reducing depression and enhancing motivation (Kiper et al. 2022; Raglio et al. 2017; Sun et al. 2024)) through its unique integration of auditory, rhythmic, and emotional stimulation. Mechanistically, music enhances recovery by promoting neuroplasticity through structural and functional reorganization of motor and auditory networks (Grau‐Sánchez et al. 2013; Raglio et al. 2015; Rodriguez‐Fornells et al. 2012), facilitating sensorimotor integration via rhythmic auditory stimulation to synchronize movement (Sihvonen et al. 2022), and boosting emotional engagement by activating dopaminergic reward pathways to sustain rehabilitation adherence (François et al. 2015). Despite clinical efficacy, cellular mechanisms remain unclear. Recently, a study reveals that music upregulates NTFs (e.g., BDNF) and activates astrocytes (via GFAP expression) in stroke models, enhancing neuronal survival, synaptic repair, and tissue remodeling at lesion sites while modulating inflammation (W. Chen et al. 2021). Future research should refine music‐based therapies to leverage these cellular pathways, advancing personalized, noninvasive strategies to optimize stroke rehabilitation outcomes.

4.3. Astrocytes in Acupuncture

Acupuncture has been used in China for thousands of years in two forms: acupuncture (MA) and electroacupuncture (EA). Studies have confirmed its therapeutic effects on poststroke patients (Xiao et al. 2023). Hundreds of acupuncture points are distributed throughout the human body and can be activated by acupuncture needles. Acupuncture‐induced signals are then transmitted to the spinal cord and related brain regions. This mechanism may involve the regulation of neural transmitters and inflammatory factors, thereby exerting neuroprotective effects.

Reactive astrogliosis is a common phenomenon in ischemic stroke and contributes to axonal remodeling and recovery of neurological function after stroke (Z. Liu et al. 2014). EA at the LI11 and ST36 acupoints was shown to exert neuroprotective effects via the activation of GFAP/vimentin/nestin‐positive reactive astrocytes and the expression of BDNF in a rat model of cerebral I/R injury (Tao et al. 2016). Astrocyte activation was significantly reduced after 1 and 2 weeks of EA treatment (J. Y. Wang et al. 2018), and the inactivation of spinal astrocytes contributed to the anti‐allodynic effect of EA (Liang et al. 2016). The expression of astrocytic GFAP and measured factors implicated in inflammation, such as matrix metalloproteinase‐9 (MMP‐9), matrix metalloproteinase‐2 (MMP‐2), IL‐1β, TNFα, and immunoglobulin G (IgG), were reduced in the EA‐ST36 group (Gim et al. 2011). IL‐10, a key cytokine, is mainly synthesized by astrocytes and microglia to suppress excessive inflammatory responses. Another study showed that the anti‐inflammatory cytokine IL‐10 acts as a protective factor in spinal astrocytes during EA‐induced pain (Dai et al. 2019). These results prove that the analgesic effect of EA may be related to a reduction in inflammation in astrocytes.

Many molecules and signaling pathways, such as the endocannabinoid system, are involved in the mechanisms underlying the ischemic tolerance induced by EA. EA pretreatment increases ambient endocannabinoid (eCB) levels and subsequently activates the ischemic penumbral astroglial cannabinoid type 1 receptor (CB1R), leading to a moderate upregulation of extracellular glutamate that protects neurons from cerebral ischemic injury (C. Yang et al. 2021). The crucial role of STAT3 in cell survival and proliferation is widely recognized. STAT3 is involved in the neuroprotection induced by EA pretreatment through CB1Rs after transient focal cerebral ischemia in rats (Zhou et al. 2013).

It is known that brain energy metabolism is also disrupted in cerebral ischemia (T. Zhang et al. 2023), and lactate in astrocytes is considered to be the main energy substrate for surviving neurons during the recovery period after ischemia. Glucose transported into the brain is converted to lactate in astrocytes and then delivered to neuronal cells via a monocarboxylic acid transporter (MCT) (Yamagata 2022). EA treatment induces the activation of lactate metabolism in the resident astrocytes surrounding the ischemic area, leading to the upregulation of astrocytic monocarboxylate transporter 1 (MCT1) expression in rats. This upregulation facilitates the transfer of intracellular lactate to the extracellular domain, allowing its use by injured neurons to ameliorate neurological deficits (Lu et al. 2015).

4.4. Astrocytes in HBOT

HBOT has been widely used in poststroke rehabilitation and has a multitude of neuroprotective effects on pathological and physiopathological condition, immunological function, and cellular and molecular mechanisms. Reactive astrocytes play an important role in the acute phase of stroke injury. Repeated HBO treatment leads to a long‐lasting antinociceptive response by inhibiting astrocyte activation (Günther et al. 2005; Zhao et al. 2014). The infarct site is surrounded by activated microglia and astrocytes after the occurrence of stroke, and the activated astrocytes express inducible nitric oxide synthase (iNOS), which is also an “A1” astrocyte‐specific marker (Rao et al. 2024). Massive synthesis of NO can enhance pain generation and further lead to the production of various cytokines and inflammatory factors. Early HBO treatment significantly improves hyperalgesia in rats by inhibiting astrocyte activation and decreasing iNOS and neuronal nitric oxide synthase (nNOS) expression (Y. Ding et al. 2018). Thus, reduced expression of iNOS and nNOS in astrocytes may be an important mechanism by which early HBO helps to alleviate neuropathic injury. HBO treatment inhibits astrocyte expression and the release of inflammatory factors, including TNF‐α and IL‐1β (Y. Ding et al. 2018). The anti‐inflammatory effect of HBOT may be mediated by hyperoxia, which interferes with NF‐κB and IκBα (De Wolde et al. 2021). The molecular mechanisms of HBO have not been fully elucidated. According to some existing studies, HBOT inhibits neuroinflammation via regulation of the NF‐κB/MAPK‐CCL2/CXCL1 signaling pathway in cultured astrocytes (Xia et al. 2022). In addition, HBO preconditioning alleviates inflammation in stroke by transferring resilient mitochondria from astrocytes to primary rat neuronal cells, thereby reducing cell death (Lippert and Borlongan 2019).

Nuclear factor erythroid 2‐related factor 2 (Nrf2) is a key transcription factor for genes regulated by antioxidant response elements. Activation of Nrf2 in astrocytes contributes to ischemic tolerance induced by hyperbaric oxygen preconditioning (J. Xu et al. 2014). Another study showed that compared with the corresponding controls, cultured astrocytes at 21% O2 promoted the expression of NTFs, including nerve growth factor (NGF), BDNF, neurotrophin‐3 (NT‐3), and GDNF (Xing et al. 2018), which are essential for cell growth, survival, and synaptic plasticity, compared with corresponding controls.

Abnormal glutamate metabolism in astrocytes induces excitatory neuronal toxicity. Research has shown that HBO exposure increases glutamate levels while significantly decreasing glutamine levels. HBO exposure affects the glutamate metabolism in astrocytes, which is closely related to poststroke epilepsy (Y. L. Chen, Li et al. 2016). HBO exposure regulates adenosine metabolism in astrocytes and inhibits HBO‐induced oxygen toxicity in the CNS, which is important for the generation and transmission of excitability (Y. L. Chen, Zhang et al. 2016). Furthermore, a previous study showed that HBO attenuated the expression of superoxide dismutase 2 (SOD2) in astrocytes, thus contributing to the attenuation of the oxidant/antioxidant imbalance that occurs after brain injury (Parabucki et al. 2012).

4.5. Astrocytes in EEs

Clinical epidemiological studies have shown that EEs have direct clinical relevance to neurological and psychiatric disorders. An EE is considered a classic and effective means of rehabilitation in animal stroke models and usually consists of a large cage containing ladders, beams, ramps, and a variety of toys (Kempermann 2019). The mechanism by which an EE promotes recovery of neural function has not yet been clearly elucidated. Compared with a standard environment, an EE provides more physical and social stimuli and facilitates motor, sensory, and cognitive activities. Research has shown that EEs are effective in normalizing dysregulation after stroke. One mechanism by which EEs improve cognitive function may be based on the reciprocal effect of EEs and astrocytes, as astrocytes are responsible for myelin formation through direct interaction with oligodendrocyte lineage cells (Gao et al. 2022). GFAP is a specific marker for astrocytes. EEs increased the number of GFAP‐positive astrocytes in the rat hippocampus after middle cerebral artery occlusion (MCAO) (X. Zhang et al. 2021) and increased astrocyte activity after intracerebral hemorrhage (ICH) (Caliaperumal and Colbourne 2014).

An EE is a promising technique for promoting neural plasticity to aid recovery from stroke (Han et al. 2023). Neural plasticity that occurs during stimulation by an EE plays an important role in the functional stabilization that allows the brain to adapt to environmental changes during development and adulthood. In addition to the high plasticity of neurons, morphological changes in astrocytes have also been observed after exposure to EEs (Markham and Greenough 2004). Further studies support an increased contact between features related to astrocyte morphology and synapse formation in rats (Jones and Greenough 1996). EEs promote synaptic transmission and plasticity (Eckert and Abraham 2013) and communication between astrocytes and synapses by controlling synaptic transmission (Durkee and Araque 2019; Q. Zhang and Haydon 2005). It is well known that astrocytes not only support neuronal activity through their mechanical and structural effects but also promote functional recovery after stroke by secreting cytokines and growth factors. Another study showed that EE increased astrocyte‐derived BDNF and vascular endothelial growth factor (VEGF) expression in rats with ischemic stroke (Guo and Bi 2024). Moreover, EE‐induced astrocyte proliferation and BDNF expression are significantly correlated with the outcome of neural function in rats after MCAO (X. Chen et al. 2017). In conclusion, EEs promote neuroplastic processes and exert a neuroprotective effect via astrocytes in ischemic stroke.

5. Conclusions

We have described the multidimensional functions of astrocytes in different rehabilitation modalities after stroke with a focus on enhancing neuroprotection (Table 1). In addition to the rehabilitation methods mentioned in this review, speech and language therapy, cognitive behavioral therapy (CBT), paraffin therapy, massage, traction, herbal fumigation, and psychotherapy are widely used in poststroke rehabilitation. However, the involvement of astrocytes in these therapies has rarely been reported.

TABLE 1.

Therapeutic targets for astrocyte associated with ischemic stroke.

Treatment types Mediator Full name Species/Model Roles References
Exercise E2 17β‐Estradiol Global cerebral ischemia (GCI) model in mice Inducts the A2 astrocyte phenotype Brann et al. (2022)
GLT‐1 Glutamate transporter 1 MCAO model in rats Promotes the glutamate reuptake ability X. Yang et al. (2012), F. Zhang et al. (2010)
HSP20 Heat shock protein 20 MCAO model in rats Attenuates both neuronal and glial apoptosis Qian et al. (2009), Lin et al. (2015)
AQP4 Aquaporin‐4 MCAO model in rats Suppresses brain edema Murata et al. (2020), Gono et al. (2023)
Transcranial magnetic stimulation PSD‐95 Postsynaptic density protein‐95 OGD/R injury in astrocytes Increases axonal density and promotes neural plasticity Hong et al. (2020)
CaMKII Calcium/Calmodulin‐dependent protein kinase‐II OGD/R injury in astrocytes Increases axonal density and promotes neural plasticity Hong et al. (2020)
Synapsin I / OGD/R injury in astrocytes Increases axonal density and promotes neural plasticity Hong et al. (2020)
Synaptophysin / OGD/R injury in astrocytes Increases axonal density and promotes neural plasticity Hong et al. (2020)
GDNF Glial cell line‐derived neurotrophic factor OGD injury in astrocytes Contributes to in neuronal protection Gava‐Junior et al. (2023), Roque et al. (2021)
ERK1/2 Extracellular signal‐regulated kinase‐1/2 OGD/R in neuron‐glia cortical cultures Associates with neuronal proliferation, differentiation, and apoptosis Cruz‐Mendoza et al. (2022), Sahu et al. (2021)
c‐Fos / OGD/R in neuron‐glia cortical cultures A brain activity marker and attributes to neurons Cruz‐Mendoza et al. (2022), Sahu et al. (2021)
PDGFRβ Platelet‐derived growth factor receptor beta PT stroke model in rats Associates with A2 astrocytes in stroke Zong, Li, et al. (2020)
TNF‐α Tumor necrosis factor alpha OGD/R in astrocytes Proinflammatory cytokine and promotes neuronal death Hong et al. (2020)
IL‐10 Interleukin‐10 OGD/R in astrocytes Anti‐inflammatory cytokine and alleviates neuronal death Hong et al. (2020)
Transcranial electrical stimulation SEPP1 Selenoprotein P1 Cerebral I/R injury in rats Exerts a neural protect function H. Wang et al. (2024)
Music therapy BDNF brain‐derived neurotrophic factor MCAO model in rats Promotes long‐term neuronal repair W. Chen et al. (2021)
Acupuncture BDNF Brain‐derived neurotrophic factor Cerebral ischemia‐reperfusion injury model in rats Promotes neuroprotective effects Tao et al. (2016)
CB1R Cannabinoid receptor type1 MCAO model in mice Protects neurons from ischemic brain injury C. Yang et al. (2021)
MCT1 Monocarboxylate transporter 1 MCAO model in rats Facilitates the transfer of lactate in the injured brain Lu et al. (2015)
Hyperbaric oxygen therapy NGF Nerve growth factor Cultured with 7% O2 in astrocytes Promotes cell growth, survival and synaptic plasticity Xing et al. (2018)
BDNF Brain‐derived neurotrophic factor Cultured with 7% O2 in astrocytes Promotes cell growth, survival and synaptic plasticity Xing et al. (2018)
NT‐3 Neurotrophin‐3 Cultured with 7% O2 in astrocytes Promotes cell growth, survival and synaptic plasticity Xing et al. (2018)
GDNF Glial cell line‐derived neurotrophic factor Cultured with 7% O2 in astrocytes Promotes cell growth, survival and synaptic plasticity Xing et al. (2018)
Enriched environment BDNF Brain‐derived neurotrophic factor MCAO model in rats Promotes poststroke functional recovery X. Chen et al. (2017), Guo and Bi (2024)
VEGF Vascular endothelial growth factor MCAO model in rats Promotes angiogenesis Guo and Bi (2024)
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This review summarizes the contributions of astrocytes to neuroprotection in various clinical rehabilitation settings. Activated astrocytes play essential roles in glial scarring, synaptic remodeling, inflammatory responses, glutamate transport, lactate metabolism, and BBB repair. These effects depend in part on various molecules secreted by reactive astrocytes, including NTFs, inflammatory factors, and neurotransmitters. Although targeting astrocyte autophagy may enhance neuroprotection in ischemic stroke, the modulation of astrocyte function involved in astrocyte autophagy has not been proposed.

Overall, we have provided an overview of the various ways in which astrocytes are important in stroke rehabilitation. Current data suggest that astrocytes are promising targets for therapeutic intervention in future rehabilitation research. However, the modulation of astrocyte function in ischemic stroke remains controversial. Therefore, further investigation is needed before attempting to utilize astrocytes for rehabilitative applications.

Author Contributions

Ying Han: conceptualization, investigation, funding acquisition, writing – original draft, writing – review and editing, visualization, formal analysis, project administration. Li Huang: conceptualization, investigation, writing – review and editing. Jiaojiao Wu: investigation. Guiling Wan: investigation. Linhong Mo: supervision, data curation, project administration, writing – review and editing. Aixian Liu: data curation, supervision, resources, project administration, writing – review and editing.

Conflicts of Interest

The authors declare no conflicts of interest.

Peer Review

The peer review history for this article is available at https://publons.com/publon/10.1002/brb3.70551.

Ying Han and Li Huang contributed equally to the article as first authors.

Funding: This work is supported by the National Key Research and Development Program of China (2021YFC2009405), the R&D Program of Beijing Municipal Education Commission (KM202310025001), and the Special Funding Project for Scientific and Technological Development of Beijing Rehabilitation Hospital, Capital Medical University (2022‐014).

Contributor Information

Linhong Mo, Email: molinhong@163.com.

Aixian Liu, Email: Lax721@163.com.

Data Availability Statement

Data sharing does not apply to this article, as no new data were created or analyzed in this study.

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