The biphasic regulatory effect of adenosine A2B receptor in ischemic brain injury and its therapeutic potential

Abstract

Ischemic brain injury is the leading cause of neurological disability and death worldwide. Adenosine A2B receptor (A2BR) is a member of the G protein-coupled receptor family, playing a crucial role in regulating excitotoxicity, inflammation, cell apoptosis, and vascular homeostasis. New evidence suggests that adenosine A2BR has a biphasic, time-dependent effect on ischemic brain injury. Its antagonists exhibit neuroprotective effects in the acute phase, while agonists have anti-inflammatory and vascular protective effects in the later stage, providing a new therapeutic direction for improving the long-term prognosis of patients with ischemic brain injury. This article reviews the research progress of A2BR in ischemic brain injury, including its molecular structure, expression kinetics, cell distribution, mechanism of action, pharmacological intervention, and systemic significance. We also discussed the therapeutic prospects of targeting A2BR and provided future prospects for personalized treatment strategies.

Introduction

Ischemic brain injury is a kind of nervous system disease caused by local ischemia and hypoxia in brain tissue, which leads to motor, sensory, cognitive, and speech dysfunction in patients. It is characterized by a high incidence rate, high disability rate, and high mortality, which seriously threaten human normal health [1]. At present, thrombolytic drugs such as tissue plasminogen activator (tPA) are one of the most effective methods for restoring blood supply to ischemic areas of the brain. However, due to factors such as “contraindications” and “window periods,” this therapy is difficult to promote on a large scale, and most patients suffer from serious sequelae due to failure to take thrombolytic therapy in a timely manner. Therefore, in-depth exploration of the molecular progression mechanism of ischemic brain injury, searching for disease-specific biochemical markers, and establishing more targeted personalized intervention methods have important clinical practice value.

Adenosine is a key regulatory factor in the central nervous system (CNS), which can regulate various pathophysiological processes such as excitotoxicity, inflammatory response, cell death, and nerve repair by acting on four different receptor subtypes: A1, A2A, A2B, and A3. Among them, adenosine A2B receptor (A2BR) exhibits “pathological high activation” expression and functional characteristics in pathological microenvironments such as ischemia and hypoxia, and its multidimensional signal regulation role is gradually being revealed. In recent years, it has become a core research hotspot in the exploration of ischemic brain injury mechanisms and the development of targeted therapies [4–6]. However, as a relatively scarce subtype in the adenosine receptor family, research on A2BR is still limited in academia. The specific regulatory mechanisms of A2BR in the process of ischemic brain injury, including its targets at different stages and interaction patterns with glial cells and inflammatory cells, have not yet formed a systematic understanding, and there are still many key issues that need to be clarified urgently. Therefore, this article will systematically review the research progress of adenosine A2BR in ischemic brain injury, covering the expression and regulation characteristics, molecular mechanisms, pharmacological intervention applications, and future research directions of A2BR, aiming to provide more comprehensive theoretical support for related basic and clinical research.

Expression, function, and activation characteristics of adenosine A2B receptor

Molecular structure of adenosine A2B receptor

A2BR belongs to the G protein-coupled receptor (GPCR) family and has a typical seven transmembrane domain. Its gene is located on human chromosome 17p11.2, and the coding region contains approximately 1100 nucleotides, encoding a protein composed of 332 amino acid residues [7, 8]. The structure of A2BR includes an extracellular N-terminus, seven transmembrane alpha helices, three intracellular loops, three extracellular loops, and an intracellular C-terminus. The extracellular N-terminal and transmembrane domains participate in ligand binding, while the intracellular domain interacts with G proteins to transmit signals. Compared with other subtypes of adenosine receptors, A2BR has lower sequence homology, with homology of approximately 30%, 45%, and 35% with A1, A2A, and A3 receptors, respectively [9]. This structural difference leads to the unique ligand binding properties and signal transduction mechanism of A2BR.

Expression dynamics of adenosine A2B receptor

A2BR is the lowest affinity subtype of adenosine receptors (requiring micromolar concentrations of adenosine activation), with low expression levels under physiological conditions, but significantly upregulated under pathological stimuli such as ischemia, hypoxia, and inflammatory responses [10]. This upregulation may be related to the sharp increase in extracellular adenosine concentration under pathological conditions [11], suggesting that A2BR may be a key factor involved in the pathophysiological processes of ischemic brain injury.

Research has found that ischemia, hypoxia, and inflammatory response can rapidly increase the expression of A2BR in brain tissue, which is driven by transcriptional upregulation mediated by hypoxia inducible factor (HIF-1 α) [4, 12, 13]. In addition, exogenous adenosine synthetases such as CD39 and CD73 are also upregulated in ischemic tissues, promoting an increase in local adenosine content and initiating protective signals through A2BR activation [14, 15]. Experimental data show that after ischemia-reperfusion, the expression of A2BR mRNA and protein in cerebral microvessels and damaged nerve areas significantly increases, and its dynamic changes are closely related to inflammatory response, cell apoptosis, and tissue repair [12, 16, 17].

It is worth noting that compared with receptors such as A1 and A2A, the upregulation time window of A2BR is more persistent, and its function is mainly reflected in the late stage of ischemia and reperfusion [18, 19]. A1 and A2A receptors are rapidly activated in the early stages of ischemia, mainly responding to acute injury, but their duration is short and difficult to cover the repair process in the later stages of ischemia [20, 21]; however, A2BR maintains high expression in the late stage of ischemia and can continue to participate in key processes such as inflammation resolution and vascular repair [22, 23], thereby forming a “relay” protection with other receptors, further indicating that A2BR is an important signaling node connecting injury and repair. This provides the possibility for A2BR as a therapeutic target for ischemic brain injury (Fig. 1).

Fig. 1.

Expression dynamics of adenosine A2B receptor

Distribution differences of adenosine A2B receptors

A2BR is relatively widely distributed and expressed in neurons, microglia, astrocytes, microvascular endothelial cells, and immune cells [24]. However, its effects vary in cell specificity, and activation on glial cells, peripheral blood vessels, and inflammatory cells can produce different effects. A2BR on neurons is mainly expressed in the postsynaptic membrane and participates in regulating neuronal excitability and synaptic transmission [17]. A2BR on microvascular endothelial cells is closely related to blood-brain barrier function, and its activation can regulate the expression of tight junction proteins, promote vascular stability, and reduce inflammatory cell infiltration [16, 17, 25, 26]. A2BR on microglia is involved in inflammatory response and immune regulation, while A2BR in astrocytes plays an important role in regulating microglial proliferation, signal communication, and preventing excitotoxicity [14, 25, 27]. In addition, white blood cells in peripheral blood also express A2BR, which regulates the inflammatory and immune environment of brain tissue [28].

It should be specifically mentioned here that this multicellular distribution pattern enables A2BR to achieve functional integration of paracrine signals in the brain. Research has shown that anti-inflammatory factors (such as IL-10) released by endothelial cells after activating A2BR can diffuse to adjacent microglia, enhancing their A2BR mediated anti-inflammatory phenotype transformation [29]. Astrocytes regulate glutamate transporter (GLT-1) activity through A2BR, which can alleviate neuronal excitotoxicity and affect endothelial cell barrier function by regulating extracellular glutamate concentration [30, 31]. From this, it can be seen that this cross-cellular signal interaction allows A2BR to break through the limitations of a single cell and form a comprehensive protection system covering “neural function maintenance vascular protection inflammation regulation.” It also provides a molecular basis for designing multi-cell synergistic therapy strategies targeting A2BR (Table 1).

Table 1.

Distribution of adenosine A2B receptors

Distribution area	Mechanism of action	References
Neurons	Regulating neuronal excitability and synaptic transmission	[17]
Microglia	Inflammatory response and immune regulation	[14, 25, 27]
Astrocytes	Regulating microglial cell proliferation, signal communication, and preventing excitotoxicity	[14, 25, 27]
Microvascular endothelial cells	Regulating the integrity of the blood-brain barrier	[16, 17, 25, 26]
Immune cells	Anti-inflammatory and inhibit the migration of inflammatory cells	[28]

Signal transduction network of adenosine A2B receptor

A2BR can regulate the information transmission and functional interaction between neurons, glial cells, and immune cells through multidimensional signaling pathways and is the core signaling hub for maintaining neural network homeostasis and mediating brain injury repair. Recent studies have shown that A2BR on astrocytes can participate in the regulation of brain tissue energy metabolism and indirectly affect synaptic plasticity. Both in vitro primary cell experiments and in vivo animal model studies have confirmed that activation of A2BR can specifically recruit the classical cAMP/PKA signaling pathway, which drives the upregulation of key enzymes in glucose metabolism (such as PKM2, LDHA) in astrocytes, achieving rapid activation of glucose metabolism and efficient release of lactate, thereby reshaping synaptic transmission efficiency and providing important support for the survival and repair of neurons after ischemia [32].

The effects of A2BR on glial cells include inhibiting the pro-inflammatory phenotype, regulating NLRP3 inflammasome activation, and promoting the secretion of cytokines that facilitate repair, which contribute to the transition of neurons from the inflammatory injury state to the repair stage [33–35]. A2BR also affects the proliferation and differentiation of microglia, and under ischemic or hypoxic conditions, it reduces astrocyte pyroptosis by inhibiting NF-κ B inflammatory signaling, thereby protecting brain tissue [14]. A2BR on immune-related white blood cells reduces the production of pro-inflammatory cytokines and regulates the migration of inflammatory cells, thereby alleviating systemic and local inflammatory responses [17, 36, 37].

From this, it can be seen that by playing a coordinating role in multiple cell types, A2BR helps promote the formation of new connections and functional integration between neurons and glial cells. A2BR constitutes an important signaling hub between glial cells, neurons, and immune cells and is a potential therapeutic target for ischemic brain injury repair and neurological function reconstruction.

Synergistic mechanism of adenosine A2B receptor with other receptor subtypes

The subtypes of adenosine receptor family play different but complementary protective and regulatory roles in ischemic brain injury. The A1 receptor is mainly active in the early ischemic stage and can directly inhibit the release of excitatory neurotransmitters [38–40]; A2A receptors are involved in the regulation of excitotoxicity and immune cell infiltration, affecting the inflammatory response in brain regions and are highly sensitive to drug regulation [41–43]; the A3 receptor has low expression in the brain, but it has unique value in peripheral injury and inflammation regulation [5, 44]. A2BR exhibits strong anti-inflammatory protection and vascular homeostasis regulation ability during the period of elevated adenosine concentration and chronic injury and is a key node for later brain injury repair [4–6, 36] (Table 2).

Table 2.

Mechanisms of action of other adenosine receptor subtypes

Adenosine receptor subtypes	Mechanism of action	References
A1R	Inhibit the release of excitatory neurotransmitters	[38–40]
A2AR	Excitatory toxicity regulation and inhibition of immune cell infiltration	[41–43]
A2BR	Anti-inflammatory protection, vascular homeostasis regulation, excitotoxicity control, tissue repair	[4–6, 36]
A3R	Regulating peripheral injury and inflammation	[5, 44]

Therefore, using multi-target combination drugs to exert immune regulation can more effectively achieve brain protection. For example, the “functional complementarity” of A2BR and other adenosine receptor subtypes in controlling excitotoxicity provides a new approach for the staged treatment of ischemic brain injury. In the acute ischemic phase, the short-term peak of adenosine alternates with direct protective or excitatory effects mediated by A1/A2A, and the combination of A1 receptor agonists, A2A receptor antagonists, and A2BR antagonists can be considered to rapidly control excitotoxicity [45, 46]; during the repair phase after injury stabilization, A2BR may play a more significant role in regulating inflammation, promoting reparative metabolic networks, and supporting remodeling processes. Therefore, the application of A2BR agonists can be explored [47]. Experimental evidence shows that local selective modulation of A2BR agonists or antagonists can significantly alter ischemic volume, inflammatory markers, and behavioral recovery [17]. By precisely regulating A2BR activity, a synergistic therapeutic effect of “acute phase protection late stage repair” can be achieved.

From the above, it can be seen that the various subtypes of the adenosine receptor family form a regulatory network with complementary functions and temporal division of labor in the pathological process of ischemic brain injury. A2BR, as a core node in this network, has become a key target for linking acute protection and later repair due to its regulatory characteristics at different stages of brain injury. At the same time, this staged and multi-target joint regulation strategy based on receptor subtype functional differences breaks the limitations of single target intervention and provides a more targeted theoretical basis for optimizing treatment plans for ischemic brain injury.

The mechanism of action of adenosine A2B receptor in ischemic brain injury

Neuroprotection and maintenance of blood brain barrier steady state

Most studies have confirmed that A2BR activation can effectively reduce nerve damage, alleviate brain edema, and protect the integrity of the blood-brain barrier (BBB). In a transient middle cerebral artery occlusion model (tMCAo) in rats, continuous administration of A2BR agonist BAY 60–6583 (0.1 mg/kg ip, twice a day) for 7 days significantly reduced the risk of inflammation-related bleeding and hemorrhagic transformation (HT) and improved neurobehavioral function [16, 36]. MMP-9, as a key protease that destroys the BBB, can degrade the tight junction structure between endothelial cells when its activity is too high [48], while the inhibitory effect mediated by A2BR can effectively block this pathological process [49]. Another study also found that the dual agonist MRS3997 (0.1 mg/kg ip, twice a day) of A2A and A2BR can provide higher neuroprotection in post-ischemic injury. Within 7 days after tMCAo, neurological deficits were improved, ischemic brain damage in the cortex and striatum was significantly reduced, ischemic-induced neuronal death was counteracted, myelin damage was reduced, and morphological changes in the activation of microglia and astrocytes were inhibited [17, 36].

The emergence of this significant neuroprotective phenomenon may be closely related to the receptor subtype cross interaction induced by the agonist MRS3997, especially the complex synergistic or intermodulation effects between A2BR and A2AR, which will significantly affect the final biological function.

Control excitotoxicity and cell apoptosis

After ischemic injury, excitatory amino acids (such as glutamate) are violently released, leading to neuronal overactivation and damage. Adenosine can exert protective effects through different receptors after a large release. A1 receptors mainly inhibit glutamate release, while A2BR activation has a regulatory effect on excitotoxicity [38, 39, 41]. Research has shown that A2BR contributes to the occurrence of glutamate-mediated excitotoxicity in early ischemia, and the inhibitory effect of receptor antagonists such as PSB603 can effectively counteract glutamate overload transmission [25, 30, 31]. In an in vitro oxygen glucose deprivation (OGD) model, selective use of A2BR antagonists PSB603 (50 nM 7 min) or MRS1754 (500 nM 7 min) can regulate the PKC/HIF-1 α pathway, delay neuronal depolarization, and reduce apoptosis and cell death, indicating that inhibiting A2BR can prevent acute nerve damage induced by energy metabolism disorders [12, 25]. And hypoxia depolarization is a clear sign of glutamate-induced excitotoxicity during OGD [41]. However, in vivo or long-term observation, activation of A2BR may achieve more prioritized neuroprotection by inhibiting inflammation and promoting repair mechanisms. Therefore, A2BR has a time-dependent bidirectional effect on excitotoxicity and late-stage injury [17, 36, 50].

The difference in this bidirectional effect is due to the adaptive response of A2BR to different pathological stages of ischemic brain injury. In the early stage of ischemia, energy metabolism in the brain is rapidly disrupted, and the excitotoxicity caused by the accumulation of large amounts of glutamate progresses explosively [43]. At this time, A2BR activation may enhance the sensitivity of neurons to excitatory signals or interfere with the inhibitory effect of A1 receptors on glutamate release [24], thereby exacerbating cell damage. Therefore, using antagonists such as PSB603 and MRS1754 to block A2BR can directly cut off this “damage amplification pathway” and provide neurons with a critical time window for energy metabolism recovery. As the injury enters the later stage, the pathological core shifts from acute excitotoxicity to chronic inflammation and tissue repair imbalance [44]. At this time, the activation of A2BR indirectly reduces the sustained damage of the inflammatory response to neurons by regulating the secretion of inflammatory factors and promoting immune cell polarization, while providing a favorable environment for synaptic remodeling and cell regeneration [45, 46], forming a protective effect that is completely opposite to the early stage.

Anti-inflammatory and immune regulation

A2BR is known for its significant anti-inflammatory function in the late stage of ischemic brain injury, which can effectively inhibit the infiltration of inflammatory cells such as neutrophils, reduce the expression of pro-inflammatory factors (such as TNF-α, IL-1 β, IL-6), and promote the release of anti-inflammatory factors (such as IL-10), thereby reducing tissue damage and accelerating repair [17, 37]. In the overactivated immune response, A2BR regulates the NF-κ B signaling pathway, inhibits the inflammatory response of astrocytes and white blood cells, and helps protect brain tissue and stabilize the local microenvironment [14]. A2BR signaling can also affect metabolic reprogramming and polarization through key regulatory factors such as mTOR, AMPK, and HIF-1 α, thereby promoting immune tolerance or activation [48].

Meanwhile, some studies have found that A2BR has weak or no significant anti-inflammatory effect. This study focuses on the regulatory effects of A2BR on IL-6 and TNF-α through in vitro and in vivo control experiments of A2BR knockout (A2B KO) mice and wild-type mice. Researchers stimulated wild-type mice with the adenosine receptor agonist NECA and found a significant increase in IL-6 levels in their plasma, while lipopolysaccharide (LPS)-induced TNF-α levels were inhibited; however, when the same agonist was used on A2BR knockout mice, the NECA-induced plasma IL-6 elevation almost completely disappeared, and the inhibitory effect on LPS-induced TNF-α was not affected. This indicates that activation of A2BR only promotes the production of pro-inflammatory cytokine IL-6 and does not enhance the anti-inflammatory inhibitory effect of adenosine on TNF-α. It can be seen that the activation of A2BR not only does not exert anti-inflammatory effects, but also upregulates the expression of pro-inflammatory cytokine IL-6, confirming that A2BR has no significant anti-inflammatory effect in related inflammation regulation [51].

The core reason for the contradictory results mentioned above may be that the differences in ligand specificity and intervention timing affect the interpretation of conclusions. Early studies lacked highly selective A2BR ligands, making it difficult to rule out cross activation with subtypes such as A2AR. However, the intervention time points chosen by different studies (early and late ischemia) corresponded precisely to the bidirectional functional window of A2BR, further amplifying the contradiction. In addition, the cell specificity of the detection object is also ignored, and there is heterogeneity in the expression and function of A2BR on glial cells, vascular endothelial cells, and peripheral inflammatory cells. Some studies do not distinguish the effects of specific cell populations and only use whole brain tissue as the detection object, resulting in bias towards its true function.

Vascular protection and alleviation of reperfusion injury

In the ischemia-reperfusion model, A2BR activation can promote cerebral vasodilation, increase local blood flow recovery, and regulate microvascular structure and barrier function, thereby helping to slow down the “secondary damage” caused by reperfusion. Animal model studies have also shown that A2BR agonists can significantly reduce hemorrhagic transformation and block vascular damage in brain regions by regulating the expression of MMP-9 and TIMP-1 and protect brain microcirculation [16]. In vitro experiments on human microvascular endothelial cells, activation of A2BR drives angiogenesis mediated expression of VEGF and eNOS, improves hemodynamics, and promotes the recovery of vascular structure and endothelial function [24]. In addition, the balanced nucleoside transporter-2 (ENT2) indirectly affects A2BR-mediated vascular protection and brain metabolic effects by regulating adenosine levels. ENT2 deficiency can enhance A2BR-related metabolic adaptation and protective response, thereby reducing neurological deficits such as infarct volume, brain edema, and neuroinflammation in mice with cerebral ischemia-reperfusion injury [52].

The protective properties of A2BR and ENT2 in reperfusion injury can be optimized for the “reperfusion treatment window” of ischemic stroke patients. Although thrombolysis and thrombectomy commonly used in clinical practice can restore blood flow, they are prone to causing reperfusion injury. The combination of A2BR agonists or ENT2 inhibitors is expected to restore blood flow while protecting microvascular structure, alleviating inflammatory response, and reducing the risk of complications such as hemorrhagic transformation and cerebral edema [53, 54]. This synergistic regulation mode of “transporter receptor” suggests that in the future, more efficient vascular protection strategies can be constructed by jointly regulating ENT2 activity and A2BR expression (Fig. 2).

Fig. 2.

The mechanism of action of adenosine A2B receptor in ischemic brain injury

Pharmacological interventions related to adenosine A2B receptors

Neuroprotective effects of A2B receptor agonists

A2BR agonists, as potential therapeutic drugs, have shown certain neuroprotective effects in experimental studies of ischemic brain injury. Multiple studies have confirmed that A2BR agonists have dual neuroprotective and anti-inflammatory effects. A2BR agonists such as BAY 60–6583 and MRS3997 can significantly improve neurological function, reduce infarct volume, alleviate brain edema, decrease activation of microglia and astrocytes, and effectively inhibit inflammatory cell infiltration in the tMCAO model. These agonists also help maintain the stability of the blood-brain barrier, regulate cytokine balance, and are particularly sensitive to late-stage inflammatory responses [16, 17, 36].

In view of the anti-inflammatory advantages of A2BR agonists in the late stage of ischemia, the sequential combination mode with thrombolysis and thrombectomy therapy can be explored in the future [55]. After reperfusion therapy, the use of A2BR agonists can compensate for the shortcomings of reperfusion therapy by inhibiting late stage inflammation, protecting the blood-brain barrier, and forming a complete treatment chain of “acute reperfusion late stage protection,” providing more comprehensive protection for the prognosis improvement of patients with ischemic brain injury.

However, the clinical application of A2BR agonists also faces some challenges, such as the selectivity and dose dependence of agonists, the blood-brain barrier penetration ability of drugs, and the impact of individual differences in patients on drug efficacy. Studies have confirmed that high-dose A2BR agonists may cause peripheral vasodilation, leading to adverse reactions such as decreased blood pressure [56]. Therefore, further optimizing the structure of agonists and improving their selectivity and safety is an important direction for future research.

Anti injury effects of A2B receptor antagonists

Compared with agonists, there is relatively less research on A2BR antagonists in the field of ischemic brain injury, but they have also shown certain therapeutic potential. Some studies suggest that A2BR can promote excitotoxicity and cell death during the acute ischemic phase. Therefore, antagonists (such as PSB-603) have shown preventive effects on neuronal depolarization and apoptosis in vitro OGD models and can alleviate early cell damage [25, 50]. In a model of periventricular leukomalacia (PVL) induced by ischemia, hypoxia, and inflammation, A2BR antagonist PSB-603 (50 nM for 7 min) was found to reduce Caspase-3 levels and inhibit microglial activation through the PKC/Erk/Creb/HIF-1 α axis and weaken myelin formation by promoting myelin basic protein (MBP) expression and oligodendrocyte differentiation, thereby improving hypoxic-ischemic damage in PVL [12].

Based on the above research, it can be found that A2BR may exert different physiological effects in different stages of ischemic brain injury. In the early stage, it may mainly have pro-inflammatory and damaging effects, while in the later stage, it participates in the process of neural repair. Therefore, given the temporal regulatory characteristics of A2BR, such drugs may require a well-designed intervention window and strict control of the timing and dosage of A2BR antagonists [57]. By monitoring the expression level of A2BR in the brain, the balance of pro-inflammatory/anti-inflammatory factors (TNF-α/IL-10 ratio), and myelin repair-related indicators (MBP content), the stage of injury can be dynamically determined. When the peak expression of A2BR is detected accompanied by an increase in TNF-α, it indicates that the patient is in the acute ischemic phase and can initiate antagonist therapy; when IL-10 increases and MBP begins to recover, it is necessary to stop or reduce it in a timely manner to avoid affecting nerve repair (Fig. 3).

Fig. 3.

The regulatory mechanisms of adenosine A2BR antagonists and A2BR agonists

Prospects of multi-target combination therapy

Given the complex role of A2B receptors in ischemic brain injury, single activation or antagonism therapy may not achieve ideal results; therefore, combination therapy strategies are gradually receiving attention. Research has found that the combination of A2BR agonists and tPA may have a synergistic effect. tPA is currently the main medication for treating ischemic stroke in clinical practice, but its use may increase the risk of HT [58]. The tMCAO experiment showed that tPA can reduce the expression of A2BR in ischemic cerebral microvessels [16], while A2BR agonist BAY 60–6583 can alleviate HT caused by tPA, which may be related to the inhibition of MMP-9 activation enhanced by tPA and the increase of TIMP-1 expression [59]. Therefore, A2BR agonists as adjuvant therapy for tPA can help reduce the risk of tPA treatment and improve treatment efficacy.

In addition, the combination of A2BR modulators with other neuroprotective drugs also has potential application value. For example, the combination of A2BR agonists with NMDA receptor antagonists, calcium channel blockers, etc. can effectively alleviate ischemic brain injury through multi-target action [60–62]. It is also possible to explore the “stage adaptation combination” of A2BR antagonists with other therapeutic methods, such as combining PSB-603 with glutamate receptor antagonists during the acute ischemic phase to enhance the blocking effect on excitotoxicity [25, 45]; after entering the repair phase, antagonists can be used sequentially with A2BR agonists [63], or in combination with myelin repair promoters (such as oligodendrocyte differentiation inducers) [64, 65], to enhance neural repair effects while avoiding inflammatory damage.

In addition to a single target, the joint development of A2A/A2B dual agonists or antagonists has become a new trend. Research has shown that the combined use of A2A/A2B agonists or antagonists can achieve more comprehensive neuroprotective and inflammatory regulatory effects, effectively reducing side effects and tolerance issues. The application of multi-target drugs such as MRS3997 significantly enhances neuroprotection in ischemic areas and improves cellular structure and functional recovery [36, 50]. P626, as a dual antagonist, demonstrated the ability to delay energy depletion and reduce the depolarization rate, providing new ideas for multi-target compound design [50].

Regulation of exogenous and endogenous adenosine pathways

Developing drugs based on adenosine production and metabolic pathways, such as CD73 activators or adenosine degrading enzyme inhibitors, is also a promising research direction. During ischemic injury and repair, CD73, as a key enzyme for adenosine production, can further enhance the activation effect of A2BR by increasing local adenosine concentration, thereby inhibiting astrocyte pyroptosis, controlling inflammatory response, and promoting tissue repair [14, 15]. Animal experiments have also shown that overexpression of CD73 can significantly reduce cell death and tissue inflammation in acute cerebral ischemia and achieve this effect through the A2BR/NF-κ B pathway [14]. Therefore, the author believes that the relevant technology of nanocarriers [66] can be used to target the delivery of CD73 activators to ischemic brain areas, causing them to specifically aggregate around vascular endothelial cells and glial cells in ischemic brain tissue, significantly increasing local CD73 activity, promoting adenosine production, activating A2BR, and thus more effectively reducing neuroinflammation and promoting vascular repair and nerve regeneration.

Similarly, adenosine degrading enzyme inhibitors, such as adenosine deaminase (ADA) inhibitors, also have great potential. During ischemia, ADA blocks adenosine degradation, maintaining a high level of adenosine concentration in the ischemic area and continuously activating multiple repair mechanisms such as neuroprotection, inflammation regulation, and vascular remodeling involving A2BR. Clinical studies have shown that after administration of ADA inhibitors, adenosine levels in ischemic tissues significantly increase, and the A2BR mediated anti-inflammatory and tissue repair signaling pathways continue to activate, effectively reducing the volume of cerebral infarction and improving neurological function prognosis [68].

Summary and prospect

Adenosine A2B receptors have gradually become cutting-edge targets in central nervous system research and drug development due to their regulatory, protective, and reparative roles in ischemic brain injury. The latest literature confirms that A2BR expression significantly increases after cerebral ischemia and achieves neuroprotective effects through various cellular mechanisms such as maintaining blood-brain barrier integrity, excitotoxic constraints, metabolic regulation, and inflammation control [14, 16, 17, 25, 36]. In terms of pharmacological intervention, A2BR agonists and antagonists exhibit unique advantages according to different stages of pathological progression. Therefore, the development of multi-target combination therapy provides a solid foundation for future clinical translation. In addition, key enzymes such as CD73 that generate adenosine have opened up new pathways for nerve injury repair and inflammation control by regulating A2BR activity [14, 15].

At present, it is necessary to further explore the pathological activation mechanism, temporal regulation characteristics, and systemic effects of A2BR and optimize the selectivity, safety, and personalized intervention window of drugs. Especially in future research, highly selective A2BR modulators should be selected as much as possible to reduce cross activation of other adenosine receptor subtypes. At the same time, receptor knockout models or subtype-specific inhibitors can be used to clarify the independent function of a single receptor and the synergistic ratio of the two, providing a basis for precise targeted therapy. Overall, the adenosine A2B receptor, as an emerging molecular target for the protection and repair of cerebral ischemic injury, has broad prospects and enormous value and deserves continuous attention and in-depth research.

Xu Rui

Male, medical doctor, mainly engaged in the mechanism research of integrated traditional Chinese and Western medicine treatment of cerebral ischemia.

Author contribution

This article was co conceived by all authors. Xu Rui and Wang Xi, Li Mengzhu designed the review, and Su Peiwei, Zhu Chao, Liu Mudong, Luo Wanyu drafted the manuscript, which was later edited by Zhao Haijun. Jinan City School Integration Development Strategy Project, JNSX2024019.

Funding 

This work was supported by the National Natural Science Foundation of China (Grant No. 82474660) and the Shandong Provincial Natural Science Foundation Innovation and Development Joint Fund (Grant No. ZR2021LZY014). 

Data availability

No datasets were generated or analysed during the current study.

Compliance with ethical standards

Competing interests

The authors declare no coterests.