1. Introduction
Stroke remains the second leading cause of death and the third leading cause of death and disability combined worldwide, as indicated by disability-adjusted life-years (DALYs) lost [
1]. The highest burden of stroke disability is observed in developing countries of Asia and the stroke belt of the United States [
2]. Despite remarkable progress and advancements in evidence-based acute care therapies, such as intravenous thrombolysis and endovascular therapy, the burden of stroke remains significantly high [
3].
In 2023, a significant advancement in the treatment of ischemic stroke due to proximal intracranial arterial occlusion was marked by compelling evidence from several clinical trials that supported endovascular therapy, particularly for patients with a large ischemic core [
4]. Thus, endovascular therapy has entered a new era since the first clinical trial favoring endovascular therapy. However, more patients receiving endovascular therapy does not equal a better prognosis. Patients with stroke experience long-term dysfunction, and the percentage is much higher in patients with large ischemic cores. Therefore, numerous tasks must be performed to optimize acute stroke treatment strategies and improve rehabilitative care.
The central nervous system (CNS) is traditionally regarded as a privileged compartment isolated from the rest of the body. The blood-brain barrier (BBB) was initially thought to be an absolute barrier to many proteins and factors. Recently, numerous novel functional and anatomical pathways transmitting neural, cellular, and molecular signals have been discovered. This crosstalk between the CNS and the body has ignited new hope for neuroprotection or cytoprotection [
5].
Moreover, some factors, even if unable to cross the BBB, can still transmit signals by interacting with receptors in the BBB [
6]. More importantly, new proteomic and single-cell RNA sequencing technologies have discovered many factors that mediate the cross-talk between the CNS and the body [
7]. These advancements provide us with an opportunity to reconsider potential targets and enhance stroke recovery from a systemic biological perspective of brain communication.
2. Revascularization therapy for patients with stroke
In 1995, the National Institute of Neurological Disorders and Stroke trial demonstrated that recombinant tissue plasminogen activator (rt-PA) significantly improved the clinical outcomes of patients with acute ischemic stroke when administered within 3 h of stroke onset [
8]. The US Food and Drug Administration approved rt-PA for the treatment of acute ischemic stroke the following year, initiating the era of intravenous thrombolytic therapy. The European Cooperative Acute Stroke Study III trial subsequently extended the time window for intravenous thrombolysis to 4.5 h [
9]. Nevertheless, the time window for intravenous thrombolysis remains narrow, and multiple contraindications restrict the appropriate population for this treatment. Additionally, approximately 40% of acute ischemic strokes are caused by acute occlusion of large intracranial vessels, which increases the mortality rate by 3.5 times at the sixth month and reduces the proportion of patients with favorable outcomes by 33% [
10]. New technologies have promoted new modes of intravenous thrombolytic therapy. For example, these treatments can be initiated in a mobile stroke unit and performed in patients outside a time window of 4.5 h. New types of human tissue plasminogen activators, such as tenecteplase, have also been clinically used [
2], [
5].
In patients with acute ischemic stroke resulting from acute occlusion of intracranial large vessels, the recanalization rate of intravenous thrombolysis is only about one-third [
3]. In 2015, the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands and other four randomized controlled trials demonstrated that endovascular therapy within 6 h can significantly improve the clinical prognosis of acute ischemic stroke caused by a proximal intracranial arterial occlusion of the anterior circulation [
11]. After endovascular therapy, 46.0% of patients had a functional outcome (modified Rankin scale (mRS) score 0-2) after three months, compared with only 26.5% in medical therapy alone group (adjusted odds ratio 2.71 [2.07-3.55];
p < 0.0001) [
3]. The successful recanalization rate could reach up to 70% after the endovascular therapy. Subsequent trials, such as the Diffusion-Weighted Imaging (DWI) or Computed Tomography Perfusion (CTP) Assessment with Clinical Mismatch in the Triage of Wake-Up and Late Presenting Strokes Undergoing Neurointervention with Trevo and Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke trials, extended the therapeutic time window to 24 h [
12], [
13]. As a result, endovascular therapy is now recognized as the most effective therapy for acute ischemic stroke caused by large-vessel occlusion and is recommended by multiple clinical guidelines [
14]. However, the therapeutic efficacy of endovascular procedures for posterior circulation was not demonstrated in clinical trials until 2022. Basilar Artery Occlusion Chinese Endovascular and Endovascular Treatment for Acute Basilar-Artery Occlusion trials have validated the safety and efficacy of endovascular therapy for acute ischemic stroke caused by acute occlusion of the basilar artery [
15], [
16]. Revascularization therapy for acute ischemic stroke has entered a new era, with over 80% of patients experiencing successful recanalization after endovascular therapy. Furthermore, a series of randomized controlled trials optimized the process and protocol of endovascular treatment for acute ischemic stroke. This optimization includes screening of infarct volume, perioperative blood pressure control, and a prehospital transport protocol, contributing to further enhancement of the clinical efficacy of endovascular therapy [
17], [
18].
Despite significant advancements in stroke treatment in recent years, more than 50% of stroke patients do not experience a favorable outcome in the era of reperfusion therapy, and 75% of the patients are left with lifelong disabilities after stroke [
19]. After cerebral vascular occlusion, neurons in the ischemic core area undergo irreversible cell death within minutes. In patients with poorly compensated collateral circulation, a large infarct core and a small ischemic penumbra developed quickly, limiting the benefits of recanalization therapy. According to the current guidelines, endovascular therapy is deemed effective for patients with small-core infarctions [
20]. The results of the Recovery by Endovascular Salvage for Cerebral Ultra-Acute Embolism-Japan Large Ischemic Core Trial indicated that although endovascular therapy remains superior to optimal medical therapy, the clinical prognosis for patients is significantly poor. Specifically, only 14% of patients had a good 90 d outcome (mRS 0-2) after endovascular therapy [
18]. Additionally, even when large vessels were completely recanalized, one in four patients still experienced microvascular and brain tissue hypoperfusion, indicating no reflow [
21]. This can lead to reperfusion injury and exacerbating damage to brain tissue. Revascularization therapy presents new opportunities and challenges for the treatment of acute ischemic stroke. Brain protection is an urgent scientific problem that must be addressed in the era of reperfusion therapy.
3. Protecting the brain from a view of systemic biology
Golden time window is crucial after stroke. Recanalization therapy has paved the way for brain rescue. Neuroprotection and cytoprotection are important for rescuing damaged cells after a stroke. Over the past decades, neuroprotection of ischemic brain tissue has shifted from protecting neurons alone to protect the neurovascular unit (NVU), including neurons, glia, and vascular compartments, appropriately termed cytoprotection [
22]. Neuroprotectants, such as edaravone and nerinetide, have been utilized in clinical trials. Despite displaying favorable effects, their efficacy in treating ischemic stroke remains restricted owing to their limited ability to penetrate the BBB and access the ischemic penumbra, resulting in inadequate drug concentrations. Addressing this challenge has become a pivotal focus of current research aimed at discovering more efficient drug delivery methods [
23]. Hence, given the intricate pathological mechanisms of ischemic stroke, diverse functional nanoparticles have been engineered as promising drug delivery platforms, which are expected to improve the therapeutic effect of ischemic stroke [
24]. Moreover, cell death plays an important role in the occurrence and development of ischemic stroke, including pyroptosis, apoptosis, necroptosis, ferroptosis, and PANoptosis [
25]. Emerging evidence suggests that inhibiting ferroptosis or targeting senescent cells in the chronic phase of ischemic stroke can delay the progression of the disease and further improve prognosis [
26]. Therefore, targeted cell death is also an effective means of treating ischemic stroke. Stem cell therapy has emerged as a promising treatment for stroke, offering the potential to regenerate lost brain cells. Some functional mechanisms of stem cell therapy include the secretion of neurotrophic factors, restoration of characteristics, cell replacement, and formation of biological bridges. The neuroprotective and regenerative abilities of stem cells in the phase [
27], [
28] and chronic events [
29] suggest that stem cell transplantation remains a promising approach to address defects after stroke onset. Although the success of stem cell therapy largely depends on the type of stem cells used, the transplantation method is equally important, because different delivery routes trigger different therapeutic mechanisms and exhibit unique functional benefits. A more appealing strategy is the use of cytoprotective methods that target multiple components of the ischemic cascade, such as neuropeptides, hypothermia, and MgSO
4 [
30], [
31]. Moreover, significant emphasis has been placed on the concept of vascular protection in the era of high reperfusion. Many studies have found that subtle BBB leakage occurs as early as 30 min after stroke in a mouse model, and early BBB protection is closely associated with better stroke outcomes [
32], [
33]. In addition, enhancing the cerebrovascular circle reserve or endogenous collaterals is also crucial for cytoprotection [
34].
Furthermore, the communication between various cell types within the NVU is associated with stroke prognosis, for example, adenosine triphosphate (ATP) transfer between astrocytes and neurons and “help-me” signals that mediate injury into recovery transition within the NVU [
35]. After acute ischemic stroke, microglia can be rapidly activated and polarized into pro-inflammatory M1 type and anti-inflammatory M2 types, playing dual roles of tissue damage and neuroprotection [
36]. Among them, M2 microglia play a key role in myelin formation and reformation, neuronal regeneration, and angiogenesis, and are the main targets for promoting neuronal regeneration after ischemic stroke [
37]. Therefore, for the future treatment of ischemic stroke, we can promote the polarization of microglia to M2 type, reduce the transformation of M2 type to M1 type, increase the expression time of M2 microglia, and promote neural regeneration and functional recovery. In addition, the accumulation of reactive oxygen species caused by ischemia-related disorders of oxidative homeostasis promotes molecular and cellular damage related to oxidative stress. Oxidative stress is an important pathophysiological mechanism in the progression of ischemic stroke and is closely related to the occurrence of ischemia-reperfusion injury. Therefore, targeting oxidative stress, including antioxidants, and searching for biomarkers of oxidative stress may be potential therapeutic methods for ischemic stroke [
38]. Thus, pharmacological or non-pharmacological modalities that target multiple aspects of the ischemic cascades and exert benefits to all components of the NVU after stroke are attractive and hold translational potential in the reperfusion era.
Neurorestorative strategies, which promote angiogenesis, axonal remodeling, neurogenesis, and synaptogenesis, provide promising opportunities for functional recovery after stroke [
39]. Previously, neuro-restoration therapy was considered less effective after brain injuries. Over the past few years, the brain-gut, brain-bone, brain-liver, brain-hear, and brain-skeletal muscle axes have been discovered, and they are considered to play crucial roles in communication between the brain and peripheral organs (
Fig. 1). Notably, in preclinical studies [
40], [
41] and clinical research [
42], a significant reduction in spleen size after ischemic stroke was observed, indicating an important role of the spleen in peripheral inflammation after stroke. Furthermore, studies have confirmed that the removal of the spleen can further reduce infarct volume, and the addition of splenic cell therapy can reverse this therapeutic effect [
43]. Additionally, radiation-induced reduction in splenic function can also decrease infarct volume [
44]. The aforementioned evidence confirms that reducing splenic inflammation plays a crucial role in the treatment of ischemic stroke. Blood-borne signals have been found to account for the benefits to the brain after leveraging systemic and lifestyle interventions on both the bench and bedside, including caloric restriction, exercise, and preconditioning. For example, selenoprotein P, which is upregulated in the blood of mice after four days of voluntary wheel running, could transport selenium across the BBB and increase hippocampal neurogenesis [
45]. Meanwhile, anti-inflammatory exercise factors were observed after exercise in both humans and animals. More importantly, these factors are transferable, target the cerebrovasculature, and benefit the brain [
46]. It is increasingly recognized that these blood-borne signals, including cytokines, nucleic acids, lipids, microbiomes, and metabolites, serve as signals from the peripheral system to facilitate neuro-restoration after stroke.
Moreover, growing evidence suggests that both innate and adaptive immune systems play important roles in mediating disease progression after ischemia/reperfusion. The inflammatory response to stroke occurs via a highly orchestrated series of events involving various cell types from both the central and peripheral immune systems. A preclinical study published as an abstract of a conference revealed that anti-inflammatory treatment based on the recanalization of cerebral infarction vessels may play a beneficial role [
47]. Therefore, anti-inflammatory treatment is expected to further improve the poor prognosis of patients with this condition. However, further clinical trials are needed to validate these preliminary findings. Several clinical trials have attempted to modify inflammatory responses to improve long-term function after stroke [
48]. However, no definite benefits are currently available. Furthermore, the influence of the gut on the brain after a stroke has attracted significant attention. Multiple lines of evidence have shown that not only gut microbiota directly influence neuro-restoration after stroke, but also gut metabolites affect brain function in various ways [
49], [
50]. Currently, modulating gut bacteria has become a promising intervention to improve neuro-restoration in both patients and animal models, including fecal microbiota transplantation therapy and treatment with probiotics, prebiotics, or synbiotics [
5]. Moreover, Bonkhoff and Grefkes [
51] discussed existing artificial intelligence approaches and single-subject prediction scenarios in outcome research on acute, subacute, and chronic stroke. They outlined how the increasing richness of data leads to new scientific insights and ultimately contributes to improving outcomes after stroke [
51]. In summary, to establish these systemic interventions as clinical routines and further improve the adverse outcomes of stroke patients, more research is required to address current challenges, such as optimal initiation time, specific targets, and selection of the most suitable patient.
4. Conclusions and outlook
In recent decades, recanalization therapy has been revolutionized by the development of thrombolysis and endovascular thrombectomy. The number of candidates for recanalization therapy has increased because of the accumulation of clinical evidence and advancements in new endovascular materials and imaging methods. The application of artificial intelligence methods will also help us make precise treatment choices for stroke patients at different stages in the near future. However, it is imperative to improve the long-term functional outcomes of highly effective reperfusion.
In recent years, the brain has been widely accepted as an important organ that interacts bidirectionally with systemic biology after ischemic stroke. Communication between the central and peripheral nervous systems has been observed due to technological advances in proteomic and transcriptomic analyses. With recent research emphasizing ways to improve long-term functional outcomes, future treatments for ischemic stroke will likely need to be multipronged. For patients in the acute stage, it is necessary to emphasize methods to protect the NVU through both vascular- and cell-based mechanisms. For patients in the chronic stage, the promotion of beneficial communication with the brain by increasing angiogenesis, neurogenesis, and synaptogenesis will improve long-term functional outcomes after stroke.
Acknowledgments
This study was supported by the National Natural Science Foundation of China (82027802, 82371470, and 82071468). We would like to thank Editage (www.editage.cn) for English language editing.
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