Ischemic stroke refers to blood supply disorders that result in cerebral ischemia and hypoxia and ultimately lead to ischemic damage and necrosis of brain tissue. In China, there are approximately 2.4 million new stroke patients each year, and the number of deaths from stroke have increased by 43.0% in the past decade (Collaborators, 2021; Wang et al., 2017). While neuroscientists and clinicians have made significant strides in understanding the pathophysiological mechanisms of stroke, there are still challenges regarding its prevention and treatment. Unfortunately, there have been few significant breakthroughs in the development of innovative drugs or clinical therapies with definitive therapeutic effects for stroke (Lo & Ning, 2016).

Vascular embolism, or thrombosis, is a crucial pathological process in the development of stroke. The concept of “thrombolysis” was first introduced in 1933 by Tillett and Garner, who discovered that hemolytic streptococci in plasma could break down fibrin in blood samples from febrile patients (Tillett & Garner, 1933). Thrombolytic therapy is one of the most effective treatments for acute ischemic stroke. Based on research, thrombolytic drugs have been divided into three generations. Among them, recombinant tissue plasminogen activator(rt-PA) has been approved by the U.S. Food and Drug Administration (FDA), becoming the first and only thrombolytic drug approved for treating ischemic stroke (Noorian, Gupta, & Nogueira, 2012). However, there are still many limitations and challenges to be solved in clinical applications. First, the therapeutic window is narrow, requiring administration within 4.5 to 6 hours of the onset of stroke (Wang et al., 2015). Second, its half-life is only 5 minutes because its activity is quickly inhibited by its endogenous inhibitor, plasminogen activator inhibitor-1 (Schoenhard et al., 2008). To improve the efficiency of thrombolysis and reduce the dosage of thrombolytic drugs, researchers need to continuously develop new strategies. Many studies have focused on combining low molecular weight heparin with antiplatelet or defibrillation drugs for the treatment of transient cerebral ischemia (Albers, Amarenco, Easton, Sacco, & Teal, 2008; Navi et al., 2018).

Despite the progress made in strategies for thrombolysis, its limitations have led researchers to explore alternative options for treating ischemic stroke. Neuroprotective drugs have been the focus of research for the past 40 years (Chamorro, Lo, Renu, van Leyen, & Lyden, 2021; Cheng, Al-Khoury, & Zivin, 2004), as they offer protective effects by blocking and controlling various stages of neuronal injury or promoting neuronal repair. However, only a few of the 114 clinical trials worldwide have confirmed the efficacy of these drugs, involving up to 49 neuroprotective agents (Lu & Han, 2019). This has prompted intense discussions and doubts regarding the concept of neuroprotection. As a result, many neuroscientists have shifted their focus toward the concept of “brain protection” (Hassan & Rohatgi, 2009), with a more comprehensive understanding of stroke mechanisms.

In 2001, the National Institute of Neurological Diseases and Stroke introduced the concept of the neurovascular unit (NVU), which offers a new perspective and direction for neuroprotective targets (Iadecola, 2017). The NVU model simulates the complex cellular communication and interactions involved in clinical pathological processes, rather than focusing solely on the mechanisms of neuronal protection. By broadening the goal of neuroprotection to encompass comprehensive protection of the various components of the NVU after cerebral infarction, researchers may achieve greater success in treating ischemic brain injury (Chamorro et al., 2021). Although numerous studies have focused on the NVU, challenges still persist due to the complexity of the research system, difficulties in developing research methods, limitations in applying new technologies, or the need to validate this approach by evaluating drug candidates. Therefore, much work remains to be done to study the treatment of stroke through the NVU system.

Although several treatment options are available for stroke, their efficacy and safety require further consideration. In addition, the development of new drugs for stroke treatment faces obstacles and difficulties, including the following four major issues: (1)the time window for thrombolytic therapy is narrow, with only a tiny proportion of patients able to receive this treatment (Schellinger & Kohrmann, 2014); (2)there is a lack of effective therapeutic drugs for protecting the NVU in clinical practice; (3)achieving effective therapeutic drug concentrations at the ischemic site is difficult due to the blood–brain barrier (BBB) and limitations of drug half-life; and (4)precise administration of drugs to focal ischemic brain regions is currently challenging. Clinically, drug therapy for ischemic stroke remains a difficult area in cerebrovascular disease research, and further in-depth research is needed. The pathological mechanism of stroke is complex and had yet to be fully elucidated. Emerging research indicates that the signaling pathways associated with disruptions in energy metabolism, brain inflammation, oxidative/nitrosative stress, and neurovascular remodeling are potentially linked to the pathological mechanisms underlying ischemic stroke. These findings hold promise in offering novel approaches for diagnosing and treating this condition.

Based on our current understanding of stroke pathology, we propose two signaling intervention strategies: one is to inhibit the molecular events that lead to damage, such as energy metabolism disorders, brain inflammation, and oxidative/nitrosative stress; the other is to enhance endogenous protective factors and promote functional repair of the NVU. In this review, we highlight three shifts in our comprehension of stroke mechanisms and treatment: from a unidimensional process to a multidimensional process involving mediators from various cells that engage signaling pathways and effector systems throughout the cerebrovascular network; from the view of neuron targeting to NVU targeting; and from drug therapy targeting a single molecule or mechanism to drug therapy that integrates multiple cellular components. By focusing on integrity, multicellularity, and systematization, we summarize the complex mechanisms of stroke occurrence, intervention methods, and recent research progress.