Hindawi Oxidative Medicine and Cellular Longevity Volume 2021, Article ID 6687386, 45 pages https://doi.org/10.1155/2021/6687386 Review Article Neuroprotective Phytochemicals in Experimental Ischemic Stroke: Mechanisms and Potential Clinical Applications Hui Xu ,1,2 Emily Wang,3 Feng Chen,1 Jianbo Xiao ,4 and Mingfu Wang 1,2 1Institute for Advanced Study, Shenzhen University, Shenzhen 508060, China 2School of Biological Sciences, The University of Hong Kong, Pokfulam Road, Hong Kong, China 3Rice University, Houston, Texas, USA 4International Research Center for Food Nutrition and Safety, Jiangsu University, Zhenjiang 212013, China Correspondence should be addressed to Jianbo Xiao; [email protected] and Mingfu Wang; [email protected] Received 22 December 2020; Revised 10 March 2021; Accepted 29 March 2021; Published 29 April 2021 Academic Editor: Daniele Vergara Copyright © 2021 Hui Xu et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Ischemic stroke is a challenging disease with high mortality and disability rates, causing a great economic and social burden worldwide. During ischemic stroke, ionic imbalance and excitotoxicity, oxidative stress, and inflammation are developed in a relatively certain order, which then activate the cell death pathways directly or indirectly via the promotion of organelle dysfunction. Neuroprotection, a therapy that is aimed at inhibiting this damaging cascade, is therefore an important therapeutic strategy for ischemic stroke. Notably, phytochemicals showed great neuroprotective potential in preclinical research via various strategies including modulation of calcium levels and antiexcitotoxicity, antioxidation, anti-inflammation and BBB protection, mitochondrial protection and antiapoptosis, autophagy/mitophagy regulation, and regulation of neurotrophin release. In this review, we summarize the research works that report the neuroprotective activity of phytochemicals in the past 10 years and discuss the neuroprotective mechanisms and potential clinical applications of 148 phytochemicals that belong to the categories of flavonoids, stilbenoids, other phenols, terpenoids, and alkaloids. Among them, scutellarin, pinocembrin, puerarin, hydroxysafflor yellow A, salvianolic acids, rosmarinic acid, borneol, bilobalide, ginkgolides, ginsenoside Rd, and vinpocetine show great potential in clinical ischemic stroke treatment. This review will serve as a powerful reference for the screening of phytochemicals with potential clinical applications in ischemic stroke or the synthesis of new neuroprotective agents that take phytochemicals as leading compounds. 1. Introduction: Ischemic Stroke each year (WHO health statistics). Besides, stroke has a high disability rate, resulting in permanent disability for Stroke occurs when the blood supply to the brain tissue is around 50% of its survivors [3]. Many risk factors are asso- interrupted or reduced. Generally, stroke can be divided ciated with stroke, such as age, hypertension, obesity, into two major categories: ischemic stroke and hemorrhagic hyperlipidemia, diabetes, smoking, and alcohol consump- stroke, according to how the blood flow is disrupted. Ische- tion. With the great increase in the aging population, the mic stroke is caused by the occlusion of cerebral arteries by occurrence of stroke is predicted to continue rising, and thrombi or embolisms, blocking the blood flow to one part the mortality of stroke may exceed 12% by 2030 [4]. Hence, of the brain. Hemorrhagic stroke results from the ruptures stroke is a challenging disease that greatly increases the of a weakened blood vessel, leading to the accumulation of worldwide economic and social burden. blood in the surrounding brain tissue [1]. Of the two, ische- mic stroke is the primary type, accounting for about 80% of 1.1. Pathophysiology of Ischemic Stroke. When ischemic all strokes [2]. Stroke ranks second in the cause of death stroke occurs, blood flow to the specific territory of the brain worldwide, and about 5.5 million people die from stroke that is supplied by the occluded artery is reduced. Generally, 2 Oxidative Medicine and Cellular Longevity the ischemic area of the brain can be divided into the infarct 1.2.1. Thrombolysis. Intravenous (IV) thrombolysis with core and the ischemic penumbra according to the severity of recombination tissue plasminogen activator (r-tPA, alte- the blood flow reduction. The infarct core is characterized by plase) is the only US Food and Drug Administration- a rapid decrease in ATP levels and energy stores and severe (FDA-) approved pharmacological treatment for acute ionic disruption, which result in cell death within a few ischemic stroke [12]. tPA promotes the conversion of plas- minutes. Surrounding the core area is the ischemic penum- minogen to plasmin, an active proteolytic enzyme that bra. In this area, blood flow reduction is less severe due to cleaves the cross-linkages between fibrin molecules of clots perfusion from collateral blood vessels. Hence, the insult to [13]. Notably, r-tPA has a very short therapeutic window the ischemic penumbra is much milder than that to the and is best when administrated within 3 h after symptom infarct core. As a result, multiple milder cell death mecha- onset. Patients can still benefit from r-tPA when it is admin- nisms occur in this area such as inflammation and apoptosis, istrated between 3 and 4.5 h after cerebral ischemia. How- providing promising therapeutic targets for ischemic stroke ever, r-tPA is not recommended for patients whose [5]. Notably, the ischemic penumbra is dynamic, in which treatment cannot be initiated within 4.5 h because it will the infarct core expands at the cost of the penumbra during greatly increase the rate of intracranial hemorrhage and neu- cerebral ischemia. Hereby, early reperfusion is the most effec- ronal excitotoxicity [14]. Clinically, the short therapeutic tive manner to reduce the cerebral infarction of ischemic window drastically limits the eligible patients and only about stroke patients [6]. 15% of the hospitalized patients are treated with r-tPA [14]. Ischemic stroke injuries include two parts: ischemic injury and reperfusion injury. The cell death mechanisms 1.2.2. Antiplatelets and Anticoagulants. Antiplatelet and anti- of the ischemic brain are redundant, and at least three coagulant therapies are aimed at preventing the reoccurrence dominant mechanisms are involved: ionic imbalance and of stroke via the prevention of clot formation. Antiplatelets excitotoxicity, oxidative/nitrosative stress, and inflamma- inhibit platelet activation or aggregation, while anticoagu- tion. Notably, those mechanisms are developed in a rela- lants suppress the functions of clot-forming factors such as tively certain order and become the dominant events at factors II, VII, and X. The common antiplatelet agents different stages of ischemic stroke. Generally, ionic imbal- include aspirin, clopidogrel, dipyridamole, tirofiban, and ance and excitotoxicity play a critical role in the ischemic eptifibatide. Clinical studies show that the risk of early recur- phase, and oxidative/nitrosative stress peaks at the begin- rent stroke is decreased by aspirin administration within 48 h ning phase of reperfusion, while inflammation lasts for of ischemic stroke onset [15]. As for anticoagulants such as several days or weeks after reperfusion. After activation, heparin, warfarin, dabigatran, rivaroxaban, and apixaban, it those mechanisms affect the function of cell membranes is found that urgent therapeutic anticoagulation benefits and organelles such as the mitochondria, endoplasmic retic- high-risk cardioembolic stroke patients. Yet, the use of anti- ulum (ER), lysosomes, and nuclei. Consequently, different coagulants may lead to symptomatic intracranial hemor- cell death pathways are activated, including apoptosis and rhage in unselected ischemic stroke patients [13]. necrosis [5]. Autophagy/mitophagy is also activated in ische- mic stroke, but whether it promotes or decreases the cerebral ischemia-reperfusion (I/R) injuries has not been agreed upon 1.2.3. Neuroprotection. Neuroprotective agents could reduce at present. Studies suggested that apoptosis and cytoprotec- ischemic brain injuries via the promotion of neuronal tive autophagy/mitophagy tended to be induced by moderate survival, neuroplasticity, synaptogenesis, and neurogenesis. cerebral I/R injuries, while necrosis or destructive autopha- Hence, neuroprotection therapy could be combined with gy/mitophagy was activated during severe I/R damage [7]. thrombolytic agents to reduce the second injuries of reperfu- The major mechanisms of cell death in ischemic stroke are sion [16]. Over the past two decades, over 1000 potential illustrated in Figure 1. neuroprotective agents were found in experimental ischemic stroke, with nearly 200 agents having undergone clinical 1.2. Major Pharmacological Therapies for Ischemic Stroke. trials [17]. Particularly, edaravone and Dl-3-n-butylphtha- Major approaches to treat ischemic stroke can be divided into lide show great efficacy in clinical treatment and have been two types: recanalization and neuroprotection. Recanaliza- approved for ischemic stroke treatment in Japan and China, tion is aimed at restoring the blood flow with thrombolytic respectively. agents or accessory devices in the acute phase of ischemic Edaravone, with the trade name Radicut/Radicava, is