A Review of Post-Stroke Cognitive Impairment and the Potential Benefits of Stingless Bee Honey Supplementation.

Post-stroke cognitive impairment (PSCI) is a common decline in cognitive abilities that occurs within 3 months after a stroke. During recovery, stroke survivors often experience varying degrees of cognitive decline, with some patients experiencing permanent cognitive deficits. Thus, it is crucial to prioritise recovery and rehabilitation after a stroke to promote optimal protection of and improvement in cognitive function. Honey derived from stingless bees has been linked to various therapeutic properties, including neuroprotective effects. However, scientific evidence for the mechanisms through which these honey supplements enhance cognitive function remains limited. This narrative review aims to provide an overview of the causes of PSCI, current treatments, the biomarkers influencing cognition in post-stroke patients and the potential of stingless bee honey (SBH) as a neuroprotective agent against the progression of PSCI.

Melatonin: a promising neuroprotective agent for cerebral ischemia-reperfusion injury.

Cerebral ischemia-reperfusion (CIR) injury is initiated by the generation of reactive oxygen species (ROS), which leads to the oxidation of cellular proteins, DNA, and lipids as an initial event. The reperfusion process impairs critical cascades that support cell survival, including mitochondrial biogenesis and antioxidant enzyme activity. Failure to activate prosurvival signals may result in increased neuronal cell death and exacerbation of CIR damage. Melatonin, a hormone produced naturally in the body, has high concentrations in both the cerebrospinal fluid and the brain. However, melatonin production declines significantly with age, which may contribute to the development of age-related neurological disorders due to reduced levels. By activating various signaling pathways, melatonin can affect multiple aspects of human health due to its diverse range of activities. Therefore, understanding the underlying intracellular and molecular mechanisms is crucial before investigating the neuroprotective effects of melatonin in cerebral ischemia-reperfusion injury.

Investigation of Cognitive Impairment in the Course of Post-COVID Syndrome.

(1) Background: The study presents results from an investigation of cognitive impairment in patients hospitalized in the first psychiatric clinic in Bulgaria to treat patients with COVID-19 during the pandemic period between 2020 and 2022. One hundred and twenty patients who had recovered from acute COVID-19 infection (up to 12 weeks ago) and had no previous history of cognitive impairment participated in the study. In 23 of them (19.17%), disturbance of cognitive functioning was observed. (2) Methods: All 23 patients underwent neuropsychological (Luria's test, Platonov's Maze test, MMSE, Boston Naming test) and neuroimaging examinations. Only seven of them had evidence of cortical atrophy on CT/MRI images. The most significantly demonstrative image of one of those patients is presented. (3) Results: The neuropsychological testing results of both groups show a certain decrease in fixation and memory retention as well as in the range, concentration, distribution and switching of attention. Deviations from the norm on the MMSE, as well as on the Boston Naming Test, were found in the group of patients with cortical atrophy (mild to moderate aphasia). Neuroprotective agents such as Citicoline, Piracetam and Memantine were prescribed to the patients with evident cortical atrophy. After 3 months, positive results of the neuropsychological examination were reported in both groups. (4) Conclusions: Although there are limited data on the benefit of prescribing pro-cognitive agents in the post-COVID period, our clinical experience suggests that it might be useful in the recovery process from the infection's consequences on cognition for patients with brain pathology.

Alpha-pinene moderates memory impairment induced by kainic acid via improving the BDNF/TrkB/CREB signaling pathway in rat hippocampus.

Introduction: The potential benefits of natural ingredients in the alleviation of neurodegenerative disorders are of great interest. Alpha-pinene (APN) is an essential oil belonging to monoterpenes with multiple beneficial effects. In this study, the possible improving effects of alpha-pinene on memory impairment induced by kainic acid and the underlying molecular mechanisms were examined. Methods: Memory impairment was induced by i.c.v. injection of kainic acid (KA) in male Wistar rats. Alpha-pinene (50 mg/kg/day, i.p.) was injected for 21 days, including 14 days before the KA injection and seven days afterward. Spatial working memory and inhibitory avoidance (IA) memory performance were assessed five and even days following KA injection, respectively. The hippocampal protein levels of brain-derived neurotrophic factor (BDNF), tropomyosin-like receptor kinase B (TrkB), cAMP response element binding protein (CREB), and neuronal loss in the CA1 region were also examined. Results: Results revealed that the i.c.v. injection of KA triggered memory impairment, which was notably diminished by alpha-pinene pre-and post-treatment. Histopathological evaluation revealed that alpha-pinene significantly moderated the attenuation in CA1 alive neurons induced by KA injection. Western blotting analysis confirmed that alpha-pinene pre-and post-treatment significantly reversed the KA-induced decreases in the hippocampal levels of BDNF, TrkB, phosphorylated TrkB, CREB, and phosphorylated CREB. Discussion: These findings suggest that alpha-pinene pre-and post-treatment moderate memory impairment induced by KA by restoring the BDNF/TrkB/CREB signaling pathway in the rat hippocampus.

Structural diversification of bioactive bibenzyls through modular co-culture leading to the discovery of a novel neuroprotective agent.

Bibenzyls, a kind of important plant polyphenols, have attracted growing attention for their broad and remarkable pharmacological activities. However, due to the low abundance in nature, uncontrollable and environmentally unfriendly chemical synthesis processes, these compounds are not readily accessible. Herein, one high-yield bibenzyl backbone-producing Escherichia coli strain was constructed by using a highly active and substrate-promiscuous bibenzyl synthase identified from Dendrobium officinale in combination with starter and extender biosynthetic enzymes. Three types of efficiently post-modifying modular strains were engineered by employing methyltransferases, prenyltransferase, and glycosyltransferase with high activity and substrate tolerance together with their corresponding donor biosynthetic modules. Structurally different bibenzyl derivatives were tandemly and/or divergently synthesized by co-culture engineering in various combination modes. Especially, a prenylated bibenzyl derivative (12) was found to be an antioxidant that exhibited potent neuroprotective activity in the cellular and rat models of ischemia stroke. RNA-seq, quantitative RT-PCR, and Western-blot analysis demonstrated that 12 could up-regulate the expression level of an apoptosis-inducing factor, mitochondria associated 3 (Aifm3), suggesting that Aifm3 might be a new target in ischemic stroke therapy. This study provides a flexible plug-and-play strategy for the easy-to-implement synthesis of structurally diverse bibenzyls through a modular co-culture engineering pipeline for drug discovery.

A novel promising neuroprotective agent: Ganoderma lucidum polysaccharide.

Nervous system diseases (NSDs) are characterized by a wide range of symptoms, a complex pathophysiology, an unclear etiology, a great deal of variation in treatment response, and lengthy therapy cycles, all of which pose considerable hurdles to clinical treatment. A traditional valuable medicine known as Ganoderma lucidum (GL) has a significant role to play in preserving health and treating diseases. Ganoderma lucidum polysaccharides (GLP) is one of the cardinal effective active ingredients of GL, which has a number of pharmacological actions, including liver protection, immune regulation, antioxidant activity, anticancer activity, antibacterial activity, and antiviral activity. Recently, studies on the structural characterization and biological functions of GLP were presented in this article to review the progress of researches about GLP on NSDs and summarize the potential mechanisms of action. These studies were anticipated to provide new research ideas for GLP as a novel promising neuroprotective agent and provide a reference for better development and utilization of GLP.

Hybridization of amantadine with gardenamide A enhances NMDA antagonism and in vivo anti-PD effects.

Eight hybrids of amantadine (ATD) with a natural modulator gardenamide A (GA) via an alkylene carbonyl bridge or alkylene bridge have been designed and synthesized. Evaluated by electrophysiological assay, compound 5b was confirmed an enhanced NMDAR antagonist compared to ATD with IC50 value of 10.2 ± 1.2 µM. 5b has been demonstrated to reverse the damages of behavioral performance, the loss of dopaminergic neurons, the reduction of TH positive, and the increase of α-synuclein in both MPTP-treated mice and zebrafish models. In both ethological and ecological experiments, the activity of 5b was confirmed better than ATD or ATD/GA combination, and was almost equal to the positive selegiline. In vivo and in vitro, 5b is shown to reverse the ascend of NR1 and i-NOS levels. This candidate was also demonstrated the activity to down-regulated MPTP-increased Ca2+ influx in SH-SY5Y cells in a steep and sharp mode. It is displayed that 5b exerts neuroprotective effect partly by activating the PI3K/Akt signaling pathway. Taken all together, our data support that 5b is a more promising agent against PD than ATD.

Efficacy，safety and cost-effectiveness of edaravone dexborneol and compound porcine cerebroside ganglioside in the treatment of acute ischemic stroke / 中国药房

OBJECTIVE To evaluate efficacy， safety and cost-effectiveness of edaravone dexborneol and compound porcine cerebroside ganglioside in the treatment of acute ischemic stroke， and to provide decision-making reference for clinical treatment selection. METHODS The medical records of 488 patients with acute ischemic stroke hospitalized from Jan. 2021 to Dec. 2021 were collected and divided into two groups according to the treatment plan， i.e. 268 patients in edaravone dexborneol group， and 220 patients in compound porcine cerebroside ganglioside group. After baseline levels of the two groups were balanced using propensity score matching method， curative effect was evaluated according to the changes of NIHSS scores before and after treatment； the occurrence of adverse drug reactions in patients were collected from the hospital adverse reaction reporting system； from the perspective of China’s health system， the cost-effectiveness of the two options were analyzed， and one-way sensitivity analysis was conducted. RESULTS After the propensity score matching， 125 patients were included in the edaravone dexborneol group and compound porcine cerebroside ganglioside group， respectively. The response rates were 81.6% and 74.4%， respectively， with no significant difference. The average costs were 13 560.30 yuan and 14 958.68 yuan， respectively； the cost of edaravone dexborneol group was lower than that of compound porcine cerebroside ganglioside group. No adverse reaction reporting information was retrieved in both groups. Results of one-way sensitivity analysis showed that other drug costs in compound porcine cerebroside ganglioside group was relatively sensitive parameters. CONCLUSIONS Short-term efficacy and safety of edaravone dexborneol are equivalent to those of compound porcine cerebroside ganglioside in treating acute ischemic stroke. But edaravone dexborneol regimen had lower cost and is a more economical scheme.

Structural diversification of bioactive bibenzyls through modular co-culture leading to the discovery of a novel neuroprotective agent

Bibenzyls, a kind of important plant polyphenols, have attracted growing attention for their broad and remarkable pharmacological activities. However, due to the low abundance in nature, uncontrollable and environmentally unfriendly chemical synthesis processes, these compounds are not readily accessible. Herein, one high-yield bibenzyl backbone-producing Escherichia coli strain was constructed by using a highly active and substrate-promiscuous bibenzyl synthase identified from Dendrobium officinale in combination with starter and extender biosynthetic enzymes. Three types of efficiently post-modifying modular strains were engineered by employing methyltransferases, prenyltransferase, and glycosyltransferase with high activity and substrate tolerance together with their corresponding donor biosynthetic modules. Structurally different bibenzyl derivatives were tandemly and/or divergently synthesized by co-culture engineering in various combination modes. Especially, a prenylated bibenzyl derivative ( 12) was found to be an antioxidant that exhibited potent neuroprotective activity in the cellular and rat models of ischemia stroke. RNA-seq, quantitative RT-PCR, and Western-blot analysis demonstrated that 12 could up-regulate the expression level of an apoptosis-inducing factor, mitochondria associated 3 (Aifm3), suggesting that Aifm3 might be a new target in ischemic stroke therapy. This study provides a flexible plug-and-play strategy for the easy-to-implement synthesis of structurally diverse bibenzyls through a modular co-culture engineering pipeline for drug discovery.

Edaravone for Acute Ischemic Stroke: A Systematic Review and Meta-analysis.

PURPOSE: The management of acute stroke is challenging. The aim of this meta-analysis was to determine the efficacy and tolerability of edaravone, with or without thrombolytic therapy, in the treatment of patients with acute ischemic stroke. METHODS: The PubMed, EMBASE, and Cochrane databases were searched for randomized controlled trials (RCTs) and cohort studies. Mean differences (MD), risk ratios (RR), 95% confidence interval (CI), and heterogeneity were calculated. FINDINGS: Totals of nine RCTs and four cohort studies were included, for a total of 2102 patients. In patients with acute ischemic stroke, edaravone monotherapy was associated with significantly improved Barthel Index of functioning in activities for daily living (MD, 23.95; 95% CI, 18.48 to 29.41; P < 0.001) and neurologic deficit, (as measured using the National Institutes of Health Stroke Scale score) (MD = -3.49; 95% CI, -5.76 to 1.22; P = 0.003), on short-term follow-up. However, edaravone was not associated with an improved rate of death or disability (RR = 0.75; 95% CI, 0.45 to 1.23; P = 0.25) on long-term follow-up.When plus to thrombolytic therapy, edaravone was associated with significant improvements in recanalization rate (RR = 1.71; 95% CI, 1.05 to 2.77; P = 0.03) and neurologic deficit (MD = 3.97; 95% CI, 5.14 to 2.79; P < 0.001), without an increase in the prevalence of bleeding events (RR = 1.11; 95% CI, 0.76 to 1.62; P = 0.59). However, edaravone did not have a significant effect on death or disability (RR = 0.85; 95% CI, 0.69 to 1.04; P = 0.12). IMPLICATIONS: Based on the findings from the present meta-analysis, edaravone was an effective and well-tolerated neuroprotective agent in these patients with ischemic stroke. With the use of edaravone, activities of daily living and neurologic deficits, along with recanalization rates, were improved on short-term follow-up, but the long-term effects still need confirmation in larger-scale clinical trials.

Nelonemdaz for Patients With Acute Ischemic Stroke Undergoing Endovascular Reperfusion Therapy: A Randomized Phase II Trial.

BACKGROUND: Nelonemdaz is a multitarget neuroprotectant that selectively blocks N-methyl-D-aspartate receptors and scavenges free radicals, as proven in preclinical ischemia-reperfusion studies. We aimed to evaluate the safety and efficacy of nelonemdaz in patients with acute ischemic stroke receiving endovascular reperfusion therapy. METHODS: This phase II randomized trial involved participants with large-artery occlusion in the anterior circulation at baseline who received endovascular reperfusion therapy <8 hours from symptom onset at 7 referral stroke centers in South Korea between October 29, 2016, and June 1, 2020. Two hundred thirteen patients were screened and 209 patients were randomly assigned at a 1:1:1 ratio using a computer-generated randomization system. Patients were divided into 3 groups based on the medication received-placebo, low-dose (2750 mg) nelonemdaz, and high-dose (5250 mg) nelonemdaz. The primary outcome was the proportion of patients with modified Rankin Scale scores of 0-2 at 12 weeks. RESULTS: Two hundred eight patients were assigned to the placebo (n=70), low-dose (n=71), and high-dose (n=67) groups. The groups had similar baseline characteristics. The primary outcome was achieved in 183 patients, and it did not differ among the groups (33/61 [54.1%], 40/65 [61.5%], and 36/57 [63.2%] patients; P=0.5578). The common odds ratio (90% CI) indicating a favorable shift in the modified Rankin Scale scores at 12 weeks was 1.55 (0.92-2.60) between the placebo and low-dose groups and 1.61 (0.94-2.76) between the placebo and high-dose groups. No serious adverse events were reported. CONCLUSIONS: The study arms showed no significant difference in the proportion of patients achieving modified Rankin Scale scores of 0-2 at 12 weeks. Nevertheless, nelonemdaz-treated patients showed a favorable tendency toward achieving these scores at 12 weeks, without serious adverse effects. Thus, a large-scale phase III trial is warranted. REGISTRATION: URL: https://clinicaltrials.gov; Unique identifier: NCT02831088.

Curcumin as a Promising Neuroprotective Agent for the Treatment of Spinal Cord Injury: A Review of the Literature.

Curcumin is a polyphenolic chemical derived from the rhizomes of Curcuma longa. It has been used throughout the Indian subcontinent for medicinal purposes, religious events, and regional cuisine. It has various pharmacological benefits owing to its anti-inflammatory and antioxidant properties. Its neuroprotective effects on the brain and peripheral nerves have been demonstrated in several in vivo neuronal tissue studies. Because of these functional properties of curcumin, it is considered to have great potential for use in the treatment of spinal cord injuries (SCIs). Numerous immunopathological and biochemical studies have reported that curcumin can help prevent and alleviate subsequent secondary injuries, such as inflammation, edema, free radical damage, fibrosis, and glial scarring, after a primary SCI. Furthermore, following SCI, curcumin administration resulted in better outcomes of neurological function recovery as per the Basso, Beattie, and Bresnahan locomotor rating scale. However, to date, its utility in treating SCIs has only been reported in laboratories. More studies on its clinical applications are needed in the future for ensuring its bioavailability across the blood-brain barrier and for verifying the safe dose for treating SCIs in humans.

The Role of Microbiome in Brain Development and Neurodegenerative Diseases.

Hundreds of billions of commensal microorganisms live in and on our bodies, most of which colonize the gut shortly after birth and stay there for the rest of our lives. In animal models, bidirectional communications between the central nervous system and gut microbiota (Gut-Brain Axis) have been extensively studied, and it is clear that changes in microbiota composition play a vital role in the pathogenesis of various neurodevelopmental and neurodegenerative disorders, such as Autism Spectrum Disorder, Alzheimer's disease, Parkinson's disease, Multiple Sclerosis, Amyotrophic Lateral Sclerosis, anxiety, stress, and so on. The makeup of the microbiome is impacted by a variety of factors, such as genetics, health status, method of delivery, environment, nutrition, and exercise, and the present understanding of the role of gut microbiota and its metabolites in the preservation of brain functioning and the development of the aforementioned neurological illnesses is summarized in this review article. Furthermore, we discuss current breakthroughs in the use of probiotics, prebiotics, and synbiotics to address neurological illnesses. Moreover, we also discussed the role of boron-based diet in memory, boron and microbiome relation, boron as anti-inflammatory agents, and boron in neurodegenerative diseases. In addition, in the coming years, boron reagents will play a significant role to improve dysbiosis and will open new areas for researchers.

Optimization of NAMPT activators to achieve in vivo neuroprotective efficacy.

NAMPT is the rate-limiting enzyme in the NAD salvage pathway, which makes it an attractive target for the treatment of many diseases associated with NAD exhaustion such as neurodegenerative diseases. Herein, we present the systematic optimization of NAT, an initial hit of NAMPT activator discovered by us through high-throughput screening, based on the co-crystal structure of the NAMPT-NAT complex. Over 80 NAT derivatives have been designed and synthesized, among which compound 72 showed notably improved potency as NAMPT activator and effectively protected cultured cells from FK866-mediated toxicity. Moreover, compound 72 exhibited strong neuroprotective efficacy in a mouse model of chemotherapy-induced peripheral neuropathy (CIPN) without any overt toxicity, which renders it a promising candidate for the development of novel neuroprotective agents.

Exploring the journey of emodin as a potential neuroprotective agent: Novel therapeutic insights with molecular mechanism of action.

Emodin is an anthraquinone derivative found in the roots and bark of a variety of plants, molds, and lichens. Emodin has been used as a traditional medication for more than 2000 years and is still common in numerous herbal drugs. Emodin is plentiful in the three plant families, including Polygonaceae (Rheum, Rumex, and Polygonum spp.), Fabaceae (Cassia spp.), and Rhamnaceae (Rhamnus, Frangula, and Ventilago spp.). Emerging experimental evidences indicate that emodin confers a wide range of pharmacological activities; special focus was implemented toward neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, cerebral ischemia, anxiety and depression, schizophrenia, chronic hyperglycemic peripheral neuropathy, etc. Numerous preclinical evidences were established in support of the neuroprotection of emodin. However, this review highlighted the role of emodin as a potent neurotherapeutic agent; therefore, its evidence-based functionality on neurological disorders (NDs).

Whether Erythropoietin can be a Neuroprotective Agent against Premature Brain Injury: Cellular Mechanisms and Clinical Efficacy.

Preterm infants are at high risk of brain injury. With more understanding of the preterm brain injury's pathogenesis, neuroscientists are looking for more effective methods to prevent and treat it, among which erythropoietin (Epo) is considered as a prime candidate. This review tries to clarify the possible mechanisms of Epo in preterm neuroprotection and summarize updated evidence considering Epo as a pharmacological neuroprotective strategy in animal models and clinical trials. To date, various animal models have validated that Epo is an anti-apoptotic, antiinflammatory, anti-oxidant, anti-excitotoxic, neurogenetic, erythropoietic, angiogenetic, and neurotrophic agent, thus preventing preterm brain injury. However, although the scientific rationale and preclinical data for Epo's neuroprotective effect are promising, when translated to bedside, the results vary in different studies, especially in its long-term efficacy. Based on existing evidence, it is still too early to recommend Epo as the standard treatment for preterm brain injury.

Research advances on how metformin improves memory impairment in "chemobrain".

Cognitive impairment caused by chemotherapy, referred to as "chemobrain," is observed in approximately 70% of cancer survivors. However, it is not completely understood how chemotherapy induces cognitive dysfunction, and clinical treatment strategies for this problem are lacking. Metformin, used as a first-line treatment for type 2 diabetes mellitus, is reported to reduce the effects of chemobrain. Recently, several studies have examined the effect of metformin in rescuing chemobrain. This review discusses recent clinical/preclinical studies that addressed some mechanisms of chemobrain and evaluates the effect of metformin in rescuing chemobrain and its potential mechanisms of action.

Metabolic characterization of a potent natural neuroprotective agent dendrobine in vitro and in rats.

Dendrobine is the main sesquiterpene alkaloid of Dendrobium nobile Lindl, which exhibits potent neuroprotective activity. However, its metabolism and disposition are little known. In this study, we investigated the metabolic characteristics of dendrobine in vitro and in rats. The metabolic stability and temporal profile of metabolites formation of dendrobine were assayed in human/rat liver microsomal and S9 fractions. Dendrobine metabolites were separated and identified mainly by UPLC-Q/Orbitrap MS. After oral administration of dendrobine (50 mg/kg) to rats, the accumulative excretion rate of dendrobine in feces, urine, and bile was 0.27%, 0.52%, and 0.031%, respectively, and low systematic exposure of dendrobine (AUC0-∞ = 629.2 ± 56.4 ng·h/mL) was observed. We demonstrated that the elimination of dendrobine was very rapid in liver microsomal incubation (the in vitro elimination t1/2 in rat and human liver microsomes was 1.35 and 5.61 min, respectively). Dendrobine underwent rapid and extensive metabolism; cytochrome P450, especially CYP3A4, CYP2B6, and CYP2C19, were mainly responsible for its metabolism. Aldehyde dehydrogenase, alcohol dehydrogenase and aldehyde oxidase were involved in the formation of carboxylic acid metabolites. By the aid of in-source fragmentation screening, hydrogen/deuterium exchange experiment, post-acquisition processing software, and available reference standards, 50 metabolites were identified and characterized in liver microsomal incubation and in rats. The major metabolic pathways of dendrobine were N-demethylation, N-oxidation, and dehydrogenation, followed by hydroxylation and glucuronidation. Collectively, the metabolic fate of dendrobine elucidated in this study not only yields benefits for its subsequent metabolism study but also facilitates to better understanding the mode of action of dendrobine and evaluating the pharmacologic efficiency of the high exposure metabolites.

Sphingosine-1-Phosphate Signaling in Ischemic Stroke: From Bench to Bedside and Beyond.

Sphingosine-1-phosphate (S1P) signaling is being increasingly recognized as a strong modulator of immune cell migration and endothelial function. Fingolimod and other S1P modulators in ischemic stroke treatment have shown promise in emerging experimental models and small-scale clinical trials. In this article, we will review the current knowledge of the role of S1P signaling in brain ischemia from the aspects of inflammation and immune interventions, sustaining endothelial functions, regulation of blood-brain barrier integrity, and functional recovery. We will then discuss the current and future therapeutic perspectives of targeting S1P for the treatment of ischemic stroke. Mechanism studies would help to bridge the gap between preclinical studies and clinical practice. Future success of bench-to-bedside translation shall be based on in depth understanding of S1P signaling during stroke and on the ability to have a fine temporal and spatial regulation of the signal pathway.

Challenges and Improvements of Novel Therapies for Ischemic Stroke.

Stroke is the third most common disease all over the world, which is regarded as a hotspot in medical research because of its high mortality and morbidity. Stroke, especially ischemic stroke, causes severe neural cell death, and no effective therapy is currently available for neuroregeneration after stroke. Although many therapies have been shown to be effective in preclinical studies of ischemic stroke, almost none of them passed clinical trials, and the reasons for most failures have not been well identified. In this review, we focus on several novel methods, such as traditional Chinese medicine, stem cell therapy, and exosomes that have not been used for ischemic stroke till recent decades. We summarize the proposed basic mechanisms underlying these therapies and related clinical results, discussing advantages and current limitations for each therapy emphatically. Based on the limitations such as side effects, narrow therapeutic window, and less accumulation at the injury region, structure transformation and drug combination are subsequently applied, providing a deep understanding to develop effective treatment strategies for ischemic stroke in the near future.