1. Introduction

IJFN

International Journal of Functional Nutrition

2632-2919 2632-2919

D.A. Spandidos

10.3892/ijfn.2020.5

IJFN-0-0-00005

Review

Experimental models and plant-based therapy for experimental cerebral ischemia (Review)

Ezzelarab

Nada M.

1 * Saleh

Naela

1 * Khalil

Eman A.

2 * Abdellatif

Ahmed

1 2

1Biotechnology Graduate Program, School of Sciences and Engineering, The American University in Cairo, Cairo 11835, Egypt 2Department of Biology, School of Sciences and Engineering, The American University in Cairo, Cairo 11835, Egypt

Correspondence to: Dr Ahmed Abdellatif, Department of Biology, School of Sciences and Engineering, The American University in Cairo, Cairo 11835, Egypt ahmed.abdellatif@aucegypt.edu

^*Contributed equally

Abbreviations: BBB, blood-brain barrier; BCCAO, bilateral common carotid artery occlusion; CCAs, common carotid arteries; MCA, middle cerebral artery; MCAO, middle cerebral artery occlusion; MRI, magnetic resonance imaging; SD, Sprague-Dawley; STAIR, Stroke Therapy Academic Industry Roundtable

09 2020

11 08 2020

1 1

13 05 2020 10 08 2020

2020

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Cerebral ischemia is a leading cause of mortality worldwide. Available treatments are mainly thrombolytic agents for restoring blood flow to the brain. However, this approach has a very narrow treatment window. Despite extensive research, there is still a need for further investigations to identify and develop novel treatment approaches. The present review aimed to summarize and discuss evidence from the literature regarding the best models with which to study cerebral ischemia and the available herbal sources that may provide potential treatment strategies for cerebral ischemia. The present review was based on research published between 1990 and 2020. Herbal remedies provide a promising research area that warrants further attention from researchers in the field. Different models have been used to investigate the pathophysiology of cerebral ischemia/reperfusion, and to examine various treatment approaches. The plant kingdom is rich in various phytochemicals with neuroprotective functions. From the literature search performed herein, it can be concluded that middle cerebral and bilateral common carotid artery occlusion models are the most convenient, cost-effective and easily reproducible models. A number of plants, particularly those from Southeast Asia, have used for cerebral ischemia research; however, many more need to be investigated, particularly plants from Africa.

cerebral ischemia animal models stroke herbal medicine cerebral ischemia/reperfusion

1. Introduction

Cerebral ischemia occurs when the blood flow to the brain is restricted, and it claims the lives of millions worldwide (1,2). In total, 16% of humans will have a stroke during their lifetime, with >15 million cases noted annually (1,3). Stroke is a complex disease with a narrow time window for therapeutic intervention to restore the blood supply and prevent permanent brain tissue damage (2). As a result, currently available strategies are considered inadequate (2). Therefore, there is a need for further research in order to understand the pathophysiology of the disease and to identify techniques that can reduce its severe complications (2).

Clinically relevant models are essential for cerebral ischemia research. These models should be clinically relevant and reproducible to aid in the understanding of the pathophysiology of ischemic stroke, as well as to function as a platform for the development of novel therapeutic approaches for stroke treatment.

For a number of years, plants and natural remedies have been the primary tool for folk medicine. Medicinal plants provide a cost-effective source of drugs with significant therapeutic benefits and few side-effects in comparison to commercial synthetic drugs. Herbal remedies may provide a source of novel compounds that may present novel therapeutic tools for cerebral ischemia and stroke. However, with the variants of models of cerebral ischemia, the literature lacks the link between the efficacy of the plant and the model used, which may represent a possible strategy with which to understand the mechanisms of these natural remedies.

The present review aimed to summarize and discuss the literature for data related to animal models utilized in the research of cerebral ischemia, along with the herbal-based treatment approaches used in cerebral ischemia, in order to draw a full picture of the model used for treatment. The present review also aimed to illustrate the possible association between the natural ingredient in question that proved effective and the models of cerebral ischemia.

2. Data collection methods <sec> <title>Search strategy

Following the guidelines of Preferred Reporting Items For Systematic Reviews And Meta-Analyses (PRISMA) (4), the present review was conducted. The present review aimed to illustrate the data from peer-reviewed original articles on cerebral ischemia phytotherapy or from studies using in vivo models of cerebral ischemia. A search was conducted to obtain targeted articles through PubMed (https://pubmed.ncbi.nlm.nih.gov/) using the following keywords: ‘Cerebral ischemia and herbal medicine’. The search span was between 1990 and 2020. In addition, the results were restricted to studies in the English language.

Selection criteria

The inclusion criteria were as follows: i) Only original studies between 1990 and 2020 were included in the present review; ii) any original article that assessed or used herbal extracts as a treatment approach for animal models of cerebral ischemia. On the other hand, the exclusion criteria were expanded to the following: i) Articles that reported the combination of plants as a formula/recipe; ii) research that was not published in the English language and were between 1990 and 2020; iii) case reports, review articles, or any secondary publications.

Data extraction

Search results were imported into Endnote X8 (Thompson Reuter) for the deletion of duplicates. The references were then screened by 3 reviewers, independently, using the eligibility criteria. The included articles were then reviewed, and data extraction was performed by 3 independent reviewers. Any disagreement in the extraction steps was raised to the supervisor to reach a consensus.

Risk of bias for individual studies

The included articles were investigated through the ‘The Cochrane Collaboration's tool for assessing the risk of bias’ (5). Any disagreements were discussed between authors to reach a consensus.

3. Search results <sec> <title>Search results and study characteristics

The search revealed 830 records; following title/abstract screening, 370 articles were selected. Following the screening of the full text of the articles, 52 studies were included in the present review.

Using the Cochrane risk of bias tool, we were uncertain of the bias regarding domains 4, 5 and 6(5). However, most of the included studies showed a low risk of bias in the other domains.

Pathophysiology of cerebral ischemia

Ischemic stroke accounts for approximately 90% of all stroke cases in humans, followed by intracerebral hemorrhage (9%) and subarachnoid hemorrhage (3%). Ischemic stroke occurs due to the blockage of the middle cerebral artery (MCA). Cerebral tissue hypoxia and ischemia follow within minutes, leading to neuronal cell death and permanent damage to the brain (6). Thrombolytics and the rapid restoration of the blood supply remain the only treatment options with which to prevent further neuronal damage and decrease disability (6).

Ischemic damage to both white and grey matter causes permanent damage to brain tissue (7-9). Chronic cerebral hypoperfusion causes microglia/astrocyte activation, matrix metalloproteinase stimulation, blood-brain barrier disruption and endothelial abnormalities (10-12). Chronic cerebral hypoperfusion generates neuroinflammation, oxidative stress and apoptosis of the oligodendroglia (10-12). Aging, diabetes, atherosclerosis and hypertension are the most common risk factors that lead to chronic cerebral hypoperfusion (10-12).

In vitro models of cerebral ischemia

Testing different treatment approaches on human cells in vitro provides highly valuable, cost-effective and high-throughput systems for studies on stroke (13,14). Although in vivo models are preferred in cerebral ischemia, genetic differences and structural variations, as well as molecular differences exist, which renders clinical translation problematic (13); therefore in vitro models are still critical for the understanding of the molecular mechanisms of the disease. With the introduction of new technologies, there is an excellent opportunity for the development of in vitro systems to model stroke and improve drug discovery (15). For a full review of the in vitro models of cerebral ischemia, please see the study by Holloway and Gavins, 2016(15).

Animal models in cerebral ischemia Brain structure and function: Humans vs. animals

Although there are apparent differences between the human brain and the brains of other species, animal studies are critical in translational research. The debate continues as to whether these differences render the use of animal models in stroke studies irrelevant to the clinical application (16). These differences are evident in infarct localization (16). Another significant difference is the amount of white matter in the brain. The white matter accounts for 60% of brain tissue in humans, compared to 35% in dogs, 20% in rabbits, 15% in rats and only 10% in mice (17). This white matter difference poses a problem, as the ischemic damage of the white matter is a key player in the pathophysiology of stroke in humans (18).

Small vs. large animal models in cerebral ischemia. A number of animal species are used to investigate the mechanisms underlying cerebral ischemia (19-22). Different methods are used to generate cerebral ischemia, such as bilateral common carotid artery (CCA) occlusion (BCCAO) in rats (19), bilateral CCA stenosis (20), or asymmetric CCA surgery in mice (21), and three-vessel occlusions (3VO) in primates (22). The pros and cons of these models are illustrated in Fig. 1.

The majority of the stroke preclinical studies are conducted using small animals, particularly rodents. These studies have assisted researchers in understanding the molecular and biochemical processes within the ischemic tissue (23), as well as in understanding the different aspects of the injury mechanisms (24). However, despite the ease of handling rodents and the cognitive impairment produced as a consequence of chronic cerebral hypoperfusion, no motor abnormalities or white matter infarcts have been generated (10,25,26).

The guidelines of the Stroke Therapy Academic Industry Roundtable (STAIR), dictate that clinical studies cannot be performed on humans before testing the new proposed pharmaceutical drugs on higher animal species (27-29). Nonetheless, the use large animal models in research is associated with various issues. One of these is the need for invasive surgery to generate and monitor ischemia and this causes a high mortality rate (24). Furthermore, large animal models are costly to maintain and are labor-intensive (24). Moreover, animal rights organizations have raised several concerns regarding the use of large animals (16).

One of the apparent advantages of using large animals, such as dogs, cats, pigs, sheep and primates (30) is that imaging is easier than with the use of small animals (31). It is also more suitable to monitor the physiology, e.g., blood pressure, and blood gases in large animals compared to small ones (24).

Another advantage is that the brain of large animals is similar to the human brain in terms of functionality and structure, i.e. gyrencephalic, while rodents have lissencephalic brains (24,32). In addition, the ratio of the neocortex to the basal ganglia and the volume of white matter indicate that large animals are closer to the human neuroanatomy (17,33,34). Furthermore, large animals are considerably similar to humans in several behavioral aspects, as well as sensorimotor integration (35). Primates exhibit similarities to humans regarding the cerebral structure and high white matter percentage (29,36). Furthermore, the baboon 3-vessel occlusion (3VO) model has exhibited a tau pathology and amyloid-β deposition similar to humans (37).

On the other hand, small animals, particularly rodents, are less costly to maintain compared to large animals (17,38). Moreover, the rat physiology and cerebrovascular anatomy are similar to those of humans (38,39), and mice have homogeneous genes, and as a result, genetic mutations are easily achievable to generate transgenic mice, commonly used to investigate the molecular pathophysiology of stroke (40,41). The small brain size in rats and mice may be seen as an advantage, as various fixation procedures can be performed for neurochemical and biochemical investigations (21).

Methods used to induce cerebral ischemia in animal models. Ischemic stroke in humans occurs, in most cases, due to middle cerebral artery (MCA) occlusion (MCAO) (42). A number of models are designed to restrict cerebral blood flow, permanently or transiently, either directly by occlusion of the MCA or indirectly by common carotid artery ligation (43). A craniectomy is required for the direct occlusion of one or more cerebral vessels, through ligation, clipping, with hooks, or electrocoagulation (44). This model resembles human cases in terms of transient and permanent ischemia (44). Cerebral ischemia (CI) in this approach affects most of the cortices (45) and protects the thalamic, hypothalamic, hippocampal and midbrain regions from damage, since it produces small infarcts, unlike other MCAO models (45). It also creates a high percentage of infarct size and neurological deficits. The visual confirmation of successful MCAO is achieved during the surgery, with subsequent reperfusion of the ischemic areas (46).

On the other hand, this technique can lead to the injury of the underlying cortex or rupture of vessels by drilling or electrocoagulation (46). Additionally, the intracranial pressure and blood-brain barrier (BBB) function are greatly affected, and, as a result, it requires superior surgical skills (46). All in all, this method is highly invasive, with several complications. Therefore, other models have been introduced to avoid such complications.

MCAO models. This technique is similar to 70% of cerebral ischemic strokes that occur in humans (33,47). Koizumi et al (48) first established the intraluminal suture technique in 1986 in rats, and it was modified in the 1990s for use in mice (49). The intraluminal suture model offers two options: Transient ischemia with reperfusion or a permanent occlusion based on the time in which the suture is left in place (50). A craniotomy is not required in this model (50). A significant disadvantage is that it stimulates a larger infarction beyond the MCA zone to spread to the hippocampus and thalamus (51).

This model is reproducible in terms of primary ischemic injury and, consequently, cell death, blood-brain barrier (BBB) damage and glial activation (33,52). It is also appropriate for neuroprotection studies, due to the considerable existence of ischemic penumbra at the early stages post-occlusion (33). The infarct size in this model can be affected by the rat or mouse strain and the coating material for sutures. Strokes in spontaneously hypertensive rats (SHRs) are comparatively large and consistent in size. By contrast, in Sprague-Dawley (SD) rats, the infarcts are small and vary in size (53). An inadequate suture type may result in insufficient MCAO, leading to vessel rupture and subsequent subarachnoid hemorrhage (SAH). Silicone or poly-l-lysine coating suture is more adherent to neighboring vascular endothelium, compared to the uncoated suture, which leads to larger infarcts and minimizes inter-animal variability (54,55).

Unlike humans, following 60 min of MCAO, hypothalamic damage occurs (56). Following MCAO, hyperthermia occurs in rats and mice for at least 1 day due to hypothalamic ischemia (56,57). Approximately 12 h is needed in the transient MCAO mouse model for the damage to be repaired and for recovery to take place, which is a long therapeutic time, unlike stroke in humans (58). These two different mechanisms in the two MCAO models lead to varying results, which may be the reasons for the failure of neuroprotective agents in clinical experiments (58).

BCCAO. In several human cases of stroke, cerebral ischemia is a complication of thromboembolic conditions, such as carotid artery stenosis (59), atrial fibrillation (60) and heart failure (61). The BCCAO model is a relatively rapid and easy rat model that can be used to produce temporary or chronic cerebral ischemia (25). Rats usually exhibit white matter damage accompanied by cognitive impairments resembling those associated with stroke in humans. However, the affection of the visual pathways following the rat BCCAO compromises behavioral assessments. Therefore, C57/Bl mice have been used instead of rats, since the mouse model does not cause visual impairment and is, therefore, suitable for behavioral studies. This model is relatively easy to use, and training researchers on this mouse model decreases the mortality rate to <2%.

The bilateral common carotid artery stenosis (BCAS) model is a modification that causes carotid stenosis; the severity of cerebral hypoperfusion can be easily controlled by changing the diameter of micro-coils inserted in the carotid artery. This model is used worldwide and can be regarded as one of the most promising models of chronic cerebral hypoperfusion (10,20,62,63). This model mimics the white matter lesions induced by chronic cerebral hypoperfusion in humans (64).

Thromboembolic models. Thromboembolism is another cause of stroke. The thromboembolic clot model depends on the application route, the number and area of the clots (38). The thromboembolic clot can be spontaneous from autologous blood, which leads to vessel occlusion, causing infarcts (38). An advantage of this model is the spontaneous lysis of the clots, followed by reperfusion, which is similar to the case in humans (65).

An alternative method is the direct injection of thrombin into the MCA or internal carotid artery (ICA) to cause vascular occlusion (66). In this model, polymerized fibrin with a low number of cells and platelets are used to produce clots, while most of the human clots contain an accumulation of both platelets and fibrin, a deposition of neutrophils and monocytes and a high aggregation percentage of erythrocyte (67). In addition, the intravascular introduction of clots causes, in most cases, multifocal infarcts with noticeable variance in size and the localization of the lesion (68).

Another method with which to induce embolic stroke is by using microsphere/macrospheres to block blood flow. The major discrepancy with this model is that the fabricated spheres lead to permanent ischemia as they do not dissolve (65). An advantage associated with this model is the fact that the occlusion in rats may be postponed, while the animal is under monitor by PET or a magnetic resonance imaging (MRI) device (69).

Endothelin-1 model (ET-1). The reversible occlusion of the MCA can be achieved using a potent vasoconstrictor, such as endothelin-1 (ET-1) (33,38,70,71). A rapid blood flow reduction to the brain can be noted after the ET-1 injection, followed by reperfusion several hours later (72). Occlusion can be achieved through various mechanisms, directly by topical application onto the exposed MCA, or by intracerebral injection (73). A primary advantage of the injection method is the low invasiveness and the low mortality rate. Although ET1 is effective in rats, it is not as effective in mice (74). Another problem with this model is the variability of the lesion size (75).

Photo thrombosis model. This model requires an intravenous injection in rats or an intraperitoneal injection in mice (76,77) of a photosensitive dye, such as Rose Bengal or erythrosin B, followed by exposing the skull laser (78). Cerebral ischemia can be induced in specific brain regions depending on the purpose of the study. Once the dye is activated, reactive oxygen species (ROS) are generated, leading to endothelial damage, platelet activation and aggregation in pial and intraparenchymal vessels, forming thrombi (17). An advantage of this model is the rapid production of ischemic cell death (79). A further advantage is that it decreases the invasion and mortality rates. A significant disadvantage is that the ischemic injury is associated with early intracellular and extracellular edema formation (80), which differ from those observed in human stroke, as intracellular edema is the main indication of acute cerebral ischemia in humans (81).

In conclusion, as demonstrated through various sudies, there are various animal models, and associated techniques to produce cerebral ischemia/reperfusion, and each model has its advantages and weaknesses. The selection of the model should be based on the objectives and goal of the research study, bearing in mind that none of these models is identical to the human stroke pathophysiology.

4. Assessment of functional deficits in cerebral ischemia models

Since stroke is associated with problems in the sensory and motor pathways, researchers have focused on studying the behavioral and cognitive aspects post-stroke (82). Various functional tests (Table I) are available for use in animals, including the Rotarod, the grip and string test, the wire hanging test, the adhesive removal test, the open field maze and the water maze test (83-95).

5. Herbal remedies as neuroprotective agents in cerebral ischemia

The MCAO model has been extensively studied with numerous natural herbal extracts. Cerebral ischemic injury results in the production of ROS, which cause lipid, DNA and protein oxidation, therefore causing cell damage and death (96). A number of these herbs possess antioxidant, anti-inflammatory and neuroprotective activity, such as Artemisia absinthium L. (97), Lavandula angustifolia (98), Scutellaria baicalensis (99) and several others. Their active ingredients exert significant neuroprotective effects and improvement in behavioral function when used before or after ischemic injury (98-100).

Chinese plants provide a rich source of herbal extracts for medicinal purposes. Some of these have been widely investigated in cerebral ischemia. Plants, such as Erigeron breviscapus (101,102) contain breviscapine, which is considered to target autophagy mechanisms, leading to a reduction in infarct size and functional improvements in rats. Scutellarin is another component of Erigeron breviscapus, which exerts a decrease in infarct size and functional improvement when injected into rats (102). Other Chinese plants include Fructus Chebulae (103) and Fructus Schisandrae (Chinese magnolia vine fruit) (104), which protect against metalloproteinase degradation. In rats, these fruits lead to a reduction in the expression of TNF-a and IL-1b, as well as reduction in the degradation of the metalloproteinases, MMP-2 and MMP-9, in ischemic hemispheres, which leads to a reduction in infarct size (104). Panax ginseng (105-107) reduces infarcts size in rats and mice and improves function through the downregulation of calpain I and caspase 3(107), and the induction of Nrf 2 downstream targets (106). Panax ginseng has also been used in global and focal ischemic models (108); it causes a decrease in lipid peroxidation and mitochondrial swelling (108).

Salvia miltiorrhiza is a potent antioxidant that is used in MCAO (100) and in spinal cord ischemia/reperfusion injury in rats (109). It exerts a decrease in edema and infarct volume, as well as functional improvements in both models. Antioxidants, such as Camellia sinensis (110,111) and Araucaria bidwillii (112) cause functional improvements when used in global and focal ischemic models by inhibiting lipid peroxidation, and decreasing apoptosis and neuronal cell death.

Other herbal extracts and their active ingredients used in rodent models of MCAO are summarized in Table II (97-107,113-129). In Table III, the commonly used herbal extracts and their active ingredients used in other rodent models of cerebral ischemia are also listed (98,108-112,130-147). The possible mechanisms of action of each are highlighted.

6. Conclusions

Different in vitro and animal models are available for the study of cerebral ischemia/reperfusion injury. The pathophysiology of cerebral ischemia/reperfusion is complex, and animal models are superior, particularly when testing various treatment approaches. It is suggested that the MCAO and BCCAO models the most convenient, cost-effective and easily reproducible models. Herbal extracts and phytochemicals provide a wide variety of neuroprotective agents that may be of value to research in cerebral ischemia. Further investigations are required to identify the active ingredients of such plants, and further testing is warranted. The literature provides a wealth of knowledge regarding herbal medicine in cerebral ischemia research, mostly using plants from south-East Asia. Plants from Africa and other regions warrant further investigation as they provide attractive targets for the development of novel therapeutic drugs.

Acknowledgements

Not applicable.

Funding

The present study was partially funded by a research support grant (SSE-BIOL-A.A-FY20) from the American University in Cairo.

Availability of data and materials

Data sharing is not applicable to this article, as no datasets were generated or analyzed during the current study.

Authors' contributions

NME, NS, EK, AA were involved in the conception and design of the study, and in the writing and revision of the manuscript. NE and NS were involved in the production of the figure and tables.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

References 1

Mozaffarian

Benjamin

Arnett

Blaha

Cushman

de Ferranti

Després

Fullerton

Howard

Heart disease and stroke statistics-2015 update: A report from the American Heart Association

Circulation131e29e3222015

25520374

10.1161/CIR.0000000000000152

Dong

Yang

Zhang

Xie

Hemopexin alleviates cognitive dysfunction after focal cerebral ischemia-reperfusion injury in rats

BMC Anesthesiol19132019

30646866

10.1186/s12871-019-0681-2

Di Carlo

Human and economic burden of stroke

Age Ageing38452009

19141505

10.1093/ageing/afn282

Moher

Liberati

Tetzlaff

Altman

Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement

Ann Intern Med1512642692009

19621072

10.1371/journal.pmed.1000097

Higgins

Altman

Gøtzsche

Jüni

Moher

Oxman

Savovic

Schulz

Weeks

Sterne

The Cochrane Collaboration's tool for assessing risk of bias in randomised trials

BMJ343d59282011

22008217

10.1136/bmj.d5928

Woodruff

Thundyil

Tang

Sobey

Taylor

Arumugam

Pathophysiology, treatment, and animal and cellular models of human ischemic stroke

Mol Neurodegener6112011

21266064

10.1186/1750-1326-6-11

O'Brien

Thomas

Vascular dementia

Lancet386169817062015

26595643

10.1016/S0140-6736(15)00463-8

Kalaria

Neuropathological diagnosis of vascular cognitive impairment and vascular dementia with implications for Alzheimer's disease

Acta Neuropathol1316596852016

27062261

10.1007/s00401-016-1571-z

Hainsworth

Markus

Do in vivo experimental models reflect human cerebral small vessel disease? A systematic review

J Cereb Blood Flow Metab28187718912008

18698331

10.1038/jcbfm.2008.91

Bink

Ritz

Aronica

Van Der Weerd

Daemen

Mouse models to study the effect of cardiovascular risk factors on brain structure and cognition

J Cereb Blood Flow Metab33166616842013

23963364

10.1038/jcbfm.2013.140

Gorelick

Counts

Nyenhuis

Vascular cognitive impairment and dementia

Biochim Biophys Acta18628608682016

26704177

10.1016/j.bbadis.2015.12.015

Venkat

Chopp

Chen

Models and mechanisms of vascular dementia

Exp Neurol272971082015

25987538

10.1016/j.expneurol.2015.05.006

Hanke

Lessons from TGN1412

Lancet36815691570author reply 15702006

17084746

10.1016/S0140-6736(06)69651-7

Römer

Berr

Avota

Battaglia

ten Berge

Einsele

Hünig

Preculture of PBMCs at high cell density increases sensitivity of T-cell responses, revealing cytokine release by CD28 superagonist TGN1412

Blood118677267822011

21931118

10.1182/blood-2010-12-319780

Holloway

Gavins

Modeling ischemic stroke in vitro: status quo and future perspectives

Stroke475615692016

26742797

10.1161/STROKEAHA.115.011932

Cook

Tymianski

Nonhuman primate models of stroke for translational neuroprotection research

Neurotherapeutics93713792012

22437447

10.1007/s13311-012-0115-z

Krafft

Bailey

Lekic

Rolland

Altay

Tang

Wardlaw

Zhang

Sudlow

Etiology of stroke and choice of models

Int J Stroke73984062012

22712741

10.1111/j.1747-4949.2012.00838.x

Ahmad

Satriotomo

Fazal

Nadeau

Doré

Considerations for the optimization of induced white matter injury preclinical models

Front Neurol61722015

26322013

10.3389/fneur.2015.00172

Edrissi

Schock

Cadonic

Hakim

Thompson

Cilostazol reduces blood brain barrier dysfunction, white matter lesion formation and motor deficits following chronic cerebral hypoperfusion

Brain Res16464945032016

27350079

10.1016/j.brainres.2016.06.036

Shibata

Ohtani

Ihara

Tomimoto

White matter lesions and glial activation in a novel mouse model of chronic cerebral hypoperfusion

Stroke35259826032004

15472111

10.1161/01.STR.0000143725.19053.60

Hattori

Enmi

Kitamura

Yamamoto

Saito

Takahashi

Iguchi

Tsuji

Yamahara

Nagatsuka

A novel mouse model of subcortical infarcts with dementia

J Neurosci35391539282015

25740520

10.1523/JNEUROSCI.3970-14.2015

Chen

Akinyemi

Hase

Firbank

Ndung'u

Foster

Craggs

Washida

Okamoto

Thomas

Frontal white matter hyperintensities, clasmatodendrosis and gliovascular abnormalities in ageing and post-stroke dementia

Brain1392422582015

26667280

10.1093/brain/awv328

McCabe

Arroja

Reid

Macrae

Animal models of ischaemic stroke and characterisation of the ischaemic penumbra

Neuropharmacology1341691772018

28923277

10.1016/j.neuropharm.2017.09.022

Traystman

Animal models of focal and global cerebral ischemia

ILAR J4485952003

12652003

10.1093/ilar.44.2.85

Farkas

Luiten

Bari

Permanent, bilateral common carotid artery occlusion in the rat: A model for chronic cerebral hypoperfusion-related neurodegenerative diseases

Brain Res Rev541621802007

17296232

10.1016/j.brainresrev.2007.01.003

Nishio

Ihara

Yamasaki

Kalaria

Maki

Fujita

Ito

Oishi

Fukuyama

Miyakawa

A mouse model characterizing features of vascular dementia with hippocampal atrophy

Stroke41127812842010

20448204

10.1161/STROKEAHA.110.581686

Stem Cell Therapies as an Emerging Paradigm in Stroke Participants: Stem cell therapies as an emerging paradigm in stroke (STEPS): Bridging basic and clinical science for cellular and neurogenic factor therapy in treating stroke. Stroke 40: 510-515, 2009.

Savitz

Chopp

Deans

Carmichael

Phinney

Wechsler

STEPS Participants: Stem cell therapy as an emerging paradigm for stroke (STEPS) II

Stroke428258292011

21273569

10.1161/STROKEAHA.110.601914

Stroke Therapy Academic Industry Roundtable (STAIR): Recommendations for standards regarding preclinical neuroprotective and restorative drug development. Stroke 30: 2752-2758, 1999.

Bacigaluppi

Comi

Hermann

Animal models of ischemic stroke. Part two: Modeling cerebral ischemia

Open Neurol J434382010

20721320

10.2174/1874205X01004020034

Marshall

Ridley

Baker

Hall

Carpenter

Wood

Serial MRI, functional recovery, and long-term infarct maturation in a non-human primate model of stroke

Brain Res Bull615775852003

14519454

10.1016/s0361-9230(03)00214-4

Cook

Teves

Tymianski

Treatment of stroke with a PSD-95 inhibitor in the gyrencephalic primate brain

Nature4832132172012

22388811

10.1038/nature10841

Howells

Porritt

Rewell

O'collins

Sena

Van Der Worp

Traystman

Macleod

Different strokes for different folks: The rich diversity of animal models of focal cerebral ischemia

J Cereb Blood Flow Metab30141214312010

20485296

10.1038/jcbfm.2010.66

Macrae

Preclinical stroke research-advantages and disadvantages of the most common rodent models of focal ischaemia

Br J Pharmacol164106210782011

21457227

10.1111/j.1476-5381.2011.01398.x

Canazza

Minati

Boffano

Parati

Binks

Experimental models of brain ischemia: A review of techniques, magnetic resonance imaging, and investigational cell-based therapies

Front Neurol5192014

24600434

10.3389/fneur.2014.00019

Madigan

Wilcock

Hainsworth

Vascular contributions to cognitive impairment and dementia: Topical review of animal models

Stroke47195319592016

27301939

10.1161/STROKEAHA.116.012066

Ndung'u

Härtig

Wegner

Mwenda

Low

Akinyemi

Kalaria

Cerebral amyloid β(42) deposits and microvascular pathology in ageing baboons

Neuropathol Appl Neurobiol384874992012

22126319

10.1111/j.1365-2990.2011.01246.x

Durukan

Tatlisumak

Acute ischemic stroke: Overview of major experimental rodent models, pathophysiology, and therapy of focal cerebral ischemia

Pharmacol Biochem Behav871791972007

17521716

10.1016/j.pbb.2007.04.015

Liu

McCullough

Middle cerebral artery occlusion model in rodents: Methods and potential pitfalls

J Biomed Biotechnol20114647012011

21331357

10.1155/2011/464701

Kraft

Göb

Schuhmann

Göbel

Deppermann

Thielmann

Herrmann

Lorenz

Brede

Stoll

FTY720 ameliorates acute ischemic stroke in mice by reducing thrombo-inflammation but not by direct neuroprotection

Stroke44320232102013

24029635

10.1161/STROKEAHA.113.002880

Göb

Reymann

Langhauser

Schuhmann

Kraft

Thielmann

Göbel

Brede

Homola

Solymosi

Blocking of plasma kallikrein ameliorates stroke by reducing thromboinflammation

Ann Neurol777848032015

25628066

10.1002/ana.24380

Dirnagl

Macleod

Stroke research at a road block: The streets from adversity should be paved with meta-analysis and good laboratory practice

Br J Pharmacol157115411562009

19664136

10.1111/j.1476-5381.2009.00211.x

Yanamoto

Nagata

Niitsu

Xue

Zhang

Kikuchi

Evaluation of MCAO stroke models in normotensive rats: Standardized neocortical infarction by the 3VO technique

Exp Neurol1822612742003

12895438

10.1016/s0014-4886(03)00116-x

Dirnagl U: Rodent models of stroke: Springer, 2010.

Buchan

Xue

Slivka

A new model of temporary focal neocortical ischemia in the rat

Stroke232732791992

1561658

10.1161/01.str.23.2.273

Sugimori

Yao

Ooboshi

Ibayashi

Iida

Krypton laser-induced photothrombotic distal middle cerebral artery occlusion without craniectomy in mice

Brain Res Brain Res Protoc131891962004

15296857

10.1016/j.brainresprot.2004.06.001

Bogousslavsky

Van Melle

Regli

The Lausanne Stroke Registry: Analysis of 1,000 consecutive patients with first stroke

Stroke19108310921988

3413804

10.1161/01.str.19.9.1083

Koizumi

Yoshida

Nakazawa

Ooneda

Experimental studies of ischemic brain edema. 1. A new experimental model of cerebral embolism in rats in which recirculation can be introduced in the ischemic area

Jpn J Stroke8181986

Smith

Russell

Granger

Gavins

Critical differences between two classical surgical approaches for middle cerebral artery occlusion-induced stroke in mice

J Neurosci Methods249991052015

25936850

10.1016/j.jneumeth.2015.04.008

Chiang

Messing

Chou

Mouse model of middle cerebral artery occlusion

J Vis Expe27612011

21372780

10.3791/2761

Garcia

Liu

Neuronal necrosis after middle cerebral artery occlusion in Wistar rats progresses at different time intervals in the caudoputamen and the cortex

Stroke26636643Discussion 6431995

7709411

10.1161/01.str.26.4.636

Kuraoka

Furuta

Matsuwaki

Omatsu

Ishii

Kyuwa

Yoshikawa

Direct experimental occlusion of the distal middle cerebral artery induces high reproducibility of brain ischemia in mice

Exp Anim5819292009

19151508

10.1538/expanim.58.19

Duverger

MacKenzie

The quantification of cerebral infarction following focal ischemia in the rat: Influence of strain, arterial pressure, blood glucose concentration, and age

J Cereb Blood Flow Metab84494611988

2968987

10.1038/jcbfm.1988.86

Belayev

Alonso

Busto

Zhao

Ginsberg

Middle cerebral artery occlusion in the rat by intraluminal suture. Neurological and pathological evaluation of an improved model

Stroke27161616231996

8784138

10.1161/01.str.27.9.1616

Schmid-Elsaesser

Zausinger

Hungerhuber

Baethmann

Reulen

A critical reevaluation of the intraluminal thread model of focal cerebral ischemia

Stroke29216221701998

9756599

10.1161/01.str.29.10.2162

Omae

Fisher

Spontaneous hyperthermia and its mechanism in the intraluminal suture middle cerebral artery occlusion model of rats

Stroke3024642470Discussion 2470-24711999

10548685

10.1161/01.str.30.11.2464

Barber

Hoyte

Colbourne

Buchan

Temperature-regulated model of focal ischemia in the mouse: A study with histopathological and behavioral outcomes

Stroke35172017252004

15155973

10.1161/01.STR.0000129653.22241.d7

Hossmann

The two pathophysiologies of focal brain ischemia: Implications for translational stroke research

J Cereb Blood Flow Metab32131013162012

22234335

10.1038/jcbfm.2011.186

Demarin

Zavoreo

Kes

Carotid artery disease and cognitive impairment

J Neurol Sci3221071112012

22925533

10.1016/j.jns.2012.07.008

de Bruijn

Heeringa

Wolters

Franco

Stricker

Hofman

Koudstaal

Ikram

Association between atrial fibrillation and dementia in the general population

JAMA Neurol72128812942015

26389654

10.1001/jamaneurol.2015.2161

Adelborg

Szépligeti

Sundbøll

Horváth-Puhó

Henderson

Ording

Pedersen

Sørensen

Risk of stroke in patients with heart failure: A population-based 30-year cohort study

Stroke48116111682017

28377383

10.1161/STROKEAHA.116.016022

Shibata

Yamasaki

Miyakawa

Kalaria

Fujita

Ohtani

Ihara

Takahashi

Tomimoto

Selective impairment of working memory in a mouse model of chronic cerebral hypoperfusion

Stroke38282628322007

17761909

10.1161/STROKEAHA.107.490151

Ihara

Taguchi

Maki

Washida

Tomimoto

A mouse model of chronic cerebral hypoperfusion characterizing features of vascular cognitive impairment

Methods Mol Biol1135951022014

24510857

10.1007/978-1-4939-0320-7_8

Washida

Hattori

Ihara

Animal models of chronic cerebral hypoperfusion: From mouse to primate

Int J Mol Sci2061762019

31817864

10.3390/ijms20246176

Sommer

Ischemic stroke: Experimental models and reality

Acta Neuropathol1332452612017

28064357

10.1007/s00401-017-1667-0

Orset

Macrez

Young

Panthou

Angles-Cano

Maubert

Agin

Vivien

Mouse model of in situ thromboembolic stroke and reperfusion

Stroke38277127782007

17702959

10.1161/STROKEAHA.107.487520

Smith

Sung

Starkman

Saver

Kidwell

Gobin

Lutsep

Nesbit

Grobelny

Rymer

Safety and efficacy of mechanical embolectomy in acute ischemic stroke: Results of the MERCI trial

Stroke36143214382005

15961709

10.1161/01.STR.0000171066.25248.1d

Niessen

Hilger

Hoehn

Hossmann

Differences in clot preparation determine outcome of recombinant tissue plasminogen activator treatment in experimental thromboembolic stroke

Stroke34201920242003

12843350

10.1161/01.STR.0000080941.73934.30

Walberer

Rueger

The macrosphere model-an embolic stroke model for studying the pathophysiology of focal cerebral ischemia in a translational approach

Ann Transl Med31232015

26207251

10.3978/j.issn.2305-5839.2015.04.02

Macrae

Robinson

Graham

Reid

McCulloch

Endothelin-1-induced reductions in cerebral blood flow: Dose dependency, time course, and neuropathological consequences

J Cereb Blood Flow Metab132762841993

8436619

10.1038/jcbfm.1993.34

Bogaert

Scheller

Moonen

Sarre

Smolders

Ebinger

Michotte

Neurochemical changes and laser Doppler flowmetry in the endothelin-1 rat model for focal cerebral ischemia

Brain Res8872662752000

11134615

10.1016/s0006-8993(00)02959-0

Biernaskie

Corbett

Peeling

Wells

Lei

A serial MR study of cerebral blood flow changes and lesion development following endothelin-1-induced ischemia in rats

Magn Reson Med468278302001

11590661

10.1002/mrm.1263

Hughes

Anthony

Ruddin

Botham

Rankine

Sablone

Baumann

Mir

Perry

Focal lesions in the rat central nervous system induced by endothelin-1

J Neuropathol Exp Neurol62127612862003

14692703

10.1093/jnen/62.12.1276

Horie

Maag

Hamilton

Shichinohe

Bliss

Steinberg

Mouse model of focal cerebral ischemia using endothelin-1

J Neurosci Methods1732862902008

18621079

10.1016/j.jneumeth.2008.06.013

Ansari

Azari

Caldwell

Regenhardt

Hedna

Waters

Hoh

Mecca

Endothelin-1 induced middle cerebral artery occlusion model for ischemic stroke with laser Doppler flowmetry guidance in rat

J Vis Exp500142013

23438950

10.3791/50014

Kim

Sugawara

Chan

Involvement of oxidative stress and caspase-3 in cortical infarction after photothrombotic ischemia in mice

J Cereb Blood Flow Metab20169017012000

11129785

10.1097/00004647-200012000-00008

Kleinschnitz

Braeuninger

Pham

Austinat

Nölte

Renné

Nieswandt

Bendszus

Stoll

Blocking of platelets or intrinsic coagulation pathway-driven thrombosis does not prevent cerebral infarctions induced by photothrombosis

Stroke39126212682008

18292385

10.1161/STROKEAHA.107.496448

Watson

Dietrich

Busto

Wachtel

Ginsberg

Induction of reproducible brain infarction by photochemically initiated thrombosis

Ann Neurol174975041985

4004172

10.1002/ana.410170513

Dietrich

Ginsberg

Busto

Watson

Photochemically induced cortical infarction in the rat. 1. Time course of hemodynamic consequences

J Cereb Blood Flow Metab61841941986

3958063

10.1038/jcbfm.1986.31

Lee

Burdett

Carpenter

Hall

Pambakian

Patel

Wood

James

Evolution of photochemically induced focal cerebral ischemia in the rat. Magnetic resonance imaging and histology

Stroke27211021191996

8898824

10.1161/01.str.27.11.2110

Provenzale

Jahan

Naidich

Fox

Assessment of the patient with hyperacute stroke: Imaging and therapy

Radiology2293473592003

14595138

10.1148/radiol.2292020402

DeVries

Nelson

Traystman

Hurn

Cognitive and behavioral assessment in experimental stroke research: Will it prove useful?

Neurosci Biobehav Rev253253422001

11445138

10.1016/s0149-7634(01)00017-3

Shiotsuki

Yoshimi

Shimo

Funayama

Takamatsu

Ikeda

Takahashi

Kitazawa

Hattori

A rotarod test for evaluation of motor skill learning

J Neurosci Methods1891801852010

20359499

10.1016/j.jneumeth.2010.03.026

Balkaya

Kröber

Rex

Endres

Assessing post-stroke behavior in mouse models of focal ischemia

J Cereb Blood Flow Metab333303382013

23232947

10.1038/jcbfm.2012.185

Lee

Park

Kim

Moon

Joo

Kim

Photochemically induced cerebral ischemia in a mouse model

Surg Neurol676206252007

17512331

10.1016/j.surneu.2006.08.077

De Luca

Tinsley

Aartsma-Rus

van Putten

Nagaraju

de La Porte

Dubach-Powell

Carlson

Use of grip strength meter to assess the limb strength of mdx mice

SOP DMD_M.22008

Ishrat

Sayeed

Atif

Stein

Effects of progesterone administration on infarct volume and functional deficits following permanent focal cerebral ischemia in rats

Brain Res1257941012009

19135987

10.1016/j.brainres.2008.12.048

Hoffman

Winder

A modified wire hanging apparatus for small animal muscle function testing

PLoS Curr 8ecurrents.md.1e2bec4e78697b7b0ff80ea25a1d38be2016

28966868

10.1371/currents.md.1e2bec4e78697b7b0ff80ea25a1d38be

Gerlai

Thibodeaux

Palmer

van Lookeren Campagne

Van Bruggen

Transient focal cerebral ischemia induces sensorimotor deficits in mice

Behav Brain Res10863712000

10680758

10.1016/s0166-4328(99)00130-8

Bouet

Boulouard

Toutain

Divoux

Bernaudin

Schumann-Bard

Freret

The adhesive removal test: A sensitive method to assess sensorimotor deficits in mice

Nat Protoc4156015642009

19798088

10.1038/nprot.2009.125

Seibenhener

Wooten

Use of the Open Field Maze to measure locomotor and anxiety-like behavior in mice

J Vis Expe524342015

25742564

10.3791/52434

Gould TD, Dao DT and Kovacsics CE: The open field test. Mood and anxiety related phenotypes in mice. Springer, pp1-20, 2009.

Vorhees

Williams

Morris water maze: Procedures for assessing spatial and related forms of learning and memory

Nat Protoc18488582006

17406317

10.1038/nprot.2006.116

Chen

Sanberg

Wang

Willing

Sanchez-Ramos

Chopp

Intravenous administration of human umbilical cord blood reduces behavioral deficits after stroke in rats

Stroke32268226882001

11692034

10.1161/hs1101.098367

Clark

Lessov

Dixon

Eckenstein

Monofilament intraluminal middle cerebral artery occlusion in the mouse

Neurol Res196416481997

9427967

10.1080/01616412.1997.11740874

Niizuma

Endo

Chan

Oxidative stress and mitochondrial dysfunction as determinants of ischemic neuronal death and survival

J Neurochem1091331382009

19393019

10.1111/j.1471-4159.2009.05897.x

Bora

Sharma

Neuroprotective effect of Artemisia absinthium L. on focal ischemia and reperfusion-induced cerebral injury

J Ethnopharmacol1294034092010

20435123

10.1016/j.jep.2010.04.030

Wang

Yuan

Liu

Wang

Zheng

Neuroprotective activity of lavender oil on transient focal cerebral ischemia in mice

Molecules17980398172012

22895026

10.3390/molecules17089803

Dai

Qiu

Yan

Zhou

Jin

Zhang

Neuroprotective effect of baicalin on focal cerebral ischemia in rats

Neural Regen Res13212921332018

30323141

10.4103/1673-5374.241464

100

Cao

Quan

Hou

Guo

Zhang

The natural therapeutic magnesium lithospermate B potently provides neuroprotective effects on cerebral ischemia/reperfusion injury in rats

J Ethnopharmacol1621911982015

25560670

10.1016/j.jep.2014.12.048

101

Pengyue

Tao

Hongyun

Liqiang

Yihao

Breviscapine confers a neuroprotective efficacy against transient focal cerebral ischemia by attenuating neuronal and astrocytic autophagy in the penumbra

Biomed Pharmacother9069762017

28343073

10.1016/j.biopha.2017.03.039

102

Guo

Wang

Shi

Liu

Kang

Gao

Neuroprotective effects of scutellarin against hypoxic-ischemic-induced cerebral injury via augmentation of antioxidant defense capacity

Chin J Physiol543994052011

22229507

10.4077/CJP.2011.AMM059

103

Gaire

Kim

Neuroprotective effects of Fructus Chebulae extracts on experimental models of cerebral ischemia

J Tradit Chin Med3469752014

25102694

10.1016/s0254-6272(14)60057-1

104

Lee

Jung

Lee

Neuroprotective effects of Schisandrin B against transient focal cerebral ischemia in Sprague-Dawley rats

Food Chem Toxicol50423942452012

22960133

10.1016/j.fct.2012.08.047

105

Chen

Yang

Yun

Zhang

Yang

Shen

Neuroprotective effect of 20(R)-ginsenoside Rg(3) against transient focal cerebral ischemia in rats

Neurosci Lett5261061112012

22925661

10.1016/j.neulet.2012.08.022

106

Liu

Vollmer

Fernandez

Dweik

Kim

Doré

Korean red ginseng pretreatment protects against long-term sensorimotor deficits after ischemic stroke likely through Nrf2

Front Cell Neurosci12742018

29628876

10.3389/fncel.2018.00074

107

Dong

Zheng

Yang

Neuroprotective effects of pretreatment of ginsenoside Rb1 on severe cerebral ischemia-induced injuries in aged mice: Involvement of anti-oxidant signaling

Geriatr Gerontol Int173383452017

26712031

10.1111/ggi.12699

108

Chen

Zhou

Cao

Neuroprotection of ginsenoside Re in cerebral ischemia-reperfusion injury in rats

J Asian Nat Prod Res104394452008

18464084

10.1080/10286020801892292

109

Duan

Wang

Gao

Qin

Metabolomics study on the effects of salvianolic acid B and borneol for treating cerebral ischemia in rats by ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry

Rejuvenation Res223133242019

30411995

10.1089/rej.2018.2099

110

Hong

Ryu

Kim

Lee

Kim

Yun

Ryu

Lee

Kim

Neuroprotective effect of green tea extract in experimental ischemia-reperfusion brain injury

Brain Res Bull537437492000

11179838

10.1016/s0361-9230(00)00348-8

111

Graham

Green tea composition, consumption, and polyphenol chemistry

Prev Med213343501992

1614995

10.1016/0091-7435(92)90041-f

112

Mukherjee

Ahamed

Kumar

Mukherjee

Houghton

Protective effect of biflavones from Araucaria bidwillii Hook in rat cerebral ischemia/reperfusion induced oxidative stress

Behav Brain Res1782212282007

17250903

10.1016/j.bbr.2006.12.025

113

Nazam Ansari

Bhandari

Islam

Tripathi

Evaluation of antioxidant and neuroprotective effect of ethanolic extract of Embelia ribes Burm in focal cerebral ischemia/reperfusion-induced oxidative stress in rats

Fundam Clin Pharmacol223053142008

18485149

10.1111/j.1472-8206.2008.00580.x

114

Ferreira Ede

Fernandes

Lima

Neves

Carmo

Lima

Fonteles

Menezes

Andrade

Neuroinflammatory response to experimental stroke is inhibited by eriodictyol

Behav Brain Res3123213322016

27353856

10.1016/j.bbr.2016.06.046

115

Lee

Park

Yoon

Kim

Choi

Kim

Neuroprotective effects of Eleutherococcus senticosus bark on transient global cerebral ischemia in rats

J Ethnopharmacol1396112012

21645606

10.1016/j.jep.2011.05.024

116

Luo

Kim

Lee

Kim

Lee

Anti-Zn²+-toxicity of 4-hydroxybenzyl alcohol in astrocytes and neurons contribute to a robust neuroprotective effects in the postischemic brain

Cell Mol Neurobiol386156262018

28608001

10.1007/s10571-017-0508-y

117

Akhtar

Maikiyo

Najmi

Khanam

Mujeeb

Aqil

Neuroprotective effects of chloroform and petroleum ether extracts of Nigella sativa seeds in stroke model of rat

J Pharm Bioallied Sci51192013

23833517

10.4103/0975-7406.111825

118

Wang

Zhang

Liu

Neuroprotective effects of emodin-8-O-beta-d-glucoside in vivo and in vitro

Eur J Pharmacol57758632007

17897641

10.1016/j.ejphar.2007.08.033

119

Guo

Tong

Yang

Dong

Wen

Neuroprotective effect of calycosin on cerebral ischemia and reperfusion injury in rats

Cell Physiol Biochem1447687742012

23123262

10.1016/j.jep.2012.09.056

120

Chang

Hsieh

Peng

Yen

Hsiao

Chou

Chen

Sheu

Neuroprotective mechanisms of puerarin in middle cerebral artery occlusion-induced brain infarction in rats

J Biomed Sci1692009

19272172

10.1186/1423-0127-16-9

121

Meng

Xie

Liang

Sun

Neuroprotective effects of radix scrophulariae on cerebral ischemia and reperfusion injury via MAPK pathways

Molecules2324012018

30235876

10.3390/molecules23092401

122

Kaneko

Eve

Shojo

Bae

Park

Roschek

B Jr

Alberte

Sanberg

Acute treatment with herbal extracts provides neuroprotective benefits in in vitro and in vivo stroke models, characterized by reduced ischemic cell death and maintenance of motor and neurological functions

Cell Med11371422010

21379315

10.3727/215517910X552818

123

Guo

Yin

Duan

Zhu

Yan

Wei

Guan

Wang

Wen

Neuroprotective effect and underlying mechanism of sodium danshensu [3-(3,4-dihydroxyphenyl) lactic acid from Radix and Rhizoma Salviae miltiorrhizae=Danshen] against cerebral ischemia and reperfusion injury in rats

Phytomedicine222832892015

25765834

10.1016/j.phymed.2014.12.001

124

Lam

Sun

Luo

Chung

Sucher

Neuroprotective effects of tanshinones in transient focal cerebral ischemia in mice

Phytomedicine102862912003

12809358

10.1078/094471103322004776

125

Cui

Zhang

Yang

Wang

Liu

Neuroprotection and underlying mechanisms of oxymatrine in cerebral ischemia of rats

Neurol Res333193242011

20626959

10.1179/016164110X12759951866876

126

Park

Nam

Lee

Cho

Koo

Mar

Neuroprotective effects of an alkaloid-free ethyl acetate extract from the root of Sophora flavescens Ait. against focal cerebral ischemia in rats

Phytomedicine16104210512009

19427179

10.1016/j.phymed.2009.03.017

127

Yang

Ling

Fang

Neuroprotective effects of DAHP and Triptolide in focal cerebral ischemia via apoptosis inhibition and PI3K/Akt/mTOR pathway activation

Front Neuroanat9482015

25954164

10.3389/fnana.2015.00048

128

Lee

Kou

Anti-inflammatory and neuroprotective effects of triptolide on traumatic brain injury in rats

Respir Physiol Neurobiol182182012

22366865

10.1016/j.resp.2012.01.016

129

Gupta

Combination of Zizyphus jujuba and silymarin showed better neuroprotective effect as compared to single agent in MCAo-induced focal cerebral ischemia in rats

J Ethnopharmacol1971181272017

27452658

10.1016/j.jep.2016.07.060

130

Chen

Kuo

Lee

Tsai

Magnolol protects neurons against ischemia injury via the downregulation of p38/MAPK, CHOP and nitrotyrosine

Toxicol Appl Pharmacol2792943022014

25038313

10.1016/j.taap.2014.07.005

131

Gong

Sun

Zhou

Duan

Zhao

Chen

Shen

Momordica charantia polysaccharides could protect against cerebral ischemia/reperfusion injury through inhibiting oxidative stress mediated c-Jun N-terminal kinase 3 signaling pathway

Neuropharmacology911231342015

25510970

10.1016/j.neuropharm.2014.11.020

132

Bora

Arora

Shri

Role of Ocimum basilicum L. in prevention of ischemia and reperfusion-induced cerebral damage, and motor dysfunctions in mice brain

J Ethnopharmacol137136013652011

21843615

10.1016/j.jep.2011.07.066

133

Dringen

Metabolism and functions of glutathione in brain

Prog Neurobiol626496712000

10880854

10.1016/s0301-0082(99)00060-x

134

Siddiqui

Aslam

Ali

Begu

Khatoon

Two new triterpenoids and a steroidal glycoside from the aerial parts of Ocimum basilicum

Chem Pharm Bull (Tokyo)555165192007

17409539

10.1248/cpb.55.516

135

Yanpallewar

Rai

Kumar

Acharya

Evaluation of antioxidant and neuroprotective effect of Ocimum sanctum on transient cerebral ischemia and long-term cerebral hypoperfusion

Pharmacol Biochem Behav791551642004

15388295

10.1016/j.pbb.2004.07.008

136

Fki

Sahnoun

Sayadi

Hypocholesterolemic effects of phenolic extracts and purified hydroxytyrosol recovered from olive mill wastewater in rats fed a cholesterol-rich diet

J Agric Food Chem556246312007

17263452

10.1021/jf0623586

137

Mohagheghi

Bigdeli

Rasoulian

Zeinanloo

Khoshbaten

Dietary virgin olive oil reduces blood brain barrier permeability, brain edema, and brain injury in rats subjected to ischemia-reperfusion

ScientificWorldJournal101801912010

20602077

10.1100/tsw.2010.128

138

Rabiei

Bigdeli

Rasoulian

Neuroprotection of dietary virgin olive oil on brain lipidomics during stroke

Curr Neurovasc Res102312372013

23713733

10.2174/15672026113109990007

139

Bayat

Azami Tameh

Hossein Ghahremani

Akbari

Mehr

Khanavi

Hassanzadeh

Neuroprotective properties of Melissa officinalis after hypoxic-ischemic injury both in vitro and in vivo

Daru20422012

23351182

10.1186/2008-2231-20-42

140

Rabiei

Rafieian-Kopaei

Neuroprotective effect of pretreatment with Lavandula officinalis ethanolic extract on blood-brain barrier permeability in a rat stroke model

Asian Pac J Trop Med7S1S421S4262014

25312161

10.1016/S1995-7645(14)60269-8

141

Cao

Maoa

Sun

Zheng

Gao

Wang

Min

Sun

Xie

Cai

Baicalin attenuates global cerebral ischemia/reperfusion injury in gerbils via anti-oxidative and anti-apoptotic pathways

Brain Res Bull853964022011

21600966

10.1016/j.brainresbull.2011.05.002

142

Han

D'Costa

Back

Parsadanian

Patel

Shah

Gidday

Srinivasan

Deshmukh

Holtzman

BDNF blocks caspase-3 activation in neonatal hypoxia-ischemia

Neurobiol Dis738532000

10671321

10.1006/nbdi.1999.0275

143

Zhang

Wang

Zhang

Sun

Zhang

Wang

A comparative study on the individual and combined effects of baicalin and jasminoidin on focal cerebral ischemia-reperfusion injury

Brain Res11231881952006

17069775

10.1016/j.brainres.2006.09.063

144

Kim

Lee

Moon

Ether fraction of methanol extracts of Gastrodia elata, medicinal herb protects against neuronal cell damage after transient global ischemia in gerbils

Phytother Res179099122003

13680822

10.1002/ptr.1246

145

Kim

Lee

Han

Lee

Kim

Hong

Kang

Gastrodia elata blume and an active component, p-hydroxybenzyl alcohol reduce focal ischemic brain injury through antioxidant related gene expressions

Biol Pharm Bull28101610202005

15930737

10.1248/bpb.28.1016

146

Joyeux

Lobstein

Anton

Mortier

Comparative antilipoperoxidant, antinecrotic and scavenging properties of terpenes and biflavones from Ginkgo and some flavonoids

Planta Med611261291995

7753918

10.1055/s-2006-958030

147

Calapai

Crupi

Firenzuoli

Marciano

Squadrito

Inferrera

Parisi

Rizzo

Crisafulli

Fiore

Caputi

Neuroprotective effects of Ginkgo biloba extract in brain ischemia are mediated by inhibition of nitric oxide synthesis

Life Sci67267326832000

11105983

10.1016/s0024-3205(00)00858-4

148

Yan

Wang

Hou

Zhou

Lithium improves the behavioral disorder in rats subjected to transient global cerebral ischemia

Behav Brain Res1772822892007

17210190

10.1016/j.bbr.2006.11.021

Figure 1

Small vs. large animal models of cerebral ischemia. BCCAO, bilateral common carotid artery occlusion; CCA, common carotid artery; BCAS, bilateral common carotid artery stenosis; 3VO, 3-vessel occlusion.

Table I

Assessment of functional neurological deficits.

Test	Use	Method	Outcome
Rotarod test	The rotarod test assesses the rodent 's motor coordination and balance, and in particular, detects abnormalities in the cerebellar function (84).	It requires putting the rodents on a cylinder, which rotates at different rates, and the time to fall is determined (85).	A significant decrease in the time the animal remains on the rod following stroke induction (86). Animal pre-training to balance on the rotarod before surgery is recommended.
Grip strength test	The grip strength test assesses the muscle force of rodents and detects any impairment in the limb strength (87).	The rodent grasps a bar or a grid attached to a force transducer to determine the strength of rodents while pulling it away (87).	Grip strength decreases significantly after stroke induction (88).
Wire hang test	As rodents tend to grasp any wire to avoid falling, the wire hang test is a cost-effective and easy method to evaluate the rodents' muscle performance.	The time that a rodent can hang, and this depends on several factors, including the weight of the rodent, its sex, muscle size, physical properties, and age (89).	In cerebral ischemia, muscle impairment is expected, and the ability to grasp the wire decreases (90). The main problem is that the recorded results are not always consistent (89).
The adhesive removal test	A sensitive technique to evaluate the rodent's sensorimotor deficiency (91).	The time to recognize the presence of adhesive tape placed on the rodent's forepaw and to remove it is recorded (91).	The prolonged time indicated a loss of sensory function.
Open field maze	The open field maze is one of the most widely used methods to investigate the rodents' behavior. It is a rapid and straight forwardmethod to evaluate the activity, both qualitatively and quantitatively (92,93).	The open field measures movements in an enclosure of varied shapes, either circular, square, or rectangular, with a surrounding fence to prevent rodents from escaping (93).	Studies have shown an increase in the crossed squares, rearing and grooming activities after ischemic stroke (148).
Water maze	The water maze method tests rodents' spatial understanding and learning (94).	The water maze test requires the placement of the rodent in a water pool, where there is a hidden platform under the water surface (94).	Memory and learning abilities are determined based on the time the rodent takes to reach the platform.
Modified neurological severity score (mNSS) points	The mNSS test (95) evaluates the motor, sensory, reflex and the beam balance on a scale from 0 to 18.		A score of 0 is normal and one of 18, is a maximal deficit.
Clark general and focal scales	The Clark scales divided into the general neurological scale and focal neurological scale (96).	The general test addresses the hair, ears, eyes, posture, spontaneous activity as well as the presence of epileptic behavior in the animals. The scores in the 6 areas are added to provide a total score ranging from 0 to 28. The focal test addresses the body and front limb symmetry, gait, climbing and circling behavior, and whisker response. The scores are added to provide a focal score ranging from 0 to 28.	The clinical score is highly correlated with the infarct volume.

Numbers in parentheses indicate relevant references.

Table II

Herbal extracts and their active ingredients used in rodent models of middle cerebral artery occlusion (MCAO).

Plant used	Doses/route	Active ingredients/action	Outcomes/results	(Refs.)
Artemisia absinthium L.	(100 mg/kg and 200 mg/kg, orally)	Antioxidant	Rat, ↓ brain oxidative stress and damage, and behavioral deficits	(97)
Eleutherococcus senticosus bark	Orally 3, 30 and 300 mg/kg twice at times of 0 and 90 min after reperfusion	Anti-inflammatory properties through the inhibition of COX-2 expression, microglia, and astrocyte expression.	Rat, vessel occlusion (4-VO)↓; hippocampal CA1 neuronal death at 300 mg/kg; ↓ COX-2, GFAP, and OX-42 in the hippocampal CA1 region	(115)
Embelia ribes Burm.	(100 and 200 mg/kg body weight; p.o.) for 30 days	Antioxidant	Rat, ↑ the grip strength activity, and GSH, GPx, GR and GST levels in hippocampus and frontal cortex; ↓ LDH levels in serum and TBARS levels in the hippocampus and frontal cortex	(113)
Erigeron breviscapus (Hand-Mazz)	i.p., 0.33 mg/kg	Breviscapine; targeting autophagy mechanisms	Rat, ↓ infarct volume, brain water content and neurofunctional deficiency	(101)
	Intraperitoneal injections of scutellarin (20 and 60 mg/kg)	Scutellarin; enhancing cellular antioxidant defense capacity	Rat, ↓ neurological deficits and brain infarct volume; ↑ endogenous antioxidant activity	(102)
Eriodictyol	Oral eriodictyol (1, 2 and 4 mg/kg) 30 min before pMCAO, 2 h after, and once daily for 5 days.	Inhibition of neuroinflammation	Rat, ↓ neuronal death, infarct area, neurological and memory deficits; ↓ MPO activity, TNF-α, iNOS, and GFAP expression	(114)
Fructus Chebulae	300 and 500 mg/kg orally	Inhibition of oxidative damages	Rat, ↓ cerebral infarct volume	(103)
Fructus Schisandrae	(10, 30 mg/kg, IP) 30 min before the onset of ischemia, and 2 h after reperfusion	Schisandrin B; inhibits Inflammation, and protects against metalloproteinase degradation.	Rat, ↓ infarct volumes; ↓ protein expression of TNF-a and IL-1b and degradation of MMP-2 and MMP-9 in ischemic hemispheres	(104)
Gastrodia elata (GE) Blume	IP 4-HBA (20 mg/kg) 1 h after MCAO	4-Hydroxybenzyl alcohol (4-HBA); antioxidant, anti-inflammatory, anti-excitotoxic, and anti-apoptotic effects	Rat, ↓ infarct volumes, motor impairments and neurological deficits; ↓ Zn²⁺-induced cell death, ROS generation, and PARP-1 induction	(116)
Ginkgo biloba	45 mg/kg injected	EGb761; activating the Akt/CREB/BDNF pathway	Rat, ↑ behavior scores; ↑ phosphorylation of AKT, CREB and BDNF in the brain	(105)
Lavandula angustifolia	Orally once/day for 3 days before ischemia and once 2 h after ischemia	Lavender oil Antioxidant	Mice, ↓ neurological deficits, infarct size, MDA levels, carbonyl, ROS ↑ antioxidant capacity	(99)
Nigella sativa seeds	400 mg/kg, per orally for 7 days	Antioxidant, free radical scavenging, and anti-inflammatory properties	Rat, ↓TBARS levels ↑ glutathione, SOD and catalase levels	(117)
Panax ginseng	IP, 10 and 20 mg kg; orally, 100 mg/kg for 7 days before MCAO; oral, (0.5, 1, 5 or 10 mg/kg), every 3 days	20(R)-ginsenoside Rg(3); downregulation of calpain I and caspase 3; through Nrf2 pathways; ginsenoside Rb1	Rat, ↓ cerebral infarct volumes; ↓ calpain I and caspase-3 mRNA; mice, ↓ acute sensorimotor deficits; ↑ induction of Nrf2-downstream targets; mice, ↓ oxidative stress	(105-107)
Polygonum cuspidatum Sieb (knotgrass)	2.5, 5, 10 mg/kg tail vein injection 15 min after occlusion	Emodin-8-O-beta-D-glucoside; antioxidative effects	Rat, ↓ neurological deficits and the cerebral infarct area; ↑antioxidative; ↓ MDA level	(118)
Astragali radix	Intragastric calycosin (7.5, 15, 30 mg/kg)	Calycosin; antioxidant	Rat, ↓ neurological deficit and infarct volume; ↓ malondialdehyde (MDA), and reactive oxygen species (ROS); ↑the activity of superoxide dismutase (SOD), catalase and glutathione peroxidase (GSH-Px); ↓ expression of 4-hydroxy-2-nonenal (4-HNE)	(119)
Pueraria radix	(25 and 50 mg/kg; intraperitoneally) 10 min before MCAO	Puerarin; inhibition of both HIF-1α and TNF-α	Rat, ↓infarct size; ↓ (HIF-1), (iNOS) and active caspase-3 protein expression; ↓ mRNA of TNF-α in ischemic regions	(120)
Scrophularia radix	2.4 g/kg-1	Regulating MAPK pathways	Mice, ↓ infarct volume, brain water content, (NO), (MDA), neurological deficits and LDH; ↑ antioxidant capacity	(121)
Salvia miltiorrhiza (Red sage) and cacao	Orally high dose (270 mg/kg) and low (27 mg/kg)	Antioxidants: Reducing the production of free radicals	Rat, ↓ ischemic cell death within the peri-infarct area; ↑ performance in routine motor and neurological tasks	(122)
Salvia miltiorrhiza (Red sage)	i.p. (15, 30 and 60 mg/kg); 30 and 60 mg/kg injected every 24 h for 5 days; i.p. 16 mg/kg	Magnesium lithospermate B; upregulation of p-Akt; vasodilation; ↓ platelet aggregation; ↓inflammation; sodium danshensu [3-(3,4-dihydroxyphenyl) lactic acid; inhibition of apoptosis by activating the PI3K/Akt pathway; tanshinones	Rat, ↓ neurological deficits; ↓ brain water content, glutamate levels, and cerebral infarct zones; rat, ↑ survival rate; ↓ infarct volume; ↓ neuronal death; ↓ number of apoptotic cells; ↑ ratio of Bcl-2/Bax; mice, 30% reduction in infarct size; improved neurological deficit	(100,123,124)
Scutellaria baicalensis (Chinese skullcap)	i.p. dose of 100 mg/kg	Baicalin; inhibits the expression of PAR-1	↑ Rat neurological function; ↓ cerebral infarct volume	(99)
Sophora flavescens Ait.	i.p. oxymatrine 120 mg/kg after MCAO	Oxymatrine; downregulation of 12/15-LOX, phospho-p38 MAPK and cPLA2	Rat; ↓ brain water content, and infarct volume; ↓ overexpression of 12/15-LOX, phospho-p38; MAPK and cPLA2	(125)
	0.5 mg kg, i.p.	Flavonoids kurarinone (45.5%) and sophoraflavone G (14.7%); inhibition of caspase-3 activation and reduction of DNA fragmentation	Rat; ↓ caspase-3 enzyme activity, and DNA fragmentation; ↓ cell apoptosis	(126)
Tripterygium wilfor0dii Hook.	Pre-treatment with TP (0.2 mg/kg) and DAHP (0.5 g/kg) by i.p. injection 0.2 mg/kg, IP 24 h before MCAO	DAHP and triptolide Activation of the PI3K/Akt/mTOR pathway and inactivation of the ERK1/2 pathway Inhibition of NF-κB activation	Rat, ↓ ischemic lesion volume, and neuronal cell death; ↓ astrocyte numbers, ↓ levels of Bax and caspase 3, ↑ NF-κB; ↑Bcl-2 expression;↑expression of PI3K, Akt, and mTOR; ↓ ERK1 and ERK2 phosphorylation (both studies) ↓ iNOS, COX-2, GFAP and NF-κB expression	(127,128)
Zizyphus jujuba and Silymarin	100, 250 and 500 mg/kg, p.o., or Silymarin (250 mg/kg, p.o.) for 3 days before MCAO	Amelioration of oxidative stress	Rat, ↓ neurological deficits, motor impairment, and cerebral infarction volume; ↓ oxidative stress	(129)

↓, decrease; ↑, increase.

Table III

Herbal extracts and their active ingredients used in other rodent models of cerebral ischemia.

Experimental model	Plant used	Dose/route	Active ingredients/actions	Outcomes/results	(Refs.)
Bilateral common carotid artery occlusion (BCAO) in rats	Araucaria bidwillii	Seven days pre-treatment with a bi-flavone fraction (BFR), 100 and 200 mg/kg	Biflavones; antioxidant	↑ Superoxide dismutase (SOD), catalase (CAT), glutathione (GSH); ↓ lipid peroxidation (LPO) in various brain regions; ↓ neurological deficit and sensory-motor function	(112)
	Camellia sinensis	Green tea extract (0.5%) orally administered	Flavanol methylxanthines, theobromine, and theophylline; increased levels of hydrogen peroxide and inhibition of lipid peroxidation products in the ipsilateral hemisphere by the ischemia/reperfusion	↑ Hydrogen peroxide, and also inhibited the increased production of lipid peroxidation products; ↓apoptosis, ↓neuronal cell death	(110,111)
	Magnolia officinalis	10 and 30 mg/kg intravenous injection	Magnolol; downregulation of p38/MAPK, CHOP, and nitrotyrosine	↓ Infarct volume; ↓ inflammatory cytokines; ↓ production of nitrotyrosine, 4-hydroxy2-nonenal (4-HNE), inducible NO synthase (iNOS), various phosphorylated p38 mitogen-activated protein kinases, and different C/EBP homologs; ↓reactive oxygen species; ↑ expression of p-Akt and (NF-κB)	(130)
Global and focal cerebral ischemia/ reperfusion in rats and mice	Panax ginseng	In vivo Re (5, 10 or 20 mg kg 21, oral for 7 days, once a day) before occlusion	Ginsenoside	↓ MDA level AND mitochondrial swelling	(108)
	Momordica charantia	50, 100, 200 mg/kg at 30 min before cerebral ischemia, or 100 or 200 mg/kg, 30 min after cerebral ischemia	M. charantia polysaccharide (MCP); inhibiting oxidative stress	↓ NO, O2, ONOO and lipid peroxidation; ↓ activation of JNK3/c-Jun/Fas-L and JNK3/cytochrome c/caspase-3; signaling cascades in ischemic brains	(131)
	Ocimum basilicum	100 and 200 mg/kg	3,7-dimethyl-1,6-octadien-3-ol (linalool; 3.94 mg/g), 1-methoxy-4-(2-propenyl) benzene (estragole; 2.03 mg/g), methyl cinnamate (1.28 mg/g), 4-allyl-2-methoxyphenol (eugenol; 0.896 mg/g), and 1, 8-cineole (0.288 mg/g); anticonvulsant, anti-inflammatory, and neurodegenerative; restoration of endogenous antioxidants; elevated brain glutathione content	↓ Infarct size and lipid peroxidation	(132-134)
	Ocimum sanctum	Orally in doses of 200 mg/kg/day	Methanolic extract of OS leaves; anti-inflammatory, antioxidant, immunomodulatory and anti-stress properties	↑ SOD activity; prevented the rise in methane dicarboxylic aldehyde (MDA) levels	(135)
	O. europaea (olive oil)	Virgin olive oil consumption at 0.75 ml/kg/day	Monounsaturated fatty acids and polyphenols; oral low-dose (2.5 mg/kg of body weight) of hydroxytyrosol and a high-dose (10 mg/kg of body weight)	↓ Infarct volume, brain edema; ↑brain cerebroside levels	(136-138)
Spinal cord ischemia/reperfusion (I/R) injury in rats.	Salvia miltiorrhiza (red sage)	1, 10, or 50 mg/kg	Salvianolic acid B; ERK activation	↓ Spinal cord edema and infarct volume; ↑ motor function of the hind limbs; ↓ generation of oxidative products; ↑ antioxidant defense activities	(109)
Transient hippocampal ischemia in rats	Melissa officinalis (lemon balm)	100 µg/ml orally	Melissa oil; inhibition of HIF-1α and oxidative stress, followed by the inhibition of apoptosis	↓ Caspase-3 activity and malondialdehyde level; ↑ antioxidant capacity in the hippocampus; ↓ HIF-1α gene expression	(139)
Transient focal cerebral ischemia in mice	Lavandula ofﬁcinalis	200 mg of lavender ofﬁcinalis	Linalool-octanone, camphor, Caryophyllene, terpinen-4-ol, and flavonoids; decrease neurological deficit scores, infarct size, the levels of MDA, carbonyl and ROS, and attenuate neuronal damage, upregulated SOD, CAT, GSH-Px activities, and GSH/GSSG ratio	↓ Neurological deﬁcit scores, infarct size, MDA, carbonyl and ROS, ↓ neuronal damage, antioxidant effects	(98,140)
Transient global ischemia in gerbils	Baicalin and Jasminoidin	Baicalin and jasminoidin, or nimodipine) were intravenously treated	Baicalin and jasminoidin; reduce neuronal damage in Gerbils hippocampus; lower MDA content, higher SOD, GSH, and GSH-PX activities	↓ Infarction area; ↓ lipid peroxidation; ↓ caspase-3	(141-143)
	Gastrodia elata		Free radical scavenging and antioxidant activity; increased expression of antioxidant genes	Protection of hippocampal neurons; ↓ infarct size in cortex and striatum	(144,145)
	Ginkgo biloba L.	Ginkgo biloba extract (37,5-150 mg/kg) orally	Ginkgo-flavone glycosides and terpenoids; antioxidant and free radical scavenging effects; decrease neurons against oxidative stress; decrease neuronal injury	Pre-treatment with G. biloba extract improved blood flow and reduced edema in the hippocampal region in a dose-dependent manner	(146,147)

↓, decrease; ↑, increase.