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. 2015 Feb 11;6(1):47–58. doi: 10.1515/tnsci-2015-0006

Treatment of acute cerebral ischemia using animal models: a meta-analysis

Peng-Fei Wang 1, Yu Zhou 1, Huang Fang 1, Sen Lin 2, Yan-Chun Wang 1, Yong Liu 1, Jun Xia 3, Guy D Eslick 4, Qing-Wu Yang 1,*
PMCID: PMC4936615  PMID: 28123790

Abstract

Background

There are numerous potential treatments assessed for acute cerebral ischemia using animal models. This study aimed to assess the effect of these treatments in terms of infarct size and neurobehavioral change. This meta-analysis was conducted to determine if any of these treatments provide a superior benefit so that they might be used on humans.

Methods

A systematic search was conducted using several electronic databases for controlled animal studies using only nonsurgical interventions for acute cerebral ischemia. A random-effects model was used.

Results

After an extensive literature search, 145 studies were included in the analysis. These studies included 1408 treated animals and 1362 control animals. Treatments that had the most significant effect on neurobehavioral scales included insulin, various antagonists, including N-methyl-D-aspartate (NMDA) receptor antagonist ACEA1021, calmodulin antagonist DY-9760e, and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist YM872, and antiviral agents. Treatments providing the greatest effect on infarct size included statins, sphingosine-1-phosphate agonist (fingolimod), alcohol, angiotensin, and leukotrienes. Treatments offering the greatest reduction in brain water content included various agonists, including sphingosine-1-phosphate agonist fingolimod, statins, and peroxisome proliferator-activated receptor gamma (PPAR-γ). Treatment groups with more than one study all had high heterogeneity (I2 > 80%), however, using meta-regression we determined several sources of heterogeneity including sample size of the treatment and control groups, the occlusion time, but not the year when the study was conducted.

Conclusions

Some treatments stand out when compared to others for acute cerebral ischemia in animals. Greater replication of treatment studies is required before any treatments are selected for future human trials.

Keywords: Acute cerebral ischemia, Animal studies, Brain water content, Infarct size, Meta-analysis, Neurobehavioral scales

Introduction

Acute cerebral ischemia is a substantial cause of morbidity and mortality among humans [1, 2]. The majority of these ischemic events occur in the middle cerebral artery. However, there are many clinical variations associated with the presentation and management of this important vascular disease. Treatment options and outcomes among humans vary widely with no single therapy available providing optimal outcomes [3].

There are numerous experimental animal models aimed at determining a novel treatment for acute cerebral ischemia [4, 5]. These laboratory-based studies are conducted under strict control conditions. The number of these types of studies have increased over the last decade [6]. Much of the information available on the pathophysiological mechanisms associated with focal cerebral ischemia was provided by animal models [6–9].

Currently, none of the hundreds of treatment options found from animal studies has been reported to be effective in a phase III human clinical trial [10]. A greater sense of urgency is required to isolate and replicate novel treatments for acute cerebral ischemia in animals, so that these agents may undergo randomized clinical trials among human patients [11–13]. There have been several meta-analysis of animal studies focused on specific treatment options for intracerebral hemorrhage and stroke [14].

The objectives of the present study were to:

  • Systematically review the collated the experimental evidence for various treatments for acute cerebral ischemia in animal models;

  • Determine if there was a treatment that was clearly superior in improving (a) the neurobehavioral outcomes; (b) infarct size; and (c) brain water content.

Methods

Study protocol

The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines were followed, where possible, in performing this systematic review [15]. A systematic search through MEDLINE (from 1950), PubMed (from 1946), EMBASE (from 1949), and Google Scholar to October 18, 2013 was performed. The search terms included combinations of ‘acute cerebral ischemia’ or ‘acute ischemic stroke’ or ‘brain ischemia’ or ‘carotid artery thrombosis’ or ‘stroke’ or ‘cerebrovascular disorders’ or ‘intracranial arterial diseases’ or ‘cerebral artery diseases’ and ‘animal model’ which were searched as text word and with the ‘explode’ feature of medical subject headings (MeSH) turned on where possible, resulting in greater number of records retrieved. Only studies published in English were included. The reference lists of relevant articles were also searched for relevant studies. A search for unpublished literature was not performed.

Study selection

Studies that met the following inclusion criteria were used: 1. Only ischemic stroke was included (not haemorrhagic), 2. Animal studies only, 3. There had to be a control group, 4. A nonsurgical intervention was used, 5. The middle cerebral artery (MCA) was used for occlusion, 5. Determined infarct size either as volume (mm3) or as percentage (%) for both treatment and control groups, 6. Determined neurobehavioral scores for both treatment and control groups, and 7. Determined brain-water content for both treatment and control groups.

Outcomes assessed

Three outcomes were to be assessed from these studies with one primary and two secondary outcomes. The primary outcome was neurobehavioral score and the secondary outcomes were (1) reduction in brain-water content and (2) the size of the infarct.

Data extraction

The data extraction was performed using a standardized data extraction form, collecting information on the publication year, sample size for treatment and control groups, country, animal type, statistical methods, occlusion time (mins), treatment, experimental time (days), neurobehavioral scores for treatment and control groups, infarct size for treatment and control groups, and brain-water content for treatment and control groups.

Quality assessment

No quality assessment was undertaken for these studies as none of them were randomized trials. The studies were comparative in nature and did not involve any forms of randomization, blinding or allocation concealment. Thus, we thought that quality assessment would be too subjective for animal studies designed in such a way.

Statistical analysis

Meta-analysis

The studies compared the treatment group with the control group. The control group was either labeled as a control or sham. The primary outcomes assessed were neurobehavioral scores, with secondary outcomes (structural measures) either infarct volume or brain water content. Treatment and control groups were compared using a standard difference in means (std diff mean) for infarct volumes, neurobehavioral scores, and brain-water content using a random effects model [16].

Assessment of heterogeneity

Heterogeneity was tested using the I2 statistic, which represents the percentage of the total variability across studies which are due to heterogeneity [17]. I2 values of 25, 50 and 75% corresponded to low, moderate and high degrees of heterogeneity, respectively.

Meta-regression

A mixed-effects meta-regression model was used for the meta-regression analysis. Meta-regression was conducted to assess if we could identify any potential causes for any heterogeneity that may be present. The main factors analyzed using meta-regression were sample size of the treatment group, sample size of the control group, the occlusion time, and the year of publication for neurobehavioral score, infarct volume and brain water content.

Publication bias

The publication bias was quantified using the Egger’s regression model [18], with the effect of bias assessed using the fail-safe number method. The fail-safe number was the number of studies that would need to be missed for the observed result to be nullified to statistical non-significance at the p < 0.05 level [19]. Publication bias is generally regarded as a concern if the fail-safe number is less than 5n+10, with n being the number of studies included in the meta-analysis. All analyses were performed with Comprehensive Meta-Analysis software (version 2.0, 2005), Englewood, NJ, USA.

Results

Search strategy

From 23053 studies initially identified, 145 met the inclusion criteria (Fig. 1) [20–160]. Studies were excluded for the following reasons: no control group, abstract only, no data, hypothermia studies, genetic study, inappropriate study design, neonates, global ischemia, duplicates, language, radiology study, and cell-based studies.

Figure 1.

Figure 1

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Flowchart of the literature search strategy.

Study characteristics

The majority of the studies used rats as the animal model (n = 125, 89%), followed by mice (n = 13, 9%), with the remaining studies used cats, dogs, rabbits, and gerbils. The median number of treated/control animals used in each outcome group was: infarct (10 vs. 10; range 3 – 83 vs. 3 – 78), neurobehavioral score (10 vs. 10; range 3 – 83 vs. 3 – 78), and brain water content (8.5 vs. 8.5; range 3 – 24 vs. 3 – 24).

Neurobehavioral outcome

There were 85 studies assessing neurobehavioral outcomes across 41 different treatments. The sample size of the neurobehavioral outcome studies was (treatment, n = 1026 vs. control, n = 991), with the median number in each study equal to ten in both treatment (range: 3 – 83) and control groups (range: 3 – 78).

The overall effect of all the treatments on neurobehavioral scores was (std diff mean −0.68). For all the studies, including those with (n = 1) the treatments which provided the greatest impact on neurobehavioral scores were insulin (std diff mean −11.20), various antagonists, including N-methyl-D-aspartate (NMDA) receptor antagonist ACEA1021, calmodulin antagonist DY-9760e, and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist YM872, (std diff mean −4.00), antiviral agents (std diff mean −3.30), peroxisome proliferator-activated receptor gamma (PPAR-γ) (std diff mean −3.18) and angiotensin (std diff mean −2.50) (Fig. 2). Interestingly, over two-thirds of treatment groups (73%) showed an improved neurobehavioral score compared with control groups.

Figure 2.

Figure 2

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Treatment studies assessed for neurobehavioral outcomes.

For groups with more than 2 studies, the overall effect of all the treatments on neurobehavioral scores was (std diff mean –1.07). In this sub-group analysis, the treatments which provided the greatest effect on neurobehavioral scores were insulin (std diff mean −11.20), PPAR-γ (std diff mean −3.18), various inhibitors (dipyridamole - inhibitor of cGMP phosphodiesterase and of cellular reuptake of adenosine into platelets, red blood cells and endothelial cells, SNJ-1945 - inhibitor of calpain, N(G)-nitro-L-arginine methyl ester (L-NAME) - inhibitor of nitric oxide synthase, riluzole - inhibitor of NMDA and 2-(aminomethyl)phenylacetic acid/ kainate, AMPA/kainate, receptors) (std diff mean −1.46), erythropoietin (std diff mean −1.45), and hyperbaric oxygen (std diff mean −1.30) (Fig. 3).

Figure 3.

Figure 3

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Treatment groups with two or more studies assessed for neurobehavioral outcomes.

There were differences in the scoring systems used to determine the change in neurobehavioral outcomes. The most commonly used neurobehavioral scoring systems were those of Bederson (n = 23) and Longa (n = 12), with 21 different scoring systems used across all studies.

Neurobehavioral scores differed across different geographical regions with the most significant improvement in neurobehavioral scores found in Australia (std diff mean −1.70), Middle East (std diff mean −1.41), North America (std diff mean −0.91), Asia (std diff mean −0.60) and Europe (std diff mean −0.48).

There was no publication bias present for the studies assessing neurobehavioral outcomes (p = 0.65).

Infarct size

There were 102 studies that determined infarct size across 46 different treatments. The sample size of the infarct studies was (treatment, n = 1369 vs. control, n = 1323), with the median number in each study equal to ten in both treatment (range: 3 – 83) and control groups (range: 3 – 78).

Overall, the effect of treatment on infarct size was (std diff mean −2.06). For all studies, including those with (n = 1), the treatments that reduced infarct size the most were statins (std diff mean −27.61), variuos agonists, including sphingosine-1-phosphate agonist fingolimod (std diff mean −18.34), alcohol (std diff mean −17.32), angiotensin (std diff mean −15.80), and leukotrienes (std diff mean −15.45) (Fig. 4). Nearly all studies (93%) showed a decrease in infarct size when compared to control groups.

Figure 4.

Figure 4

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Treatment studies comparing infarct size.

For groups with more than 2 studies the overall effect of all the treatments on infarct size was (std diff mean −1.38). For groups of treatments with more than two studies those that reduced infarct size the most were statins (std diff mean −27.61), alcohol (std diff mean −17.32), angiotensin (std diff mean −15.80), anticonvulsants (std diff mean −11.35), and various antagonists, including NMDA receptor antagonist ACEA1021, calmodulin antagonist DY-9760e, and AMPA receptor antagonist YM872 (std diff mean −11.18) (Fig. 5).

Figure 5.

Figure 5

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Treatment groups with two or more studies comparing infarct size.

Differences could also be observed in the infarct size by volume (mm3) (std diff mean −4.78) compared to percent infarct (std diff mean −1.89). There were also differences by the type of animal with rats (n = 85; std diff mean −3.50), cats (n = 4; std diff mean −2.97), mice (n = 10; std diff mean −1.61), dogs (n = 1; std diff mean −1.56), and gerbils (n = 2; std diff mean +4.28). In the rat only studies the most significant effect occurred for statins (std diff mean −27.61), alcohol (std diff mean −17.32), angiotensin (std diff mean −15.80), leukotrienes (std diff mean −15.45), and trimetazidine (inhibits beta-oxidation of fatty acids by blocking long-chain 3-ketoacyl-CoA thiolase) (std diff mean −15.18).

Infarct size varied by geographical regions with the most significant decrease in infarct size reported in Asia (std diff mean −4.49), Australia (std diff mean −4.68), Europe (std diff mean −3.21), and North America (std diff mean −2.61).

There was publication bias present for the studies assessing infarct size (p < 0.001), and the fail-safe number was greater than 1000 (studies).

Brain water content

There were 15 studies that assessed brain water content for 13 different treatments. The sample size of the brain water content (treatment, n = 137 vs. control, n = 137), with the median number in each study equal to 8.5 in both treatment and control groups (range: 3 – 24).

The overall effect on brain water content was (std diff mean −1.44). Brain water content was most significantly reduced using various agonists, including sphingosine-1-phosphate agonist fingolimod (std diff mean −8.00), statins (std diff mean −5.00), PPAR-γ (std diff mean −4.29), various plants (std diff mean −3.22), and nonsteroidal anti-inflammatory drugs (NSAIDs) (std diff mean −2.50). All these groups contained only a single study except for plants which had four studies (Fig. 6). The majority of studies (85%) showed a reduction in brain water content. There was publication bias present for the studies assessing brain water content (p = 0.03). The fail-safe number was greater than 500 (studies).

Figure 6.

Figure 6

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Treatment groups comparing the effects of brain water content.

Discussion

In this work, we presented the results of the comprehensive meta-analysis of 145 controlled animal studies, assessing 46 different treatments using 21 different neurobehavioral scales in 2692 animals. Overall, there were ten treatment groups that provided the greatest effect to the three neurological outcome groups (neurobehavioral, infarct size, brain water content). These treatment groups included insulin, various antagonists, including NMDA receptor antagonist ACEA1021, calmodulin antagonist DY-9760e, and AMPA receptor antagonist YM872, antiviral agents, statins, various agonists, including sphingosine-1-phosphate agonist fingolimod, alcohol, plants, angiotensin, leukotrienes, and PPAR-γ [32, 73, 89, 92, 115, 159].

Some treatments offered substantial improvements across multiple outcome groups (neurobehavioral outcomes, infarct size and brain water content). For treatment responses that included all studies, even those with a single study within the treatment group, angiotensin showed improved outcomes in the neurobehavioral and ischemic groups. Statins and various agonists, including sphingosine-1-phosphate agonist fingolimod, had improved outcomes in both ischemia size and brain water content groups, while PPAR-γ showed improved outcomes in the neurobehavioral and brain water content groups. There was no overlap among treatment groups that contained two or more studies with insulin, PPAR-γ, various inhibitors (dipyridamole, SNJ-1945, L-NAME, riluzole), erythropoietin, and hyperbaric oxygen, showing the greatest effects for neurobehavioral outcomes. Moreover, for the ischemic size the main treatments with two or more studies having an effect were statins, alcohol, angiotensin, anticonvulsants, and various antagonists, including NMDA receptor antagonist ACEA1021, calmodulin antagonist DY-9760e, and AMPA receptor antagonist YM872. There was only one treatment group in the brain water content outcome that had more than two studies, that was the plant group.

Further research should be conducted into these treatments as potential options for the management of acute cerebral ischemia among humans. Additional mechanistic evidence is required for these potential treatments [161, 162]. For example, recent human studies have reported that statins improve 2-year survival and 2-year functional outcome [163–165]. These data require replication in other populations and long-term follow-up to assess outcomes in these patients.

This study had a number of strengths. The PRISMA guidelines were followed, although no specific guidelines were followed for meta-analysis of animal studies. A thorough search was performed using multiple databases and we imposed no word restrictions. However, studies that did not include a control group were excluded. The use of an internal control group is recognized as a more statistically robust way of study design. There were also some limitations to this study. The majority of treatment comparisons involved only single studies, of which very few studies had been replicated, thus providing limited comparative data. However, there were some treatments which had two or more studies and these have also been reported and should be reproduced. Those treatments which contained more than one study usually had high levels of heterogeneity and we elucidated some potential causes for this heterogeneity, including sample size of the treatment and control groups and the occlusion time. The year of publication was not a reason for heterogeneity. The statistical power of these studies was also limited. Publication bias was present for infarct size and brain water content comparisons. However, due to the comprehensive literature search strategy undertaken it is extremely unlikely that we missed hundreds of studies based on the fail-safe number.

The following are some recommendations to improve the outcome data provided by these studies. Future studies for individual treatments should be replicated several times in order to provide more robust data. Studies should contain larger sample sizes in order to improve statistical power and the ability to detect small differences between treatment and control groups. Utilization of validated instruments used to assess neurobehavioral outcomes should be implemented and these should be limited to those used in studies more frequently. Standardization of the experimental protocol should also be undertaken to reduce potential bias and improve study quality.

In summary, this meta-analysis provides evidence that certain treatments improve neurobehavioral outcomes, infarct size and brain water content in animals. Future studies should aim to replicate the pathophysiological mechanisms reported in humans. Animal studies need to be substantially improved before treatments for acute cerebral ischemia can be translated into human randomized clinical trials.

Acknowledgment

Conflicts of interest statement: The authors declare no conflict of interest.

References

  • 1.Rosamond WD, Folsom AR, Chambless LE, Wang C-H, McGovern PG, Howard G, et al. Stroke incidence and survival among middle-aged adults: 9-year follow-up of the atherosclerosis risk in communities (ARIC) cohort. Stroke. 1999;30:736–743. doi: 10.1161/01.str.30.4.736. [DOI] [PubMed] [Google Scholar]
  • 2.Feigin VL, Lawes CMM, Bennett DA, Anderson CS. Stroke epidemiology: a review of population-based studies of incidence, prevalence, and case-fatality in the late 20th century. Lancet Neurol. 2003;2:43–53. doi: 10.1016/s1474-4422(03)00266-7. [DOI] [PubMed] [Google Scholar]
  • 3.Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. 2002;324:71–86. doi: 10.1136/bmj.324.7329.71. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Perel P, Roberts I, Sena E, Wheble P, Briscoe C, Sandercock P, et al. Comparison of treatment effects between animal experiments and clinical trials: systematic review. BMJ. 2007;334:197. doi: 10.1136/bmj.39048.407928.BE. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Fisher M, Feuerstein G, Howells DW, Hurn PD, Kent TA, Savitz SI, et al. Update of the stroke therapy academic industry roundtable preclinical recommendations. Stroke. 2009;40:2244–2250. doi: 10.1161/STROKEAHA.108.541128. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Hossmann K-A. The two pathophysiologies of focal brain ischemia: implications for translational stroke research. J Cereb Blood Flow Metab. 2012;32:1310–1316. doi: 10.1038/jcbfm.2011.186. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Shah K, Abbruscato T. The role of blood-brain barrier transporters in pathophysiology and pharmacotherapy of stroke. Curr Pharm Des. 2013;20:1510–1522. doi: 10.2174/13816128113199990465. [DOI] [PubMed] [Google Scholar]
  • 8.Durukan A, Strbian D, Tatlisumak T. Rodent models of ischemic stroke: a useful tool for stroke drug development. Curr Pharm Des. 2008;14:359–370. doi: 10.2174/138161208783497688. [DOI] [PubMed] [Google Scholar]
  • 9.Durukan A, Tatlisumak T. Acute ischemic stroke: overview of major experimental rodent models, pathophysiology, and therapy of focal cerebral ischemia. Pharmacol Biochem Behav. 2007;87:179–197. doi: 10.1016/j.pbb.2007.04.015. [DOI] [PubMed] [Google Scholar]
  • 10.Shuaib A, Lees KR, Lyden P, Grotta J, Davalos A, Davis SM, et al. NXY-059 for the treatment of acute ischemic stroke. New Engl J Med. 2007;357:562–571. doi: 10.1056/NEJMoa070240. [DOI] [PubMed] [Google Scholar]
  • 11.Brewer L, Horgan F, Hickey A, Williams D. Stroke rehabilitation: recent advances and future therapies. QJM. 2013;106:11–25. doi: 10.1093/qjmed/hcs174. [DOI] [PubMed] [Google Scholar]
  • 12.Ovbiagele B, Goldstein LB, Higashida RT, Howard VJ, Johnston SC, Khavjou OA, et al. Forecasting the future of stroke in the United States: a policy statement from the American Heart Association and American Stroke Association. Stroke. 2013;44:2361–2375. doi: 10.1161/STR.0b013e31829734f2. [DOI] [PubMed] [Google Scholar]
  • 13.Fisher M, Vasilevko V, Cribbs D. Mixed cerebrovascular disease and the future of stroke prevention. Transl Stroke Res. 2012;3(Suppl 1):39–51. doi: 10.1007/s12975-012-0185-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Frantzias J, Sena ES, Macleod MR, Salman RA-S. Treatment of intracerebral hemorrhage in animal models: meta-analysis. Ann Neurol. 2011;69:389–399. doi: 10.1002/ana.22243. [DOI] [PubMed] [Google Scholar]
  • 15.Moher D, Liberati A, Tetzlaff J, Altman DG PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med. 2009;151:264–269. W64. doi: 10.7326/0003-4819-151-4-200908180-00135. [DOI] [PubMed] [Google Scholar]
  • 16.DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177–188. doi: 10.1016/0197-2456(86)90046-2. [DOI] [PubMed] [Google Scholar]
  • 17.Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327:557–560. doi: 10.1136/bmj.327.7414.557. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315:629–634. doi: 10.1136/bmj.315.7109.629. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Orwin RG. A fail-safe N for effect size in meta-analysis. J Educ Stat. 1983;8:157–159. [Google Scholar]
  • 20.Aggarwal R, Medhi B, Pathak A, Dhawan V, Chakrabarti A. Neuroprotective effect of progesterone on acute phase changes induced by partial global cerebral ischaemia in mice. J Pharm Pharmacol. 2008;60:731–737. doi: 10.1211/jpp.60.6.0008. [DOI] [PubMed] [Google Scholar]
  • 21.Airavaara M, Shen H, Kuo C-C, Peranen J, Saarma M, Hoffer B, et al. Mesencephalic astrocyte-derived neurotrophic factor reduces ischemic brain injury and promotes behavioral recovery in rats. J Comp Neurol. 2009;515:116–124. doi: 10.1002/cne.22039. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Aronowski J, Strong R, Shirzadi A, Grotta JC. Ethanol plus caffeine (caffeinol) for treatment of ischemic stroke: preclinical experience. Stroke. 2003;34:1246–1251. doi: 10.1161/01.STR.0000068170.80517.B3. [DOI] [PubMed] [Google Scholar]
  • 23.Belayev L, Khoutorova L, Zhao W, Vigdorchik A, Belayev A, Busto R, et al. Neuroprotective effect of darbepoetin alfa, a novel recombinant erythropoietic protein, in focal cerebral ischemia in rats. Stroke. 2005;36:1065–1070. doi: 10.1161/01.STR.0000160753.36093.da. [DOI] [PubMed] [Google Scholar]
  • 24.Black KL, Weidler DJ, Jallad NS, Sodeman TM, Abrams GD. Delayed pentobarbital therapy of acute focal cerebral ischemia. Stroke. 1978;9:245–249. doi: 10.1161/01.str.9.3.245. [DOI] [PubMed] [Google Scholar]
  • 25.Callaway JK, Knight MJ, Watkins DJ, Beart PM, Jarrott B. Delayed treatment with AM-36, a novel neuroprotective agent, reduces neuronal damage after endothelin-1-induced middle cerebral artery occlusion in conscious rats. Stroke. 1999;30:2704–2712. doi: 10.1161/01.str.30.12.2704. [DOI] [PubMed] [Google Scholar]
  • 26.Caso JR, Moro MA, Lorenzo P, Lizasoain I, Leza JC. Involvement of IL-1 beta in acute stress-induced worsening of cerebral ischaemia in rats. Eur Neuropsychopharmacol. 2007;17:600–607. doi: 10.1016/j.euroneuro.2007.02.009. [DOI] [PubMed] [Google Scholar]
  • 27.Chabrier PE, Auguet M, Spinnewyn B, Auvin S, Cornet S, Demerle-Pallardy C, et al. BN 80933, a dual inhibitor of neuronal nitric oxide synthase and lipid peroxidation: a promising neuroprotective strategy. Proc Natl Acad Sci USA. 1999;96:10824–10829. doi: 10.1073/pnas.96.19.10824. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Chao XD, Zhou J, Chen T, Liu WB, Dong WP, Qu Y, et al. Neuroprotective effect of osthole against acute ischemic stroke on middle cerebral ischemia occlusion in rats. Brain Res. 2010;1363:206–211. doi: 10.1016/j.brainres.2010.09.052. [DOI] [PubMed] [Google Scholar]
  • 29.Chen Z, Che J, Hou Y, Cheng Y, Lin PT. The extract of inflamed rabbit skin induced by inoculation of vaccinia virus possesses antioxidant and neuroprotective effects in acute ischemic stroke. J Stroke Cerebrovasc Dis. 2009;18:475–481. doi: 10.1016/j.jstrokecerebrovasdis.2009.06.006. [DOI] [PubMed] [Google Scholar]
  • 30.Cho J, Lee H-K. Wogonin inhibits ischemic brain injury in a rat model of permanent middle cerebral artery occlusion. Biol Pharm Bull. 2004;27:1561–1564. doi: 10.1248/bpb.27.1561. [DOI] [PubMed] [Google Scholar]
  • 31.Clark DL, Penner M, Orellana-Jordan IM, Colbourne F. Comparison of 12, 24 and 48 h of systemic hypothermia on outcome after permanent focal ischemia in rat. Exp Neurol. 2008;212:386–392. doi: 10.1016/j.expneurol.2008.04.016. [DOI] [PubMed] [Google Scholar]
  • 32.Cui LL, Zhang XJ, Yang R, Wang LN, Liu LL, Li M, et al. Neuroprotection of early and short-time applying atorvastatin in the acute phase of cerebral ischemia: down-regulated 12/15-LOX, p38MAPK and cPLA2 expression, ameliorated BBB permeability. Brain Res. 2010;1325:164–173. doi: 10.1016/j.brainres.2010.02.036. [DOI] [PubMed] [Google Scholar]
  • 33.Dhote V, Balaraman R. Effect of trimetazicline on acute cerebral ischemia/reperfusion injury induced by middle cerebral artery occlusion in rat forebrain. Indian J Pharmacol. 2007;39:62. [Google Scholar]
  • 34.Elewa HF, Kozak A, El-Remessy AB, Frye RF, Johnson MH, Ergul A, et al. Early atorvastatin reduces hemorrhage after acute cerebral ischemia in diabetic rats. J Pharmacol Exp Ther. 2009;330:532–540. doi: 10.1124/jpet.108.146951. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Esneault E, Castagne V, Moser P, Bonny C, Bernalidin M. D-JNKi, a peptide inhibitor of c-Jun N-terminal kinase, promotes functional recovery after transient focal cerebral ischemia in rats. Neuroscience. 2008;152:308–320. doi: 10.1016/j.neuroscience.2007.12.036. [DOI] [PubMed] [Google Scholar]
  • 36.Fang SY, Tseng CC, Yang YL, Lee EJ, Chen HY, Bhardwaj A, et al. Nitric oxide scavenger carboxy-PTIO reduces infarct volume following permanent focal ischemia. Acta Anaesthesiol Taiwan. 2006;44:141–146. [PubMed] [Google Scholar]
  • 37.Faure S, Chapot R, Tallet D, Javellaud J, Achard JM, Oudart N. Cerebroprotective effect of angiotensin IV in experimental ischemic stroke in the rat mediated by AT(4) receptors. J Physiol Pharmacol. 2006;57:329–342. [PubMed] [Google Scholar]
  • 38.Faure S, Oudart N, Javellaud J, Fournier A, Warnock DG, Achard JM. Synergistic protective effects of erythropoietin and olmesartan on ischemic stroke survival and post-stroke memory dysfunctions in the gerbil. J Hypertens. 2006;24:2255–2261. doi: 10.1097/01.hjh.0000249704.34607.4c. [DOI] [PubMed] [Google Scholar]
  • 39.Gao M, Liu R, Zhu SY, Du GH. Acute neurovascular unit protective action of pinocembrin against permanent cerebral ischemia in rats. J Asian Nat Prod Res. 2008;10:551–558. doi: 10.1080/10286020801966955. [DOI] [PubMed] [Google Scholar]
  • 40.Garcia-Bonilla L, Sosti V, Campos M, Penalba A, Boada C, Sumalla M, et al. Effects of acute post-treatment with dipyridamole in a rat model of focal cerebral ischemia. Brain Res. 2011;1373:211–220. doi: 10.1016/j.brainres.2010.12.005. [DOI] [PubMed] [Google Scholar]
  • 41.Goericke SL, Engelhorn T, Forsting M, Speck U, Maderwald S, Ladd ME, et al. Intrathecal corticoids in permanent focal cerebral ischemia in rats. Part I: a new therapeutic approach in the acute phase. J Cereb Blood Flow Metab. 2010;30:801–807. doi: 10.1038/jcbfm.2009.243. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Guan W, Kozak A, El-Remessy AB, Johnson MH, Pillai BA, Fagan SC. Acute treatment with candesartan reduces early injury after permanent middle cerebral artery ccclusion. Transl Stroke Res. 2011;2:179–185. doi: 10.1007/s12975-010-0061-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.Harukuni I, Bhardwaj A, Shaivitz AB, DeVries AC, London ED, Hurn PD, et al. σ1-receptor ligand 4-phenyl-1-(4-phenylbutyl)-piperidine affords neuroprotection from focal ischemia with prolonged reperfusion. Stroke. 2000;31:976–982. doi: 10.1161/01.str.31.4.976. [DOI] [PubMed] [Google Scholar]
  • 44.He Z, Ibayashi S, Nagao T, Fujii K, Sadoshima S, Fujishima M. L-arginine ameliorates cerebral blood flow and metabolism and decreases infarct volume in rats with cerebral ischemia. Brain Res. 1995;699:208–213. doi: 10.1016/0006-8993(95)00907-8. [DOI] [PubMed] [Google Scholar]
  • 45.Hoang S, Liauw J, Choi M, Guzman RG, Steinberg GK. Netrin-4 enhances angiogenesis and neurologic outcome after cerebral ischemia. J Cereb Blood Flow Metab. 2009;29:385–397. doi: 10.1038/jcbfm.2008.128. [DOI] [PubMed] [Google Scholar]
  • 46.Horsburgh K, McCulloch J, Nilsen M, McCracken E, Large C, Roses AD, et al. Intraventricular infusion of apolipoprotein E ameliorates acute neuronal damage after global cerebral ischemia in mice. J Cereb Blood Flow Metab. 2000;20:458–462. doi: 10.1097/00004647-200003000-00003. [DOI] [PubMed] [Google Scholar]
  • 47.Hosomi N, Ban CR, Naya T, Takahashi T, Guo P, Song XY, et al. Tumor necrosis factor-alpha neutralization reduced cerebral edema through inhibition of matrix metalloproteinase production after transient focal cerebral ischemia. J Cereb Blood Flow Metab. 2005;25:959–967. doi: 10.1038/sj.jcbfm.9600086. [DOI] [PubMed] [Google Scholar]
  • 48.Hosomi N, Nishiyama A, Ban CR, Naya T, Takahashi T, Kohno M, et al. Angiotensin type 1 receptor blockage improves ischemic injury following transient focal cerebral ischemia. Neuroscience. 2005;134:225–231. doi: 10.1016/j.neuroscience.2005.03.054. [DOI] [PubMed] [Google Scholar]
  • 49.Huh PW, Belayev L, Zhao W, Koch S, Busto R, Ginsberg MD. Comparative neuroprotective efficacy of prolonged moderate intraischemic and postischemic hypothermia in focal cerebral ischemia. J Neurosurg. 2000;92:91–99. doi: 10.3171/jns.2000.92.1.0091. [DOI] [PubMed] [Google Scholar]
  • 50.Jiang N, Kowaluk EA, Lee C-H, Mazdiyasni H, Chopp M. Adenosine kinase inhibition protects brain against transient focal ischemia in rats. Eur J Pharmacol. 1997;320:131–137. doi: 10.1016/s0014-2999(96)00905-3. [DOI] [PubMed] [Google Scholar]
  • 51.Kashiwagi F, Katayama Y, Shimizu J, Kamiya T, Terashi A. Effect of a new hyperosmotic agent NIK-242 injection, on brain water content, metabolites and cerebral blood flow in cerebral ischemia in the spontaneously hypertensive rat. Jpn Circ J. 1991;55:1246–1251. doi: 10.1253/jcj.55.1246. [DOI] [PubMed] [Google Scholar]
  • 52.Kawai H, Yuki S, Sugimoto J, Tamao Y. Effects of a thrombin inhibitor, argatroban, on ischemic brain damage in the rat distal middle cerebral artery occlusion model. J Pharmacol Exp Ther. 1996;278:780–785. [PubMed] [Google Scholar]
  • 53.Kawamura S, Yasui N, Shirasawa M, Fukasawa H. Therapeutic effects of hyperbaric oxygenation on acute focal cerebral ischemia in rats. Surg Neurol. 1990;34:101–106. doi: 10.1016/0090-3019(90)90104-w. [DOI] [PubMed] [Google Scholar]
  • 54.Kawamura S, Yasui N, Shirasawa M, Fukasawa H. Effects of a Ca2+ entry blocker (nilvadipine) on acute focal cerebral ischemia in rats. Exp Brain Res. 1991;83:434–438. doi: 10.1007/BF00231169. [DOI] [PubMed] [Google Scholar]
  • 55.Khan MM, Ishrat T, Ahmad A, Hoda MN, Khan MB, Khuwaja G, et al. Sesamin attenuates behavioral, biochemical and histological alterations induced by reversible middle cerebral artery occlusion in the rats. Chem Biol Interact. 2010;183:255–263. doi: 10.1016/j.cbi.2009.10.003. [DOI] [PubMed] [Google Scholar]
  • 56.Kim HJ, Rowe M, Ren M, Hong J-S, Chen P-S, Chuang D-M. Histone deacetylase inhibitors exhibit anti-inflammatory and neuroprotective effects in a rat permanent ischemic model of stroke: multiple mechanisms of action. J Pharmacol Exp Ther. 2007;321:892–901. doi: 10.1124/jpet.107.120188. [DOI] [PubMed] [Google Scholar]
  • 57.Kim SH, Kim EH, Lee BI, Heo JH. Chronic cerebral hypoperfusion protects against acute focal ischemia, improves motor function, and results in vascular remodeling. Curr Neurovasc Res. 2008;5:28–36. doi: 10.2174/156720208783565627. [DOI] [PubMed] [Google Scholar]
  • 58.Kobayashi H, Ide H, Kabuto M, Handa Y, Kubota T, Ishii Y. Effect of mannitol on focal cerebral ischemia evaluated by somatosensory-evoked potentials and magnetic resonance imaging. Surg Neurol. 1995;44:55–61. doi: 10.1016/0090-3019(95)00065-8. [DOI] [PubMed] [Google Scholar]
  • 59.Koumura A, Nonaka Y, Hyakkoku K, Oka T, Shimazawa M, Hozumi I, et al. A novel calpain inhibitor, ((1S)-1((((1S)-1-benzyl-3- c yclopropylamino-2,3- di-oxopropyl)amino)carbonyl)-3- methylbutyl) carbamic acid 5-methoxy-3-oxapentyl ester, protects neuronal cells from cerebral ischemia-induced damage in mice. Neuroscience. 2008;157:309–318. doi: 10.1016/j.neuroscience.2008.09.007. [DOI] [PubMed] [Google Scholar]
  • 60.Kozak A, Ergul A, El-Remessy AB, Johnson MH, Machado LS, Elewa HF, et al. Candesartan augments ischemia-induced proangiogenic state and results in sustained improvement after stroke. Stroke. 2009;40:1870–1876. doi: 10.1161/STROKEAHA.108.537225. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 61.Krishnamurthy RG, Senut M-C, Zemke D, Min J, Frenkel MB, Greenberg EJ, et al. Asiatic acid, a pentacyclic triterpene from Centella asiatica, is neuroprotective in a mouse model of focal cerebral ischemia. J Neurosci Res. 2009;87:2541–2550. doi: 10.1002/jnr.22071. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 62.Lam BYH, Lo ACY, Sun X, Luo HW, Chung SK, Sucher NJ. Neuroprotective effects of tanshinones in transient focal cerebral ischemia in mice. Phytomedicine. 2003;10:286–291. doi: 10.1078/094471103322004776. [DOI] [PubMed] [Google Scholar]
  • 63.Leach MJ, Swan JH, Eisenthal D, Dopson M, Nobbs M. BW619C89, a glutamate release inhibitor, protects against focal cerebral ischemic damage. Stroke. 1993;24:1063–1067. doi: 10.1161/01.str.24.7.1063. [DOI] [PubMed] [Google Scholar]
  • 64.Lee E, Chen H-Y, Lee M-Y, Chen T-Y, Hsu Y-S, Hu Y-L, et al. Cinnamophilin reduces oxidative damage and protects against transient focal cerebral ischemia in mice. Free Radic Biol Med. 2005;39:495–510. doi: 10.1016/j.freeradbiomed.2005.04.004. [DOI] [PubMed] [Google Scholar]
  • 65.Lee EJ, Chen HY, Wu TS, Chen TY, Ayoub IA, Maynard KI. Acute administration of Ginkgo biloba extract (EGb 761) affords neuroprotection against permanent and transient focal cerebral ischemia in Sprague-Dawley rats. J Neurosci Res. 2002;68:636–645. doi: 10.1002/jnr.10251. [DOI] [PubMed] [Google Scholar]
  • 66.Lee EJ, Lee M-Y, Chen H-Y, Hsu Y-S, Wu T-S, Chen S-T, et al. Melatonin attenuates gray and white matter damage in a mouse model of transient focal cerebral ischemia. J Pineal Res. 2005;38:42–52. doi: 10.1111/j.1600-079X.2004.00173.x. [DOI] [PubMed] [Google Scholar]
  • 67.Lee EJ, Wu T-S, Chang G-L, Li C-Y, Chen T-Y, Lee M-Y, et al. Delayed treatment with nicotinamide inhibits brain energy depletion, improves cerebral microperfusion, reduces brain infarct volume, but does not alter neurobehavioral outcome following permanent focal cerebral ischemia in Sprague Dawley rats. Curr Neurovasc Res. 2006;3:203–213. doi: 10.2174/156720206778018749. [DOI] [PubMed] [Google Scholar]
  • 68.Lee EJ, Wu T-S, Lee M-Y, Chen T-Y, Tsai Y-Y, Chuang J-I, et al. Delayed treatment with melatonin enhances electrophysiological recovery following transient focal cerebral ischemia in rats. J Pineal Res. 2004;36:33–42. doi: 10.1046/j.1600-079x.2003.00093.x. [DOI] [PubMed] [Google Scholar]
  • 69.Lee K, Jo IY, Park SH, Kim KS, Bae J, Park JW, et al. Defatted sesame seed extract reduces brain oedema by regulating aquaporin 4 expression in acute phase of transient focal cerebral ischaemia in rat. Phytother Res. 2012;26:1521–1527. doi: 10.1002/ptr.4599. [DOI] [PubMed] [Google Scholar]
  • 70.Lee M-Y, Kuan Y-H, Chen H-Y, Chen T-Y, Chen S-T, Huang C-C, et al. Intravenous administration of melatonin reduces the intracerebral cellular inflammatory response following transient focal cerebral ischemia in rats. J Pineal Res. 2007;42:297–309. doi: 10.1111/j.1600-079X.2007.00420.x. [DOI] [PubMed] [Google Scholar]
  • 71.Lee S-T, Chu K, Jung K-H, Ko S-Y, Kim E-H, Sinn DI, et al. Granulocyte colony-stimulating factor enhances angiogenesis after focal cerebral ischemia. Brain Res. 2005;1058:120–128. doi: 10.1016/j.brainres.2005.07.076. [DOI] [PubMed] [Google Scholar]
  • 72.Lei B, Popp S, Cottrell JE, Kass IS. Effects of midazolam on brain injury after transient focal cerebral ischemia in rats. J Neurosurg Anesthesiol. 2009;21:131–139. doi: 10.1097/ANA.0b013e318191697a. [DOI] [PubMed] [Google Scholar]
  • 73.Lemay DR, Gehua L, Zelenock GB, D’Alecy LG. Insulin administration protects neurologic function in cerebral ischemia in rats. Stroke. 1988;19:1411–1419. doi: 10.1161/01.str.19.11.1411. [DOI] [PubMed] [Google Scholar]
  • 74.Ley JJ, Belayev L, Saul I, Becker DA, Ginsberg MD. Neuroprotective effect of STAZN, a novel azulenyl nitrone antioxidant, in focal cerebral ischemia in rats: dose-response and therapeutic window. Brain Res. 2007;1180:101–110. doi: 10.1016/j.brainres.2007.05.028. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 75.Li J, Luan X, Lai Q, Clark JC, McAllister JP, II, Fessler R, et al. Long-term neuroprotection induced by regional brain cooling with saline infusion into ischemic territory in rats: a behavioral analysis. Neurol Res. 2004;26:677–683. doi: 10.1179/016164104225015903. [DOI] [PubMed] [Google Scholar]
  • 76.Lin S-Z, Hoffer BJ, Kaplan P, Wang Y. Osteogenic protein-1 protects against cerebral infarction induced by MCA ligation in adult rats. Stroke. 1999;30:126–133. doi: 10.1161/01.str.30.1.126. [DOI] [PubMed] [Google Scholar]
  • 77.Little JR, Latchaw JP, Slugg RM, Lesser RP, Stowe NT. Treatment of acute focal cerebral ischemia with propranolol. Stroke. 1982;13:302–307. doi: 10.1161/01.str.13.3.302. [DOI] [PubMed] [Google Scholar]
  • 78.Liu XF, Fawcett JR, Thorne RG, DeFor TA, Frey IWH. Intranasal administration of insulin-like growth factor-I bypasses the blood-brain barrier and protects against focal cerebral ischemic damage. J Neurol Sci. 2001;187:91–97. doi: 10.1016/s0022-510x(01)00532-9. [DOI] [PubMed] [Google Scholar]
  • 79.Lou M, Eschenfelder CC, Herdegen T, Brecht S, Deuschl G. Therapeutic window for use of hyperbaric oxygenation in focal transient ischemia in rats. Stroke. 2004;35:578–583. doi: 10.1161/01.STR.0000111599.77426.A0. [DOI] [PubMed] [Google Scholar]
  • 80.Lu A, Ran R, Parmentier-Batteur S, Nee A, Sharp FR. Geldanamycin induces heat shock proteins in brain and protects against focal cerebral ischemia. J Neurochem. 2002;81:355–364. doi: 10.1046/j.1471-4159.2002.00835.x. [DOI] [PubMed] [Google Scholar]
  • 81.Ma SW, Yin HF, Chen LY, Liu HX, Zhao M, Zhang XT. Neuroprotective effect of ginkgolide K against acute ischemic stroke on middle cerebral ischemia occlusion in rats. J Nat Med. 2012;66:25–31. doi: 10.1007/s11418-011-0545-7. [DOI] [PubMed] [Google Scholar]
  • 82.Maheshwari A, Badgujar L, Phukan B, Bodhankar SL, Thakurdesai P. Protective effect of etoricoxib against middle cerebral artery occlusion induced transient focal cerebral ischemia in rats. Eur J Pharmacol. 2011;667:230–237. doi: 10.1016/j.ejphar.2011.05.030. [DOI] [PubMed] [Google Scholar]
  • 83.Mao X, Yin W, Liu M, Ye M, Liu P, Liu J, et al. Osthole, a natural coumarin, improves neurobehavioral functions and reduces infarct volume and matrix metalloproteinase-9 activity after transient focal cerebral ischemia in rats. Brain Res. 2011;1385:275–280. doi: 10.1016/j.brainres.2011.02.015. [DOI] [PubMed] [Google Scholar]
  • 84.Medhi B, Aggarwal R, Chakrabarti A. Neuroprotective effect of pioglitazone on acute phase changes induced by partial global cerebral ischemia in mice. Indian J Exp Biol. 2010;48:793–799. [PubMed] [Google Scholar]
  • 85.Merlo Pich E, Grimaldi R, Zoli M, Biagini G, Solfrini V, Toffano G, et al. Siagoside selectively attenuates morphological and functional striatal impairments induced by transient forebrain ischemia in rats. Stroke. 1992;23:234–241. doi: 10.1161/01.str.23.2.234. [DOI] [PubMed] [Google Scholar]
  • 86.Mishra V, Verma R, Raghubir R. Neuroprotective effect of flurbiprofen in focal cerebral ischemia: the possible role of ASIC1a. Neuropharmacology. 2010;59:582–588. doi: 10.1016/j.neuropharm.2010.08.015. [DOI] [PubMed] [Google Scholar]
  • 87.Mohammadi MT, Shid-Moosavi SM, Dehghani GA. Contribution of nitric oxide synthase (NOS) in blood-brain barrier disruption during acute focal cerebral ischemia in normal rat. Pathophysiology. 2012;19:13–20. doi: 10.1016/j.pathophys.2011.07.003. [DOI] [PubMed] [Google Scholar]
  • 88.Moyanova SG, Kortenska LV, Mitreva RG, Pashova VD, Ngomba RT, Nicoletti F. Multimodal assessment of neuroprotection applied to the use of MK-801 in the endothelin-1 model of transient focal brain ischemia. Brain Res. 2007;1153:58–67. doi: 10.1016/j.brainres.2007.03.070. [DOI] [PubMed] [Google Scholar]
  • 89.Nagaraja TN, Knight RA, Croxen RL, Konda KP, Fenstermacher JD. Acute neurovascular unit protection by simvastatin in transient cerebral ischemia. Neurol Res. 2006;28:826–830. doi: 10.1179/174313206X153914. [DOI] [PubMed] [Google Scholar]
  • 90.Nagel S, Su Y, Horstmann S, Heiland S, Gardner H, Koziol J, et al. Minocycline and hypothermia for reperfusion injury after focal cerebral ischemia in the rat: effects on BBB breakdown and MMP expression in the acute and subacute phase. Brain Res. 2008;1188:198–206. doi: 10.1016/j.brainres.2007.10.052. [DOI] [PubMed] [Google Scholar]
  • 91.Park CK, Rudolphi KA. Antiischemic effects of propentofylline (HWA 285) against focal cerebral infarction in rats. Neurosci Lett. 1994;178:235–238. doi: 10.1016/0304-3940(94)90767-6. [DOI] [PubMed] [Google Scholar]
  • 92.Patzer A, Zhao Y, Stock I, Gohlke P, Herdegen T, Culman J. Peroxisome proliferator-activated receptors gamma (PPAR gamma) differently modulate the interleukin-6 expression in the peri-infarct cortical tissue in the acute and delayed phases of cerebral ischaemia. Eur J Neurosci. 2008;28:1786–1794. doi: 10.1111/j.1460-9568.2008.06478.x. [DOI] [PubMed] [Google Scholar]
  • 93.Peerless SJ, Ishikawa R, Hunter IG, Peerless MJ. Protective effect of Fluosol-DA in acute cerebral ischemia. Stroke. 1981;12:558–563. doi: 10.1161/01.str.12.5.558. [DOI] [PubMed] [Google Scholar]
  • 94.Peng H-Y, Du J-R, Zhang G-Y, Kuang X, Liu Y-X, Qian Z-M, et al. Neuroprotective effect of Z-Ligustilide against permanent focal ischemic damage in rats. Biol Pharm Bull. 2007;30:309–312. doi: 10.1248/bpb.30.309. [DOI] [PubMed] [Google Scholar]
  • 95.Rahman RMA, Nair SM, Helps SC, Shaw OM, Sims NR, Rosengren RJ, et al. (−)-Epigallocatechin gallate as an intervention for the acute treatment of cerebral ischemia. Neurosci Lett. 2005;382:227–230. doi: 10.1016/j.neulet.2005.03.018. [DOI] [PubMed] [Google Scholar]
  • 96.Ritz MF, Schmidt P, Mendelowitsch A. Acute effects of 17 beta-estradiol on the extracellular concentration of excitatory amino acids and energy metabolites during transient cerebral ischemia in male rats. Brain Res. 2004;1022:157–163. doi: 10.1016/j.brainres.2004.07.004. [DOI] [PubMed] [Google Scholar]
  • 97.Roos JA, Jackson-Friedman C, Lyden P. Effects of hyperbaric oxygen on neurologic outcome for cerebral ischemia in rats. Acad Emerg Med. 1998;5:18–24. doi: 10.1111/j.1553-2712.1998.tb02569.x. [DOI] [PubMed] [Google Scholar]
  • 98.Sarhan S, Wettstein JG, Maynard KI. Delayed treatment with 5-nitro- 6,7-dichloro-1,4-dihydro-2,3-quinoxalinedione, a glycine site N-methyl-D-aspartate antagonist, protects against permanent middle cerebral artery occlusion in male rats. Neurosci Lett. 2003;347:147–150. doi: 10.1016/s0304-3940(03)00693-1. [DOI] [PubMed] [Google Scholar]
  • 99.Sato T, Morishima Y, Shirasaki Y. 3-[2-[4-(3-chloro-2-methylphenyl)-1-piperazinyl]ethyl]-5,6-dimethoxy-1-(4-imidazolylmethyl)-1H-indazole dihydrochloride 3.5 hydrate (DY-9760e), a novel calmodulin antagonist, reduces brain edema through the inhibition of enhanced blood-brain barrier permeability after transient focal ischemia. J Pharmacol Exp Ther. 2003;304:1042–1047. doi: 10.1124/jpet.102.045039. [DOI] [PubMed] [Google Scholar]
  • 100.Seren MS, Lazzaro A, Yang CL, Canella R, Bassan M, Zanoni R, et al. Orally administered glycolipid derivative LIGA20 reduces infarct volume and behavioral impairment after focal cerebral ischemia. J Pharmacol Exp Ther. 1994;268:460–465. [PubMed] [Google Scholar]
  • 101.Sheng R, Zhang LS, Han R, Gao B, Liu QX, Qin ZH. Combined prostaglandin E1 and lithium exert potent neuroprotection in a rat model of cerebral ischemia. Acta Pharmacol Sin. 2011;32:303–310. doi: 10.1038/aps.2010.211. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 102.Shi QJ, Xiao L, Zhao B, Zhang XY, Wang XR, Xu DM, et al. Intracerebroventricular injection of HAMI 3379, a selective cysteinyl leukotriene receptor 2 antagonist, protects against acute brain injury after focal cerebral ischemia in rats. Brain Res. 2012;1484:57–67. doi: 10.1016/j.brainres.2012.09.020. [DOI] [PubMed] [Google Scholar]
  • 103.Shirakura S, Sano JI, Karasawa A, Kubo K. Protective effects of benidipine on arachidonic acid-induced acute cerebral ischemia in rats. Jpn J Pharmacol. 1992;59:15–22. doi: 10.1254/jjp.59.15. [DOI] [PubMed] [Google Scholar]
  • 104.Shuaib A, Yang Y, Nakada MT, Li Q, Yang T. Glycoprotein IIb/IIIa antagonist, murine 7E3 F(ab’)2, and tissue plasminogen activator in focal ischemia: evaluation of efficacy and risk of hemorrhage with combination therapy. J Cereb Blood Flow Metab. 2002;22:215–222. doi: 10.1097/00004647-200202000-00009. [DOI] [PubMed] [Google Scholar]
  • 105.Shuaib A, Yang Y, Siddiqui MM, Kalra J. Intraarterial urokinase produces significant attenuation of infarction volume in an embolic focal ischemia model. Exp Neurol. 1998;154:330–335. doi: 10.1006/exnr.1998.6925. [DOI] [PubMed] [Google Scholar]
  • 106.Shukla PK, Khanna VK, Ali MM, Khan MY, Srimal RC. Anti-ischemic effect of curcumin in rat brain. Neurochem Res. 2008;33:1036–1043. doi: 10.1007/s11064-007-9547-y. [DOI] [PubMed] [Google Scholar]
  • 107.Shyu W-C, Lin S-Z, Chiang M-F, Yang H-I, Thajeb P, Li H. Neuregulin-1 reduces ischemia-induced brain damage in rats. Neurobiol Aging. 2004;25:935–944. doi: 10.1016/j.neurobiolaging.2003.10.012. [DOI] [PubMed] [Google Scholar]
  • 108.Smith AL, Hoff JT, Nielsen SL, Larson CP. Barbiturate protection in acute focal cerebral ischemia. Stroke. 1974;5:1–7. doi: 10.1161/01.str.5.1.1. [DOI] [PubMed] [Google Scholar]
  • 109.Takahashi M, Ni JW, Kawasaki-Yatsugi S, Toya T, Ichiki C, Yatsugi S-I, et al. Neuroprotective efficacy of YM872, an alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor antagonist, after permanent middle cerebral artery occlusion in rats. J Pharmacol Exp Ther. 1998;287:559–566. [PubMed] [Google Scholar]
  • 110.Tamura M, Aoki Y, Seto T, Itoh Y, Ukai Y. Cerebroprotective action of a Na+/Ca2+ channel blocker NS-7: II. Effect on the cerebral infarction, behavioral and cognitive impairments at the chronic stage of permanent middle cerebral artery occlusion in rats. Brain Res. 2001;890:170–176. doi: 10.1016/s0006-8993(00)03168-1. [DOI] [PubMed] [Google Scholar]
  • 111.Tanaka K, Ito D, Suzuki S, Dembo T, Kosakai A, Fukuuchi Y. A novel voltage-sensitive Na+ and Ca2+ channel blocker NS-7, prevents suppression of cyclic AMP-dependent protein kinase and reduces infarct area in the acute phase of cerebral ischemia in rat. Brain Res. 2002;924:98–108. doi: 10.1016/s0006-8993(01)03231-0. [DOI] [PubMed] [Google Scholar]
  • 112.Thoene-Reineke C, Rumschussel K, Schmerbach K, Krikov M, Wengenmayer C, Godes M, et al. Prevention and intervention studies with telmisartan, ramipril and their combination in different rat stroke models. PLoS One. 2011;6:e23646. doi: 10.1371/journal.pone.0023646. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 113.Tian J, Fu F, Geng M, Jiang Y, Yang J, Jiang W, et al. Neuroprotective effect of 20(S)-ginseno side Rg(3) on cerebral ischemia in rats. Neurosci Lett. 2005;374:92–97. doi: 10.1016/j.neulet.2004.10.030. [DOI] [PubMed] [Google Scholar]
  • 114.Tian J, Fu F, Li G, Gao Y, Zhang Y, Meng Q, et al. Protections of SMND-309, a novel derivate of salvianolic acid B, on brain mitochondria contribute to injury amelioration in cerebral ischemia rats. Phytomedicine. 2009;16:726–733. doi: 10.1016/j.phymed.2009.01.007. [DOI] [PubMed] [Google Scholar]
  • 115.Traystman RJ, Klaus JA, DeVries AC, Shaivitz AB, Hurn PD. Anticonvulsant lamotrigine administered on reperfusion fails to improve experimental stroke outcomes. Stroke. 2001;32:783–787. doi: 10.1161/01.str.32.3.783. [DOI] [PubMed] [Google Scholar]
  • 116.Tzen JTC, Jinn TR, Chen YC, Li FY, Cheng FC, Shi LS, et al. Magnesium lithospermate B possesses inhibitory activity on Na+ K+-ATPase and neuroprotective effects against ischemic stroke. Acta Pharmacol Sin. 2007;28:609–615. doi: 10.1111/j.1745-7254.2007.00544.x. [DOI] [PubMed] [Google Scholar]
  • 117.Uchida M, Palmateer JM, Herson PS, Devries AC, Cheng J, Hurn PD. Dose-dependent effects of androgens on outcome after focal cerebral ischemia in adult male mice. J Cereb Blood Flow Metab. 2009;29:1454–1462. doi: 10.1038/jcbfm.2009.60. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 118.Veltkamp R, Warner DS, Domoki F, Brinkhous AD, Toole JF, Busija DW. Hyperbaric oxygen decreases infarct size and behavioral deficit after transient focal cerebral ischemia in rats. Brain Res. 2000;853:68–73. doi: 10.1016/s0006-8993(99)02250-7. [DOI] [PubMed] [Google Scholar]
  • 119.Verma R, Mishra V, Gupta K, Sasmal D, Raghubir R. Neuroprotection by rosiglitazone in transient focal cerebral ischemia might not be mediated by glutamate transporter-1. J Neurosci Res. 2011;89:1849–1858. doi: 10.1002/jnr.22710. [DOI] [PubMed] [Google Scholar]
  • 120.VonLubitz D, Lin RCS, Jacobson KA. Cerebral ischemia in gerbils: Effects of acute and chronic treatment with adenosine A2A receptor agonist and antagonist. Eur J Pharmacol. 1995;287:295–302. doi: 10.1016/0014-2999(95)00498-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 121.Wahl F, Allix M, Plotkine M, Boulu RG. Effect of riluzole on focal cerebral ischemia in rats. Eur J Pharmacol. 1993;230:209–214. doi: 10.1016/0014-2999(93)90804-q. [DOI] [PubMed] [Google Scholar]
  • 122.Wakabayashi K, Nagai A, Sheikh AM, Shiota Y, Narantuya D, Watanabe T, et al. Transplantation of human mesenchymal stem cells promotes functional improvement and increased expression of neurotrophic factors in a rat focal cerebral ischemia model. J Neurosci Res. 2010;88:1017–1025. doi: 10.1002/jnr.22279. [DOI] [PubMed] [Google Scholar]
  • 123.Wang F, Wang Y, Geng XK, Asmaro K, Peng CY, Sullivan JM, et al. Neuroprotective effect of acute ethanol administration in a rat with transient cerebral ischemia. Stroke. 2012;43:205–210. doi: 10.1161/STROKEAHA.111.629576. [DOI] [PubMed] [Google Scholar]
  • 124.Wang J, Yang X, Camporesi CV, Yang Z, Bosco G, Chen C, et al. Propofol reduces infarct size and striatal dopamine accumulation following transient middle cerebral artery occlusion: a microdialysis study. Eur J Pharmacol. 2002;452:303–308. doi: 10.1016/s0014-2999(02)02332-4. [DOI] [PubMed] [Google Scholar]
  • 125.Wang JP, Yang ZT, Liu C, He YH, Zhao SS. L-carnosine inhibits neuronal cell apoptosis through signal transducer and activator of transcription 3 signaling pathway after acute focal cerebral ischemia. Brain Res. 2013;1507:125–133. doi: 10.1016/j.brainres.2013.02.032. [DOI] [PubMed] [Google Scholar]
  • 126.Wang Q, van Hoecke M, Tang XN, Lee H, Zheng Z, Swanson RA, et al. Pyruvate protects against experimental stroke via an anti-inflammatory mechanism. Neurobiol Dis. 2009;36:223–231. doi: 10.1016/j.nbd.2009.07.018. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 127.Wang T, Fu FH, Han B, Zhu M, Yu X, Zhang LM. Aspirin attenuates cerebral ischemic injury in diabetic rats. Exp Clin Endocrinol Diabetes. 2009;117:181–185. doi: 10.1055/s-0028-1087210. [DOI] [PubMed] [Google Scholar]
  • 128.Wang W, Xu J, Li L, Wang P, Ji X, Ai H, et al. Neuroprotective effect of morroniside on focal cerebral ischemia in rats. Brain Res Bull. 2010;83:196–201. doi: 10.1016/j.brainresbull.2010.07.003. [DOI] [PubMed] [Google Scholar]
  • 129.Wang X, Xu L, Wang H, Grzanna R, Zhan Y, Knabb RM, et al. Inhibition of factor Xa reduces ischemic brain damage after thromboembolic stroke in rats. Stroke. 2003;34:468–474. doi: 10.1161/01.str.0000049765.81774.a3. [DOI] [PubMed] [Google Scholar]
  • 130.Wang XY, Liu JX, Zhu HH, Tejima E, Tsuji K, Murata Y, et al. Effects of neuroglobin overexpression on acute brain injury and long-term outcomes after focal cerebral ischemia. Stroke. 2008;39:1869–1874. doi: 10.1161/STROKEAHA.107.506022. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 131.Wei Y, Yemisci M, Kim H-H, Yung LM, Shin HK, Hwang S-K, et al. Fingolimod provides long-term protection in rodent models of cerebral ischemia. Ann Neurol. 2011;69:119–129. doi: 10.1002/ana.22186. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 132.Wiegler K, Bonny C, Coquoz D, Hirt L. The JNK inhibitor XG-102 protects from ischemic damage with delayed intravenous administration also in the presence of recombinant tissue plasminogen activator. Cerebrovasc Dis. 2008;26:360–366. doi: 10.1159/000151639. [DOI] [PubMed] [Google Scholar]
  • 133.Willing AE, Vendrame M, Mallery J, Cassady CJ, Davis CD, Sanchez-Ramos J, et al. Mobilized peripheral blood cells administered intravenously produce functional recovery in stroke. Cell Transpl. 2003;12:449–454. doi: 10.3727/000000003108746885. [DOI] [PubMed] [Google Scholar]
  • 134.Won SJ, Xie L, Kim SH, Tang H, Wang Y, Mao X, et al. Influence of age on the response to fibroblast growth factor-2 treatment in a rat model of stroke. Brain Res. 2006;1123:237–244. doi: 10.1016/j.brainres.2006.09.055. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 135.Xi H-j, Zhang T-h, Tao T, Song C-y, Lu S-j, Cui X-g, et al. Propofol improved neurobehavioral outcome of cerebral ischemia-reperfusion rats by regulating Bcl-2 and Bax expression. Brain Res. 2011;1410:24–32. doi: 10.1016/j.brainres.2011.06.060. [DOI] [PubMed] [Google Scholar]
  • 136.Xing Y, Zhang X, Zhao K, Cui L, Wang L, Dong L, et al. Beneficial effects of sulindac in focal cerebral ischemia: a positive role in Wnt/β-catenin pathway. Brain Res. 2012;1482:71–80. doi: 10.1016/j.brainres.2012.08.057. [DOI] [PubMed] [Google Scholar]
  • 137.Yang C, Zhang X, Fan H, Liu Y. Curcumin upregulates transcription factor Nrf2 HO-1 expression and protects rat brains against focal ischemia. Brain Res. 2009;1282:133–141. doi: 10.1016/j.brainres.2009.05.009. [DOI] [PubMed] [Google Scholar]
  • 138.Yang JP, Liu HJ, Liu XF. VEGF promotes angiogenesis and functional recovery in stroke rats. J Invest Surg. 2010;23:149–155. doi: 10.3109/08941930903469482. [DOI] [PubMed] [Google Scholar]
  • 139.Yang J-P, Liu H-J, Wang Z-L, Cheng S-M, Cheng X, Xu G-L, et al. The dose-effectiveness of intranasal VEGF in treatment of experimental stroke. Neurosci Lett. 2009;461:212–216. doi: 10.1016/j.neulet.2009.06.060. [DOI] [PubMed] [Google Scholar]
  • 140.Yang Y, Li Q, Nakada MT, Yang T, Shuaib A. Angiographic evaluation of middle cerebral artery reperfusion caused by platelet glycoprotein IIb/IIIa receptor complex antagonist murine 7E3 F(ab’)2 in a model of focal cerebral ischemia in rats. J Neurosurg. 2001;94:582–588. doi: 10.3171/jns.2001.94.4.0582. [DOI] [PubMed] [Google Scholar]
  • 141.Yang Y, Li Q, Shuaib A. Neuroprotection by 2-h postischemia administration of two free radical scavengers, alpha-phenyl-n-tert-butyl- nitrone (PBN) and N-tert-butyl-(2-sulfophenyl)-nitrone (S-PBN), in rats subjected to focal embolic cerebral ischemia. Exp Neurol. 2000;163:39–45. doi: 10.1006/exnr.2000.7364. [DOI] [PubMed] [Google Scholar]
  • 142.Yang Y, Li Q, Shuaib A. Enhanced neuroprotection and reduced hemorrhagic incidence in focal cerebral ischemia of rat by low dose combination therapy of urokinase and topiramate. Neuropharmacology. 2000;39:881–888. doi: 10.1016/s0028-3908(99)00248-8. [DOI] [PubMed] [Google Scholar]
  • 143.Yang Y, Li Q, Wang C-X, Jeerakathil T, Shuaib A. Dose-dependent neuroprotection with tiagabine in a focal cerebral ischemia model in rat. Neuroreport. 2000;11:2307–2311. doi: 10.1097/00001756-200007140-00048. [DOI] [PubMed] [Google Scholar]
  • 144.Yang Y, Li Q, Yang T, Hussain M, Shuaib A. Reduced brain infarct volume and improved neurological outcome by inhibition of the NR2B subunit of NMDA receptors by using CP101,606–27 alone and in combination with rt-PA in a thromboembolic stroke model in rats. J Neurosurg. 2003;98:397–403. doi: 10.3171/jns.2003.98.2.0397. [DOI] [PubMed] [Google Scholar]
  • 145.Yano A, Shingo T, Takeuchi A, Yasuhara T, Kobayashi K, Takahashi K, et al. Encapsulated vascular endothelial growth factor-secreting cell grafts have neuroprotective and angiogenic effects on focal cerebral ischemia. J Neurosurg. 2005;103:104–114. doi: 10.3171/jns.2005.103.1.0104. [DOI] [PubMed] [Google Scholar]
  • 146.Yao D-L, Masonic K, Petullo D, Li YL, Lincoln C, Wibberley L, et al. Pretreatment with intravenous FGF-13 reduces infarct volume and ameliorates neurological deficits following focal cerebral ischemia in rats. Brain Res. 1999;818:140–146. doi: 10.1016/s0006-8993(98)01118-4. [DOI] [PubMed] [Google Scholar]
  • 147.Yasuhara T, Hara K, Maki M, Masuda T, Sanberg CD, Sanberg PR, et al. Dietary supplementation exerts neuroprotective effects in ischemic stroke model. Rejuvenation Res. 2008;11:201–214. doi: 10.1089/rej.2007.0608. [DOI] [PubMed] [Google Scholar]
  • 148.Yenari MA, Palmer JT, Sun GH, de Crespigny A, Mosely ME, Steinberg GK. Time-course and treatment response with SNX-111, an N-type calcium channel blocker, in a rodent model of focal cerebral ischemia using diffusion-weighted MRI. Brain Res. 1996;739:36–45. doi: 10.1016/s0006-8993(96)00808-6. [DOI] [PubMed] [Google Scholar]
  • 149.Yu G, Hess DC, Borlongan CV. Combined cyclosporine-A and methylprednisolone treatment exerts partial and transient neuroprotection against ischemic stroke. Brain Res. 2004;1018:32–37. doi: 10.1016/j.brainres.2004.05.056. [DOI] [PubMed] [Google Scholar]
  • 150.Zhang F, Wang S, Signore AP, Chen J. Neuroprotective effects of leptin against ischemic injury induced by oxygen-glucose deprivation and transient cerebral ischemia. Stroke. 2007;38:2329–2336. doi: 10.1161/STROKEAHA.107.482786. [DOI] [PubMed] [Google Scholar]
  • 151.Zhang J, Han XZ, Li X, Luo Y, Zhao HP, Yang M, et al. Core-shell hybrid liposomal vesicles loaded with panax notoginsenoside: preparation, characterization and protective effects on global cerebral ischemia/reperfusion injury and acute myocardial ischemia in rats. Int J Nanomed. 2012;7:4299–4310. doi: 10.2147/IJN.S32385. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 152.Zhang JX, Zhang HX, Li LF, Li YH. Effects of NG-nitro-L-arginine on focal cerebral ischemic injury in rats. Neural Regen Res. 2006;1:40–43. [Google Scholar]
  • 153.Zhang RL, Zhang C, Zhang L, Roberts C, Lu M, Kapke A, et al. Synergistic effect of an endothelin type A receptor antagonist S-0139, with rtPA on the neuroprotection after embolic stroke. Stroke. 2008;39:2830–2836. doi: 10.1161/STROKEAHA.108.515684. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 154.Zhang R-L, Chopp M, Chen H, Garcia JH, Zhang ZG. Postischemic (1 hour) hypothermia significantly reduces ischemic cell damage in rats subjected to 2 hours of middle cerebral artery occlusion. Stroke. 1993;24:1235–1240. doi: 10.1161/01.str.24.8.1235. [DOI] [PubMed] [Google Scholar]
  • 155.Zhang XL, Zhang XJ, Wang CH, Li YH, Dong LP, Cui LL, et al. Neuroprotection of early and short-time applying berberine in the acute phase of cerebral ischemia: up-regulated pAkt, pGSK and pCREB, down-regulated NF-κB expression, ameliorated BBB permeability. Brain Res. 2012;1459:61–70. doi: 10.1016/j.brainres.2012.03.065. [DOI] [PubMed] [Google Scholar]
  • 156.Zhang Y, Feustel PJ, Kimelberg HK. Neuroprotection by pyrroloquinoline quinone (PQQ) in reversible middle cerebral artery occlusion in the adult rat. Brain Res. 2006;1094:200–206. doi: 10.1016/j.brainres.2006.03.111. [DOI] [PubMed] [Google Scholar]
  • 157.Zhang Y, Wang L, Li J, Wang X-L. 2-(1-Hydroxypentyl)-benzoate increases cerebral blood flow and reduces infarct volume in rats model of transient focal cerebral ischemia. J Pharmacol Exp Ther. 2006;317:973–979. doi: 10.1124/jpet.105.098517. [DOI] [PubMed] [Google Scholar]
  • 158.Zhao B, Zhao CZ, Zhang XY, Huang XQ, Shi WZ, Fang SH, et al. The new P2Y-like receptor G protein-coupled receptor 17 mediates acute neuronal injury and late microgliosis after focal cerebral ischemia in rats. Neuroscience. 2012;202:42–57. doi: 10.1016/j.neuroscience.2011.11.066. [DOI] [PubMed] [Google Scholar]
  • 159.Zhao X, Liu SJ, Zhang J, Strong R, Aronowski J, Grotta JC. Combining insulin-like growth factor derivatives plus caffeinol produces robust neuroprotection after stroke in rats. Stroke. 2005;36:129–134. doi: 10.1161/01.STR.0000149624.87661.18. [DOI] [PubMed] [Google Scholar]
  • 160.Zhao YJ, Yang GY, Ben-Joseph O, Ross BD, Chenevert TL, Domino EF. Acute ethanol effects on focal cerebral ischemia in fasted rats. Alcohol Clin Exp Res. 1998;22:717–722. [PubMed] [Google Scholar]
  • 161.Vaughan CJ, Delanty N. Neuroprotective properties of statins in cerebral ischemia and stroke. Stroke. 1999;30:1969–1973. doi: 10.1161/01.str.30.9.1969. [DOI] [PubMed] [Google Scholar]
  • 162.Wood WG, Eckert GP, Igbavboa U, Müller WE. Statins and neuroprotection: a prescription to move the field forward. Ann NY Acad Sci. 2010;1199:69–76. doi: 10.1111/j.1749-6632.2009.05359.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 163.Hjalmarsson C, Bokemark L, Manhem K, Mehlig K, Andersson B. The effect of statins on acute and long-term outcome after ischemic stroke in the elderly. Am J Geriatr Pharmacother. 2012;10:313–322. doi: 10.1016/j.amjopharm.2012.09.001. [DOI] [PubMed] [Google Scholar]
  • 164.Makihara N, Kamouchi M, Hata J, Matsuo R, Ago T, Kuroda J, et al. Statins and the risks of stroke recurrence and death after ischemic stroke: the Fukuoka Stroke Registry. Atherosclerosis. 2013;231:211–215. doi: 10.1016/j.atherosclerosis.2013.09.017. [DOI] [PubMed] [Google Scholar]
  • 165.Moonis M. High-dose statins should be used in all acute ischemic strokes. Stroke. 2012;43:1992–1993. doi: 10.1161/STROKEAHA.111.633354. [DOI] [PubMed] [Google Scholar]

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