Experimental neuroprotection in ischemic stroke: a concise review

Free access

Acute ischemic stroke (AIS) is a leading cause of disability and death worldwide. To date, intravenous tissue plasminogen activator and mechanical thrombectomy have been standards of care for AIS. There have been many advances in diagnostic imaging and endovascular devices for AIS; however, most neuroprotective therapies seem to remain largely in the preclinical phase. While many neuroprotective therapies have been identified in experimental models, none are currently used routinely to treat stroke patients. This review seeks to summarize clinical studies pertaining to neuroprotection, as well as the different preclinical neuroprotective therapies, their presumed mechanisms of action, and their future applications in stroke patients.

ABBREVIATIONSAIS = acute ischemic stroke; MB = methylene blue; MCA = middle cerebral artery; NMDAR = N-methyl-d-aspartate receptor; Treg = regulatory T cell.

Abstract

Acute ischemic stroke (AIS) is a leading cause of disability and death worldwide. To date, intravenous tissue plasminogen activator and mechanical thrombectomy have been standards of care for AIS. There have been many advances in diagnostic imaging and endovascular devices for AIS; however, most neuroprotective therapies seem to remain largely in the preclinical phase. While many neuroprotective therapies have been identified in experimental models, none are currently used routinely to treat stroke patients. This review seeks to summarize clinical studies pertaining to neuroprotection, as well as the different preclinical neuroprotective therapies, their presumed mechanisms of action, and their future applications in stroke patients.

Acute ischemic stroke (AIS) resulted in 3.3 million deaths globally in 2013 according to Feigin et al.24 They estimated that there were close to 18 million ischemic stroke survivors worldwide in 2013. The global stroke burden continues to increase.24 Recent innovations in the clinical stroke arena include advanced imaging for stroke diagnosis9 and endovascular mechanical thrombectomy for reperfusion treatment of AIS due to large vessel occlusion, which has been validated in 7 randomized controlled trials.5,6,9,28,38,53,62 These new techniques, as well as intravenous tissue plasminogen activator, have transformed emergent stroke care. To date, however, there have been few successful adjuvant neuroprotective therapies to aid in the treatment of acute stroke. Such therapies would target reductions in secondary injury to penumbra tissue, minimizing damage before and after reperfusion while promoting neural recovery and plasticity. In this paper we review upcoming preclinical neuroprotective therapies as well as their proposed mechanisms of action. In addition, we evaluate the existing clinical data on neuroprotection in stroke.

Clinically Assessed Neuroprotective Therapies

In this review we first focus on therapies tested in patients in either a pilot study or a randomized controlled design. Despite the many preclinical studies suggesting clinical efficacy, there is a paucity of clinically proven therapies. We have created tables (Tables 13) recapping the clinically tested therapies and discuss the more relevant therapies below. Recently, randomized trials for acute stroke and neuroprotection have included growth factors, hypothermia, minocycline, natalizumab, fingolimod, and uric acid.11 Common pathways targeted for neuroprotection include free radical scavengers, excitotoxicity, immune modulation, and more.

TABLE 1.

Clinical free radical scavenging therapies for neuroprotection in AIS

Authors & YearTrial NameAgentMOANo. of Patients in StudyBenefit w/AgentDetails
Diener et al., 2008SAINTNXY-059Free radical trapping5028No clinical benefitTreated w/in 6 hrs of symptoms
Clark et al., 2001CiticolineMembrane stabilizer/free radical scavenger899No clinical benefitDaily administration for 6 wks post-stroke
Yamaguchi et al., 1998EbselenSeleno-organic compound w/antioxidant properties300Better outcome at 1 mo but not 3 mos; improvements in mBIOral administration × 2 wks post-stroke
Chamorro et al., 2014URICO-ICTUSUric acidAntioxidant411No significant benefit, but 39% vs 33% (placebo) attained mRS score ≥2Administered w/in 4.5 hrs w/alteplase

mBI = modified Barthel Index; MOA = mechanism of action; mRS = modified Rankin Scale; SAINT = Stroke Acute Ischemic NXY Treatment; URICO-ICTUS = Efficacy Study of Combined Treatment with Uric Acid and r-TPA in Acute Ischemic Stroke.

TABLE 2.

Clinical ion channel interaction/excitotoxicity blockade therapies for neuroprotection in AIS

Authors & YearTrial NameAgentMOANo. of Patients in StudyBenefit w/AgentDetails
Wahlgren et al., 1999CLASSClomethiazoleGABA A potentiator inducing membrane hyperpolarization1360No clinical benefit; in subgroup analysis, increased functional independence w/large strokeAdministered w/in 12 hrs of stroke onset
Albers et al., 2001Aptiganel hydrochlorideSelective ligand for NMDAR628No clinical benefit & possibly harmfulAdministered w/in 6 hrs of stroke onset
Davis et al., 2000SelfotelNMDAR antagonist567Stopped early given possible neurotoxic effectsAdministered w/in 6 hrs of stroke onset
Horn et al., 2001VENUSNimodipineCa++ channel blocker454No beneficial effectAdministered w/in 6 hrs
Liu et al., 2009GinsenosideCa++ channel blocker199Some benefit as determined by 15 day NIHSS14-day infusion
Saver et al., 201563FAST-MAGMagnesiumVasodilatory, neural & glial protective1700No clinical benefit at 90 daysAdministered w/in 2 hrs & a 24-hr infusion
Hill et al., 2012NA-1Inhibitor of postsynaptic density protein-95*197NA-1 group had fewer ischemic infarcts on DWI, FLAIR imaging 12–95 hrs postinfusionInfusion at end of endovascular procedure
Ladurner et al., 2005CerebrolysinPurified brain protein made from enzymatic digestion of brain protein w/neurotrophic/protective properties146Significant improvement in cognition as tested by Short Syndrome TestAdministered w/in 24 hrs, for 21 days

CLASS = Clomethiazole Acute Stroke Study; DWI = diffusion-weighted imaging; FAST-MAG = Field Administration of Stroke Therapy-Magnesium; GABA = γ-aminobutyric acid; NIHSS = National Institutes of Health Stroke Scale/Score; VENUS = Very Early Nimodipine Use in Stroke.

Postsynaptic density protein-95 is believed to regulate gating and surface expression of NMDA channels.45

Orphan category added here for convenience.

TABLE 3.

Clinical immune modulation/antiinflammatory therapies for neuroprotection in AIS

Authors & YearTrialAgentMOANo. of Patients in StudyBenefit w/AgentDetails
Zhu et al., 2015FingolimodImmune modulator*47Smaller lesion vol (10 vs 34 ml), less hemorrhage, & better NIHSS; 90-day mRS Score 0–1 in 73% vs 32%Administered w/alteplase w/in 4.5 hrs, for 3 days
Elkins et al., 2016ACTIONNatalizumabMonoclonal antibody against α4 integrin161More patients had mRS Score 0–1 at 30 & 90 days; however, no effect on infarct growthSingle dose 0–9 hrs from symptom onset
Kohler et al., 2013MinocyclineInhibit microglial & T cell activation, decrease neural apoptosis, inhibit MMP-995No clinical benefitInfusion w/in 24 hrs & every 12 hrs for total of 5 doses
Schäbitz et al., 2010AXIS AFilgrastimGranulocyte colony-stimulating factor44No significant outcome difference, but exploratory analysis revealed some benefit for DWI lesions >14 cm34 doses over 3 days w/in 12 hrs of symptoms
Emsley et al., 2005Interleukin-1 receptor antagonistBlocks interleukin-1–mediated cell death34Clinical outcomes at 3 mos better w/antagonist, decreased C-reactive protein & neutrophilsw/in 6 hrs of symptoms for 72 hrs

ACTION = Effect of Natalizumab on Infarct Volume in Acute Ischemic Stroke; AXIS = Treatment With AX200 for Acute Ischemic Stroke; MMP-9 = matrix metalloproteinase.

Fingolimod acts via immune modulation and sequesters lymphocytes via sphingosine-phosphate receptor internalization, but also reportedly is a ceramide synthase inhibitor and cannabinoid receptor antagonist.

Free Radical Scavengers

Free radicals are molecules with a free unpaired electron, making them highly reactive and capable of chain reactivity. They can react with and damage proteins, nucleic acids, and lipids.66 They are present in low levels via normal cellular respiration, but during acute ischemic episodes their levels can increase and have been postulated to contribute to cerebral edema.29 We summarize the studies on free radical scavenging therapies in Table 1.

Reduction of Excitotoxicity

Excitotoxicity is a type of neurotoxicity centered around glutamate. During acute ischemia, the extracellular concentration of glutamate rises quickly and stimulates N-methyl-d-aspartate receptor (NMDAR), which acts via calcium permeability. Excitotoxic cell death is triggered via PTEN, cdk5, and DAPK1, among other downstream targets.42 We summarize the studies on excitotoxic blocking therapies for neuroprotection in Table 2.

Immune Modulation

The immune response after ischemic stroke is multifaceted and initiates a cascade leading to secondary brain injury following the initial ictus as well as after reperfusion therapies. Gelderblom et al.27 reported increased microglia activation and an influx of macrophages, lymphocytes, and dendritic cells with increased antigen-presenting capability. The brain under normal conditions is able to maintain a relatively noninflammatory environment; however, once the brain is damaged, inflammation is left less regulated.2 We summarize studies on immune modulation therapies in Table 3.

Other Therapies

There are many ongoing clinical trials examining statins, imatinib, dapsone, interleukin-1 receptor antagonists, NA-1, hypothermia, lower limb tourniquet conditioning, insulin infusion, edaravone, and 3K3A-APC.11

American Heart Association Stroke Guidelines Related to Early Management and Neuroprotection

There are no Level 1 recommendations for neuroprotective agents in AIS. The 2013 American Heart Association stroke guidelines state the following: continuation of statin therapy is reasonable, the utility of induced hypothermia in AIS is not well established, transcranial near-infrared laser therapy for AIS is not well established, and the utility of hyperbaric oxygen therapy is inconclusive and may be harmful in AIS, unless due to air embolism.36 The guidelines also state that no neuroprotective pharmacological agents have demonstrated clinical efficacy and thus are not currently recommended.

Hypothermia

Hypothermia can target more than one aspect of secondary brain injury, including oxygen consumption and metabolic demand,15 enzymatic degradation, neurotransmitter uptake,7 membrane stabilization, and reduction in intracellular acidosis.32,55 In a small study, hypothermia post–middle cerebral artery (MCA) stroke has been shown to be tolerable, help control intracranial pressure, and possibly lead to better neurological outcomes.67 Post–cardiac arrest neural protection has also been demonstrated, with 55% of patients who underwent cooling having good outcomes versus 39% in the normothermia group.32

Other neuroprotective strategies related to hypothermia in the clinical phase include an endovascular device inserted into the vena cava for cooling to 33°C for 24 hours,18 which was used in the Cooling for Acute Ischemic Brain Damage (COOL AID) study. This therapy was generally well tolerated, with trends toward less lesion growth on diffusion-weighted imaging. In a more recent pilot study, 26 patients underwent intraarterial endovascular cooling within 8 hours of intraarterial recanalization.13 This therapy did reduce brain temperature by at least 2°C with no obvious complications. The Intravascular Cooling in the Treatment of Stroke (ICTuS) 2 trial results were recently published;50 however, only 120 patients of the intended 1600 were enrolled before the study was stopped. A femoral venous catheter was used for cooling. Mortality was 15.9% in the hypothermia group versus 8.8% in the normothermia group.

Kasner et al.39 performed a randomized controlled trial to determine if 3900 mg of acetaminophen administered daily to afebrile patients with acute stroke could reduce core body temperature, promote modest hypothermia, and prevent hyperthermia; however, these authors concluded that these effects are likely to have no robust impact on outcome. What has been shown is that fever in the first 24 hours of AIS leads to a doubling of the odds of death in 1 month post-stroke.58 Thus, despite the benefit of hypothermia on functional outcomes post–cardiac arrest,32 its use in AIS is still unproven.

Hyperbaric Oxygen

Since AIS occurs when the brain tissue oxygen supply does not meet the demand, many have investigated hyperbaric oxygen therapy as a way to boost brain oxygen levels. In a 2014 meta-analysis, Bennett et al.4 examined 11 randomized controlled trials assessing hyperbaric oxygen in AIS. These authors found no good evidence to suggest that hyperbaric oxygen improves clinical outcomes in AIS.

Near-Infrared Laser Therapy

Low-energy laser therapy has been used as a potential neuroprotective strategy in AIS. The theorized mechanism of action involves photostimulation of mitochondrial chromophores increasing enzymatic production of adenosine triphosphate, with resultant ischemic tissue preservation.54 A pooled analysis of the NeuroThera Effectiveness and Safety Trials (NEST) 1 and 2,35 involving 778 patients, supported the likelihood that transcranial laser therapy was effective when initiated within 24 hours of AIS. The authors concluded that their findings were promising but needed confirmation.

Stem Cell Therapy

In 2016 Hess et al.30 reported the results of their Phase 2 trial of MultiStem (adult, adherent stem cell product). One hundred twenty-six patients (National Institutes of Health Stroke Scale [NIHSS] Score 8–20) were randomized to receive a MultiStem infusion or placebo within 24–48 hours of symptom onset. While no significant benefit was identified, post hoc analysis did suggest early administration may provide some benefit. MultiStem treatment was associated with lower rates of infection and pulmonary events, shorter hospitalizations, and a reduction in life-threatening events and death.

Preclinically Assessed Neuroprotective Therapies

Despite the many promising therapies examined in clinical studies, none has yet gained guideline recommendation for the treatment of AIS. Many preclinical studies have been completed or are underway, and we review a few promising ones here.

Neuroprotection strategies have been traditionally divided into different mechanistic varieties including compounds or therapies that combat oxidative stress, the immune response, and excitotoxicity. Some therapies can target more than one aspect of the secondary brain injury following stroke.

Chlorpromazine/Promethazine

The phenothiazine class of drugs, which includes chlorpromazine and promethazine, have widely been used as neuroleptics but have also been shown to have depressive effects on the central nervous system through the inhibition of carbohydrate oxidation, as well as vasodilatory and anti-shivering properties.47 The drugs at high concentrations can induce hypothermia in rats.73 Liu et al.47 examined the combination of phenothiazine drugs with mild hypothermia in a rat intraluminal MCA filament model of stroke. Combination therapy reduced infarct volume and resulted in better long-term motor recovery than placebo, phenothiazine alone, or hypothermia alone. The authors concluded that phenothiazine drugs may enhance the neuroprotective effects of hypothermia by reinforcing depressive central nervous system effects and thus achieving goal hypothermia faster. These drugs can inhibit mitochondrial dysfunction and decrease free radical production.

Caffeinol (caffeine and ethanol)

Aronowski et al.,3 utilizing a rat model of common carotid artery/left MCA infarct, treated different cohorts with combinations of ethanol, caffeine, and hypothermia. They concluded that low doses of caffeine, equivalent to 2–3 cups of coffee, and low doses of ethanol, equivalent to 1 cocktail, are highly neuroprotective and can reduce cortical infarct volumes and behavioral dysfunction after transient occlusion. However, daily exposure to ethanol eliminated the efficacy through tolerance, thought to be related to NMDA and γ-aminobutyric acid (GABA) receptor changes. The caffeinol treatment was further improved with mild hypothermia. Recently, Cai et al.8 suggested that the neuroprotection mediated through mild hypothermia and ethanol was PKC-Akt-NOX mediated. A pilot study in humans did demonstrate the feasibility of the administration of both agents in AIS patients.51

Methylene Blue

Methylene blue (MB) is a drug used to treat malaria, methemoglobinemia, and cyanide poisoning.65 It is an FDA-grandfathered drug.37 Neuroprotective and memory-enhancing qualities have been demonstrated in neurode-generative disease.60 Methylene blue is thought to act as a renewable auto-oxidizer, redirecting electrons in the mitochondrial transport chain promoting ATP production and cell survival. In hypoxic conditions, MB becomes the oxidizer and sustains ATP production while lowering oxidative stress. Furthermore, MB enhances cytochrome c oxidase activity while bypassing complexes 1–3.37,75 It is also thought to augment HIF-1α activation and stabilization,61 increase cerebral blood flow to mismatched areas, and promote autophagy via p53-AMPK-TSC2-mTOR, while downregulating apoptosis via the p53-Bax-Bcl2-caspase 3 pathway in perfusion-diffusion mismatched tissue. Shen et al.68 found that MB in a 60-minute rat MCA model of stroke had no effect on the initial MRI-demonstrated lesion volume; however, at 2 days after stroke, the final infarct volumes increased in the vehicle group but decreased in the MB group, yielding a 30% overall infarct difference. Pixel by pixel analysis showed that MB salvaged more core and penumbra pixels than the control treatment. Recently, the addition of normobaric hyperoxia to MB was found to further increase functional outcome and decrease infarct volume.59

Rapamycin

Rapamycin is an immunosuppressant drug that targets mTOR and its downstream pathways. mTOR has been implicated in regulating cell survival, proliferation, growth, metabolism, and autophagy. Recently, rapamycin was found to extend lifespan in a variety of animal models.25 Chauhan et al.,12 utilizing an MCA filament model in rats, found that rapamycin could significantly improve the infarct area and apparent diffusion coefficient and improve motor impairment as compared with controls. It also reversed the changes in malondialdehyde, glutathione, nitric oxide, and myeloperoxidase. When administered daily for 1 month before injury in diabetic rats, rapamycin was found to reduce ischemic brain damage via mTOR and ERK1/2 suppression.46 Not all rodent models of stroke have shown positive results with rapamycin; for example, the drug was found to increase infarct size and oxygen consumption in a rat model.14

Inflammatory/Stress Response and Immune Modulation

The inflammatory response in AIS has been called a double-edged sword with early inflammation causing harm, but late inflammatory changes contributing to regeneration.69 Hu et al.34 found that macrophage subtype shifted from early beneficial M2 microglia to M1 microglia and suggested that new therapies should focus on adjusting the balance between good and bad subtypes. Recently, this shift from the M1 to the M2 phenotype in stroke was found to be mTOR mediated.43 Several antibodies targeting adhesion molecules designed to prevent leukotaxis have been produced in the last few years.74 Antibodies targeting anti-neutrophil markers have been shown to decrease myeloperoxidase injury, infarct volume, and edema post-reperfusion.52 Intercellular adhesion molecules and integrins have also been targeted with varying degrees of success, and some very promising experimental data have not translated into good clinical performances. One explanation is that rodents' and humans' inflammatory responses post-stroke involve different integrins and signaling responses.69 Remote ischemic preconditioning has been found to protect against focal ischemia and preserve neurological function via ameliorating post-occlusion reduction in CD3+/CD8+ T cells and CD3+/CD161a+ natural killer T cells. It induces interleukin-6 expression and tumor necrosis factor–α expression while increasing the number of noninflammatory monocytes (CD43+/CD172a+).49 Using a Cre-Lox system, De Magalhaes Fihlo et al.19 found that downregulation of insulin growth factor receptor-1 in cortical neurons also conferred neuroprotection and should be further investigated. This receptor is implicated in the stress response and hypoxic ischemic injury post-stroke.

Li et al.44 examined the therapeutic advantage of regulatory T cells (Tregs) in 2 rodent models of stroke and in in vitro Treg-neutrophil cocultures. They found that systemic administration of Tregs out to 24 hours post–MCA occlusion resulted in a marked reduction in brain infarct and prolonged improvement in neurological function. This was achieved via decreased blood-brain barrier disruption and decreased cerebral inflammation. The Tregs also decreased levels of matrix metalloproteinase-9. Despite these promising results, however, many challenges remain, namely that Tregs constitute only 5%–10% of circulating T cells. Thus, they would need to be expanded either in vivo or in vitro and properly honed for cerebral tissue, and doing so carries its own challenges.71

Doeppner et al.21 examined lithium in a rat MCA occlusion model. They noted that when lithium was administered within 6 hours of onset, reduced infarct volumes, edema, leukocyte infiltration, and microglia activation were present. They reported that lithium increased levels of miR-124, resulting in the degradation of RE1-silencing transcription factor and thus leading to postischemic neuroplasticity. This effect was independent of glycogen synthase kinase 3β (GSK3β).

Finding New Ways to Use Old Therapies and Future Directions

Lastly, it is important to remember older, previously studied neuroprotective agents. As technology changes, the ability to target previously nonspecific drugs or to change the pharmacokinetics of previously rapidly cleared compounds changes. For example, in 2014 Gaudin et al.26 reported that the conjugation of adenosine to the lipid squalene and the subsequent formation of nanoassemblies prolonged circulation and conferred neuroprotection in a rat stroke and spinal cord injury model. However, even though the delivery vehicle was improved, new data suggest a temporal effect of adenosine, namely that adenosine receptors support early excitotoxicity but then seem to attenuate the inflammatory response following.57 Regardless of this temporal finding, as technology finds new ways to deliver or improve therapies, we must be open to reassessing older agents.

In a landmark paper on experimental neuroprotection related to AIS, published in 2006, O'Collins et al.56 systematically reviewed 1026 experimental therapies in both focal and global ischemic animal models, with some studies dating back to the 1950s. These authors compared 114 drugs used clinically to 912 drugs used experimentally and found the clinical therapies to be no more efficacious experimentally than the therapies tested experimentally only. Overall, 64% of drugs tested in the focal ischemic animal models were effective, versus 70% of drugs tested in the global ischemic animal models. Interestingly, no specific drug mechanism distinguished itself by superior efficacy in the focal ischemic animal models. The authors suggested that this finding may reflect the multifaceted nature of stroke or perhaps an incorrect understanding of secondary stroke injury. Thus, they urged rigorous preclinical testing and reporting of data, so that only the most efficacious therapies move forward to clinical phases.

While many of the studies predating 2005, as compared with those from the last 10 years, and the studies reviewed in the current paper target similar pathways, many of the immune modulating and immunotherapy techniques discussed above have only recently been investigated. These studies, along with repeat validation of promising older drugs and therapies, will lay the foundation for stroke neuroprotection moving forward. Many promising therapies are available, including hibernation-like therapy, immune modulation therapy, and near-infrared laser therapy. The disconnect between the beneficial effects of hypothermia for post–cardiac arrest global neuronal ischemia and the lack of efficacy for focal ischemia due to AIS requires better understanding. As mentioned in the O'Collins et al. study,56 perhaps researchers and clinicians need to stop compart-mentalizing AIS secondary injury and instead focus on the global picture. Targeting only one aspect of a multifaceted cascade will probably result in only mild benefits.

Conclusions

Many clinical and preclinical studies of neuroprotection in stroke have been completed; however, few studies have shown clinical benefit. It is imperative that relevant high-quality preclinical studies progress to randomized clinical trials. Neuroprotection in stroke remains very promising with many avenues for improvement and discovery, including trials of current and new therapies in combination. Given the benefits of hypothermia post–cardiac arrest, future studies should determine the exact role of therapeutic hypothermia in AIS, as well as the disconnect between current post–cardiac arrest data and AIS data. Stem cell therapy and immunomodulation also appear promising.

Acknowledgments

This work was partially supported by the WSU Neurosurgery Fund, American Heart Association Grant-in-Aid No. 14GRNT20460246, and Merit Review Award No. I01RX-001964-01 from the US Department of Veterans Affairs Rehabilitation R&D Service.

References

  • 1

    Albers GWGoldstein LBHall DLesko LM: Aptiganel hydrochloride in acute ischemic stroke: a randomized controlled trial. JAMA 286:267326822001

  • 2

    Anrather JThe peripheral immune response to stroke. Chen JZhang JHHu X: Non-Neuronal Mechanisms of Brain Damage and Repair After Stroke Cham, SwitzerlandSpringer2016. 173188

  • 3

    Aronowski JStrong RShirzadi AGrotta JC: Ethanol plus caffeine (caffeinol) for treatment of ischemic stroke: preclinical experience. Stroke 34:124612512003

  • 4

    Bennett MHWeibel SWasiak JSchnabel AFrench CKranke P: Hyperbaric oxygen therapy for acute ischaemic stroke.. Cochrane Database Syst Rev 11CD0049542014

  • 5

    Berkhemer OAFransen PSBeumer Dvan den Berg LALingsma HFYoo AJ: A randomized trial of intraarterial treatment for acute ischemic stroke. N Engl J Med 372:11202015

  • 6

    Bracard SDucrocq XMas JLSoudant MOppenheim CMoulin T: Mechanical thrombectomy after intravenous alteplase versus alteplase alone after stroke (THRACE): a randomised controlled trial. Lancet Neurol 15:113811472016

  • 7

    Busto RGlobus MYDietrich WDMartinez EValdés IGinsberg MD: Effect of mild hypothermia on ischemia-induced release of neurotransmitters and free fatty acids in rat brain. Stroke 20:9049101989

  • 8

    Cai LStevenson JGeng XPeng CJi XXin R: Combining normobaric oxygen with ethanol or hypothermia prevents brain damage from thromboembolic stroke via PKC-Akt-NOX modulation.. Mol Neurobiol [epub ahead of print]2016

  • 9

    Campbell BCMitchell PJKleinig TJDewey HMChurilov LYassi N: Endovascular therapy for ischemic stroke with perfusion-imaging selection. N Engl J Med 372:100910182015

  • 10

    Chamorro ÁAmaro SCastellanos MSegura TArenillas JMartí-Fábregas J: Safety and efficacy of uric acid in patients with acute stroke (URICO-ICTUS): a randomised, double-blind phase 2b/3 trial. Lancet Neurol 13:4534602014

  • 11

    Chamorro ÁDirnagl UUrra XPlanas AM: Neuroprotection in acute stroke: targeting excitotoxicity, oxidative and nitrosative stress, and inflammation. Lancet Neurol 15:8698812016

  • 12

    Chauhan ASharma UJagannathan NRReeta KHGupta YK: Rapamycin protects against middle cerebral artery occlusion induced focal cerebral ischemia in rats. Behav Brain Res 225:6036092011

  • 13

    Chen JLiu LZhang HGeng XJiao LLi G: Endovascular hypothermia in acute ischemic stroke: pilot study of selective intra-arterial cold saline infusion. Stroke 47:193319352016

  • 14

    Chi OZBarsoum SVega-Cotto NMJacinto ELiu XMellender SJ: Effects of rapamycin on cerebral oxygen supply and consumption during reperfusion after cerebral ischemia. Neuroscience 316:3213272016

  • 15

    Chopp MKnight RTidwell CDHelpern JABrown EWelch KMA: The metabolic effects of mild hypothermia on global cerebral ischemia and recirculation in the cat: comparison to normothermia and hyperthermia. J Cereb Blood Flow Metab 9:1411481989

  • 16

    Clark WMWechsler LRSabounjian LASchwiderski UE: A phase III randomized efficacy trial of 2000 mg citicoline in acute ischemic stroke patients. Neurology 57:159516022001

  • 17

    Davis SMLees KRAlbers GWDiener HCMarkabi SKarlsson G: Selfotel in acute ischemic stroke: possible neurotoxic effects of an NMDA antagonist. Stroke 31:3473542000

  • 18

    De Georgia MAKrieger DWAbou-Chebl ADevlin TGJauss MDavis SM: Cooling for Acute Ischemic Brain Damage (COOL AID): a feasibility trial of endovascular cooling. Neurology 63:3123172004

  • 19

    De Magalhaes Filho CDKappeler LDupont JSolinc JVillapol SDenis C: Deleting IGF-1 receptor from forebrain neurons confers neuroprotection during stroke and upregulates endocrine somatotropin. J Cereb Blood Flow Metab 37:3964122017

  • 20

    Diener HCLees KRLyden PGrotta JDavalos ADavis SM: NXY-059 for the treatment of acute stroke: pooled analysis of the SAINT I and II Trials. Stroke 39:175117582008

  • 21

    Doeppner TRKaltwasser BSanchez-Mendoza EHCaglayan ABBähr MHermann DM: Lithium-induced neuroprotection in stroke involves increased miR-124 expression, reduced RE1-silencing transcription factor abundance and decreased protein deubiquitination by GSK3β inhibition-independent pathways.. J Cereb Blood Flow Metab [epub ahead of print]2016

  • 22

    Elkins JElkind MVeltkamp RMontaner JJohnston SSinghal A: Natalizumab versus placebo in patients with acute ischemic stroke (AIS): results from ACTION, a multi-center, double-blind, placebo-controlled, randomized Phase 2 clinical trial (S7.005).. Neurology 86:16 SupplS7.0052016. (Abstract)

  • 23

    Emsley HCSmith CJGeorgiou RFVail AHopkins SJRothwell NJ: A randomised phase II study of interleukin-1 receptor antagonist in acute stroke patients. J Neurol Neurosurg Psychiatry 76:136613722005

  • 24

    Feigin VLKrishnamurthi RVParmar PNorrving BMensah GABennett DA: Update on the global burden of ischemic and hemorrhagic stroke in 1990–2013: the GBD 2013 study. Neuroepidemiology 45:1611762015

  • 25

    Ferro A: Mechanistic target of rapamycin modulation: an emerging therapeutic approach in a wide variety of disease processes. Br J Clin Pharmacol 82:115611572016

  • 26

    Gaudin AYemisci MEroglu HLepetre-Mouelhi STurkoglu OFDönmez-Demir B: Squalenoyl adenosine nanoparticles provide neuroprotection after stroke and spinal cord injury. Nat Nanotechnol 9:105410622014. (Erratum in Nat Nanotechnol 10: 99 2015)

  • 27

    Gelderblom MLeypoldt FSteinbach KBehrens DChoe CUSiler DA: Temporal and spatial dynamics of cerebral immune cell accumulation in stroke. Stroke 40:184918572009

  • 28

    Goyal MDemchuk AMMenon BKEesa MRempel JLThornton J: Randomized assessment of rapid endovascular treatment of ischemic stroke. N Engl J Med 372:101910302015

  • 29

    Heo JHHan SWLee SK: Free radicals as triggers of brain edema formation after stroke. Free Radic Biol Med 39:51702005

  • 30

    Hess DCAuchus APUchino KSila CClark WMChiu D: Final results of the B01-02 phase 2 trial testing the safety and efficacy of MultiStem® in treatment of ischemic stroke.. Stroke 47:A712016. (Abstract)

  • 31

    Hill MDMartin RHMikulis DWong JHSilver FLter-Brugge KG: Safety and efficacy of NA-1 in patients with iatrogenic stroke after endovascular aneurysm repair (ENACT): a phase 2, randomised, double-blind, placebo-controlled trial. Lancet Neurol 11:9429502012

  • 32

    Holzer MCerchiari EMartens PRoine RSterz FEisenburger P: Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med 346:5495562002. (Erratum in N Engl J Med 346: 1756 2002)

  • 33

    Horn Jde Haan RJVermeulen MLimburg M: Very Early Nimodipine Use in Stroke (VENUS): a randomized, double-blind, placebo-controlled trial. Stroke 32:4614652001

  • 34

    Hu XLi PGuo YWang HLeak RKChen S: Microglia/macrophage polarization dynamics reveal novel mechanism of injury expansion after focal cerebral ischemia. Stroke 43:306330702012

  • 35

    Huisa BNStemer ABWalker MGRapp KMeyer BCZivin JA: Transcranial laser therapy for acute ischemic stroke: a pooled analysis of NEST-1 and NEST-2. Int J Stroke 8:3153202013

  • 36

    Jauch ECSaver JLAdams HP JrBruno AConnors JJDemaerschalk BM: Guidelines for the early management of patients with acute ischemic stroke: a guideline for health-care professionals from the American Heart Association/American Stroke Association. Stroke 44:8709472013

  • 37

    Jiang ZDuong TQ: Methylene blue treatment in experimental ischemic stroke: a mini review. Brain Circ 2:48532016

  • 38

    Jovin TGChamorro ACobo Ede Miquel MAMolina CARovira A: Thrombectomy within 8 hours after symptom onset in ischemic stroke. N Engl J Med 372:229623062015

  • 39

    Kasner SEWein TPiriyawat PVillar-Cordova CEChalela JAKrieger DW: Acetaminophen for altering body temperature in acute stroke: a randomized clinical trial. Stroke 33:1301342002

  • 40

    Kohler EPrentice DABates TRHankey GJClaxton Avan Heerden J: Intravenous minocycline in acute stroke: a randomized, controlled pilot study and meta-analysis. Stroke 44:249324992013

  • 41

    Ladurner GKalvach PMoessler H: Neuroprotective treatment with cerebrolysin in patients with acute stroke: a randomised controlled trial. J Neural Transm (Vienna) 112:4154282005

  • 42

    Lai TWZhang SWang YT: Excitotoxicity and stroke: identifying novel targets for neuroprotection. Prog Neurobiol 115:1571882014

  • 43

    Li DWang CYao YChen LLiu GZhang R: mTORC1 pathway disruption ameliorates brain inflammation following stroke via a shift in microglia phenotype from M1 type to M2 type. FASEB J 30:338833992016

  • 44

    Li PGan YSun BLZhang FLu BGao Y: Adoptive regulatory T-cell therapy protects against cerebral ischemia. Ann Neurol 74:4584712013

  • 45

    Lin YSkeberdis VAFrancesconi ABennett MVZukin RS: Postsynaptic density protein-95 regulates NMDA channel gating and surface expression. J Neurosci 24:10138101482004

  • 46

    Liu PYang XHei CMeli YNiu JSun T: Rapamycin reduced ischemic brain damage in diabetic animals is associated with suppressions of mTOR and ERK1/2 signaling. Int J Biol Sci 12:103210402016

  • 47

    Liu SGeng XForreider BXiao YKong QDing Y: Enhanced beneficial effects of mild hypothermia by phenothiazine drugs in stroke therapy. Neurol Res 37:4544602015

  • 48

    Liu XXia JWang LSong YYang JYan Y: Efficacy and safety of ginsenoside-Rd for acute ischaemic stroke: a randomized, double-blind, placebo-controlled, phase II multicenter trial. Eur J Neurol 16:5695752009

  • 49

    Liu ZJChen CLi XRRan YYXu TZhang Y: Remote ischemic preconditioning-mediated neuroprotection against stroke is associated with significant alterations in peripheral immune responses. CNS Neurosci Ther 22:43522016

  • 50

    Lyden PHemmen TGrotta JRapp KErnstrom KRzesiewicz T: Results of the ICTuS 2 Trial (Intravascular Cooling in the Treatment of Stroke 2). Stroke 47:288828952016

  • 51

    Martin-Schild SHallevi HShaltoni HBarreto ADGonzales NRAronowski J: Combined neuroprotective modalities coupled with thrombolysis in acute ischemic stroke: a pilot study of caffeinol and mild hypothermia. J Stroke Cerebrovasc Dis 18:86962009

  • 52

    Matsuo YOnodera HShiga YNakamura MNinomiya MKihara T: Correlation between myeloperoxidase-quantified neutrophil accumulation and ischemic brain injury in the rat. Effects of neutrophil depletion. Stroke 25:146914751994

  • 53

    Mocco JZaidat OVon Kummer RYoo AGupta RLopes D: Results of the THERAPY trial: a prospective, randomized trial to define the role of mechanical thrombectomy as adjunctive treatment to IV rtPA in acute ischemic stroke. Int J Stroke 10:10102015

  • 54

    Mochizuki-Oda NKataoka YCui YYamada HHeya MAwazu K: Effects of near-infra-red laser irradiation on adenosine triphosphate and adenosine diphosphate contents of rat brain tissue. Neurosci Lett 323:2072102002

  • 55

    Natale JAD'Alecy LG: Protection from cerebral ischemia by brain cooling without reduced lactate accumulation in dogs. Stroke 20:7707771989

  • 56

    O'Collins VEMacleod MRDonnan GAHorky LLvan der Worp BHHowells DW: 1,026 experimental treatments in acute stroke. Ann Neurol 59:4674772006

  • 57

    Pedata FPugliese AMCoppi EDettori IMaraula GCellai L: Adenosine A2A receptors modulate acute injury and neuroinflammation in brain ischemia.. Mediators Inflamm 2014:8051982014

  • 58

    Prasad KKrishnan PR: Fever is associated with doubling of odds of short-term mortality in ischemic stroke: an updated meta-analysis. Acta Neurol Scand 122:4044082010

  • 59

    Rodriguez PZhao JMilman BTiwari YVDuong TQ: Methylene blue and normobaric hyperoxia combination therapy in experimental ischemic stroke.. Brain Behav 6:e004782016

  • 60

    Rojas JCBruchey AKGonzalez-Lima F: Neurometabolic mechanisms for memory enhancement and neuroprotection of methylene blue. Prog Neurobiol 96:32452012

  • 61

    Ryou MGChoudhury GRLi WWinters AYuan FLiu R: Methylene blue-induced neuronal protective mechanism against hypoxia-reoxygenation stress. Neuroscience 301:1932032015

  • 62

    Saver JLGoyal MBonafe ADiener HCLevy EIPereira VM: Stent-retriever thrombectomy after intravenous t-PA vs. t-PA alone in stroke. N Engl J Med 372:228522952015

  • 63

    Saver JLStarkman SEckstein MStratton SJPratt FDHamilton S: Prehospital use of magnesium sulfate as neuroprotection in acute stroke. N Engl J Med 372:5285362015

  • 64

    Schäbitz WRLaage RVogt GKoch WKollmar RSchwab S: AXIS: a trial of intravenous granulocyte colony-stimulating factor in acute ischemic stroke. Stroke 41:254525512010

  • 65

    Scheindlin S: Something old... something blue. Mol Interv 8:2682732008

  • 66

    Schmidley JW: Free radicals in central nervous system ischemia. Stroke 21:108610901990

  • 67

    Schwab SSchwarz SSpranger MKeller EBertram MHacke W: Moderate hypothermia in the treatment of patients with severe middle cerebral artery infarction. Stroke 29:246124661998

  • 68

    Shen QDu FHuang SRodriguez PWatts LTDuong TQ: Neuroprotective efficacy of methylene blue in ischemic stroke: an MRI study.. PLoS One 8:e798332013

  • 69

    Siniscalchi AIannacchero RAnticoli SPezzella FRDe Sarro GGallelli L: Anti-inflammatory strategies in stroke: a potential therapeutic target. Curr Vasc Pharmacol 14:981052016

  • 70

    Wahlgren NGRanasinha KWRosolacci TFranke CLvan Erven PMAshwood T: Clomethiazole acute stroke study (CLASS): results of a randomized, controlled trial of clomethiazole versus placebo in 1360 acute stroke patients. Stroke 30:21281999

  • 71

    Xia YCai WThomson AWHu X: Regulatory T cell therapy for ischemic stroke: how far clinical translation?. Transl Stroke Res 7:4154192016

  • 72

    Yamaguchi TSano KTakakura KSaito IShinohara YAsano T: Ebselen in acute ischemic stroke: a placebo-controlled, double-blind clinical trial. Stroke 29:12171998

  • 73

    Yehuda SCarasso RL: Modification of d-amphetamine- or chlorpromazine-induced hypothermia by β-endorphin, MIF-I, and α-MSH: mediation by the dopaminergic system. Peptides 3:1051101982

  • 74

    Yu CYNg GLiao P: Therapeutic antibodies in stroke. Transl Stroke Res 4:4774832013

  • 75

    Zhang XRojas JCGonzalez-Lima F: Methylene blue prevents neurodegeneration caused by rotenone in the retina. Neurotox Res 9:47572006

  • 76

    Zhu ZFu YTian DSun NHan WChang G: Combination of the immune modulator fingolimod with alteplase in acute ischemic stroke: a pilot trial. Circulation 132:110411122015

Disclosures

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Author Contributions

Conception and design: both authors. Analysis and interpretation of data: Ding. Drafting the article: both authors. Critically revising the article: both authors. Reviewed submitted version of manuscript: both authors. Approved the final version of the manuscript on behalf of both authors: Ding. Study supervision: Ding.

If the inline PDF is not rendering correctly, you can download the PDF file here.

Article Information

INCLUDE WHEN CITING DOI: 10.3171/2017.1.FOCUS16497.

Correspondence Yuchuan Ding, Department of Neurosurgery, Lande Building, #48, 550 East Canfield, Detroit, MI 48201. email: yding@med.wayne.edu.

© AANS, except where prohibited by US copyright law.

Headings

References

1

Albers GWGoldstein LBHall DLesko LM: Aptiganel hydrochloride in acute ischemic stroke: a randomized controlled trial. JAMA 286:267326822001

2

Anrather JThe peripheral immune response to stroke. Chen JZhang JHHu X: Non-Neuronal Mechanisms of Brain Damage and Repair After Stroke Cham, SwitzerlandSpringer2016. 173188

3

Aronowski JStrong RShirzadi AGrotta JC: Ethanol plus caffeine (caffeinol) for treatment of ischemic stroke: preclinical experience. Stroke 34:124612512003

4

Bennett MHWeibel SWasiak JSchnabel AFrench CKranke P: Hyperbaric oxygen therapy for acute ischaemic stroke.. Cochrane Database Syst Rev 11CD0049542014

5

Berkhemer OAFransen PSBeumer Dvan den Berg LALingsma HFYoo AJ: A randomized trial of intraarterial treatment for acute ischemic stroke. N Engl J Med 372:11202015

6

Bracard SDucrocq XMas JLSoudant MOppenheim CMoulin T: Mechanical thrombectomy after intravenous alteplase versus alteplase alone after stroke (THRACE): a randomised controlled trial. Lancet Neurol 15:113811472016

7

Busto RGlobus MYDietrich WDMartinez EValdés IGinsberg MD: Effect of mild hypothermia on ischemia-induced release of neurotransmitters and free fatty acids in rat brain. Stroke 20:9049101989

8

Cai LStevenson JGeng XPeng CJi XXin R: Combining normobaric oxygen with ethanol or hypothermia prevents brain damage from thromboembolic stroke via PKC-Akt-NOX modulation.. Mol Neurobiol [epub ahead of print]2016

9

Campbell BCMitchell PJKleinig TJDewey HMChurilov LYassi N: Endovascular therapy for ischemic stroke with perfusion-imaging selection. N Engl J Med 372:100910182015

10

Chamorro ÁAmaro SCastellanos MSegura TArenillas JMartí-Fábregas J: Safety and efficacy of uric acid in patients with acute stroke (URICO-ICTUS): a randomised, double-blind phase 2b/3 trial. Lancet Neurol 13:4534602014

11

Chamorro ÁDirnagl UUrra XPlanas AM: Neuroprotection in acute stroke: targeting excitotoxicity, oxidative and nitrosative stress, and inflammation. Lancet Neurol 15:8698812016

12

Chauhan ASharma UJagannathan NRReeta KHGupta YK: Rapamycin protects against middle cerebral artery occlusion induced focal cerebral ischemia in rats. Behav Brain Res 225:6036092011

13

Chen JLiu LZhang HGeng XJiao LLi G: Endovascular hypothermia in acute ischemic stroke: pilot study of selective intra-arterial cold saline infusion. Stroke 47:193319352016

14

Chi OZBarsoum SVega-Cotto NMJacinto ELiu XMellender SJ: Effects of rapamycin on cerebral oxygen supply and consumption during reperfusion after cerebral ischemia. Neuroscience 316:3213272016

15

Chopp MKnight RTidwell CDHelpern JABrown EWelch KMA: The metabolic effects of mild hypothermia on global cerebral ischemia and recirculation in the cat: comparison to normothermia and hyperthermia. J Cereb Blood Flow Metab 9:1411481989

16

Clark WMWechsler LRSabounjian LASchwiderski UE: A phase III randomized efficacy trial of 2000 mg citicoline in acute ischemic stroke patients. Neurology 57:159516022001

17

Davis SMLees KRAlbers GWDiener HCMarkabi SKarlsson G: Selfotel in acute ischemic stroke: possible neurotoxic effects of an NMDA antagonist. Stroke 31:3473542000

18

De Georgia MAKrieger DWAbou-Chebl ADevlin TGJauss MDavis SM: Cooling for Acute Ischemic Brain Damage (COOL AID): a feasibility trial of endovascular cooling. Neurology 63:3123172004

19

De Magalhaes Filho CDKappeler LDupont JSolinc JVillapol SDenis C: Deleting IGF-1 receptor from forebrain neurons confers neuroprotection during stroke and upregulates endocrine somatotropin. J Cereb Blood Flow Metab 37:3964122017

20

Diener HCLees KRLyden PGrotta JDavalos ADavis SM: NXY-059 for the treatment of acute stroke: pooled analysis of the SAINT I and II Trials. Stroke 39:175117582008

21

Doeppner TRKaltwasser BSanchez-Mendoza EHCaglayan ABBähr MHermann DM: Lithium-induced neuroprotection in stroke involves increased miR-124 expression, reduced RE1-silencing transcription factor abundance and decreased protein deubiquitination by GSK3β inhibition-independent pathways.. J Cereb Blood Flow Metab [epub ahead of print]2016

22

Elkins JElkind MVeltkamp RMontaner JJohnston SSinghal A: Natalizumab versus placebo in patients with acute ischemic stroke (AIS): results from ACTION, a multi-center, double-blind, placebo-controlled, randomized Phase 2 clinical trial (S7.005).. Neurology 86:16 SupplS7.0052016. (Abstract)

23

Emsley HCSmith CJGeorgiou RFVail AHopkins SJRothwell NJ: A randomised phase II study of interleukin-1 receptor antagonist in acute stroke patients. J Neurol Neurosurg Psychiatry 76:136613722005

24

Feigin VLKrishnamurthi RVParmar PNorrving BMensah GABennett DA: Update on the global burden of ischemic and hemorrhagic stroke in 1990–2013: the GBD 2013 study. Neuroepidemiology 45:1611762015

25

Ferro A: Mechanistic target of rapamycin modulation: an emerging therapeutic approach in a wide variety of disease processes. Br J Clin Pharmacol 82:115611572016

26

Gaudin AYemisci MEroglu HLepetre-Mouelhi STurkoglu OFDönmez-Demir B: Squalenoyl adenosine nanoparticles provide neuroprotection after stroke and spinal cord injury. Nat Nanotechnol 9:105410622014. (Erratum in Nat Nanotechnol 10: 99 2015)

27

Gelderblom MLeypoldt FSteinbach KBehrens DChoe CUSiler DA: Temporal and spatial dynamics of cerebral immune cell accumulation in stroke. Stroke 40:184918572009

28

Goyal MDemchuk AMMenon BKEesa MRempel JLThornton J: Randomized assessment of rapid endovascular treatment of ischemic stroke. N Engl J Med 372:101910302015

29

Heo JHHan SWLee SK: Free radicals as triggers of brain edema formation after stroke. Free Radic Biol Med 39:51702005

30

Hess DCAuchus APUchino KSila CClark WMChiu D: Final results of the B01-02 phase 2 trial testing the safety and efficacy of MultiStem® in treatment of ischemic stroke.. Stroke 47:A712016. (Abstract)

31

Hill MDMartin RHMikulis DWong JHSilver FLter-Brugge KG: Safety and efficacy of NA-1 in patients with iatrogenic stroke after endovascular aneurysm repair (ENACT): a phase 2, randomised, double-blind, placebo-controlled trial. Lancet Neurol 11:9429502012

32

Holzer MCerchiari EMartens PRoine RSterz FEisenburger P: Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med 346:5495562002. (Erratum in N Engl J Med 346: 1756 2002)

33

Horn Jde Haan RJVermeulen MLimburg M: Very Early Nimodipine Use in Stroke (VENUS): a randomized, double-blind, placebo-controlled trial. Stroke 32:4614652001

34

Hu XLi PGuo YWang HLeak RKChen S: Microglia/macrophage polarization dynamics reveal novel mechanism of injury expansion after focal cerebral ischemia. Stroke 43:306330702012

35

Huisa BNStemer ABWalker MGRapp KMeyer BCZivin JA: Transcranial laser therapy for acute ischemic stroke: a pooled analysis of NEST-1 and NEST-2. Int J Stroke 8:3153202013

36

Jauch ECSaver JLAdams HP JrBruno AConnors JJDemaerschalk BM: Guidelines for the early management of patients with acute ischemic stroke: a guideline for health-care professionals from the American Heart Association/American Stroke Association. Stroke 44:8709472013

37

Jiang ZDuong TQ: Methylene blue treatment in experimental ischemic stroke: a mini review. Brain Circ 2:48532016

38

Jovin TGChamorro ACobo Ede Miquel MAMolina CARovira A: Thrombectomy within 8 hours after symptom onset in ischemic stroke. N Engl J Med 372:229623062015

39

Kasner SEWein TPiriyawat PVillar-Cordova CEChalela JAKrieger DW: Acetaminophen for altering body temperature in acute stroke: a randomized clinical trial. Stroke 33:1301342002

40

Kohler EPrentice DABates TRHankey GJClaxton Avan Heerden J: Intravenous minocycline in acute stroke: a randomized, controlled pilot study and meta-analysis. Stroke 44:249324992013

41

Ladurner GKalvach PMoessler H: Neuroprotective treatment with cerebrolysin in patients with acute stroke: a randomised controlled trial. J Neural Transm (Vienna) 112:4154282005

42

Lai TWZhang SWang YT: Excitotoxicity and stroke: identifying novel targets for neuroprotection. Prog Neurobiol 115:1571882014

43

Li DWang CYao YChen LLiu GZhang R: mTORC1 pathway disruption ameliorates brain inflammation following stroke via a shift in microglia phenotype from M1 type to M2 type. FASEB J 30:338833992016

44

Li PGan YSun BLZhang FLu BGao Y: Adoptive regulatory T-cell therapy protects against cerebral ischemia. Ann Neurol 74:4584712013

45

Lin YSkeberdis VAFrancesconi ABennett MVZukin RS: Postsynaptic density protein-95 regulates NMDA channel gating and surface expression. J Neurosci 24:10138101482004

46

Liu PYang XHei CMeli YNiu JSun T: Rapamycin reduced ischemic brain damage in diabetic animals is associated with suppressions of mTOR and ERK1/2 signaling. Int J Biol Sci 12:103210402016

47

Liu SGeng XForreider BXiao YKong QDing Y: Enhanced beneficial effects of mild hypothermia by phenothiazine drugs in stroke therapy. Neurol Res 37:4544602015

48

Liu XXia JWang LSong YYang JYan Y: Efficacy and safety of ginsenoside-Rd for acute ischaemic stroke: a randomized, double-blind, placebo-controlled, phase II multicenter trial. Eur J Neurol 16:5695752009

49

Liu ZJChen CLi XRRan YYXu TZhang Y: Remote ischemic preconditioning-mediated neuroprotection against stroke is associated with significant alterations in peripheral immune responses. CNS Neurosci Ther 22:43522016

50

Lyden PHemmen TGrotta JRapp KErnstrom KRzesiewicz T: Results of the ICTuS 2 Trial (Intravascular Cooling in the Treatment of Stroke 2). Stroke 47:288828952016

51

Martin-Schild SHallevi HShaltoni HBarreto ADGonzales NRAronowski J: Combined neuroprotective modalities coupled with thrombolysis in acute ischemic stroke: a pilot study of caffeinol and mild hypothermia. J Stroke Cerebrovasc Dis 18:86962009

52

Matsuo YOnodera HShiga YNakamura MNinomiya MKihara T: Correlation between myeloperoxidase-quantified neutrophil accumulation and ischemic brain injury in the rat. Effects of neutrophil depletion. Stroke 25:146914751994

53

Mocco JZaidat OVon Kummer RYoo AGupta RLopes D: Results of the THERAPY trial: a prospective, randomized trial to define the role of mechanical thrombectomy as adjunctive treatment to IV rtPA in acute ischemic stroke. Int J Stroke 10:10102015

54

Mochizuki-Oda NKataoka YCui YYamada HHeya MAwazu K: Effects of near-infra-red laser irradiation on adenosine triphosphate and adenosine diphosphate contents of rat brain tissue. Neurosci Lett 323:2072102002

55

Natale JAD'Alecy LG: Protection from cerebral ischemia by brain cooling without reduced lactate accumulation in dogs. Stroke 20:7707771989

56

O'Collins VEMacleod MRDonnan GAHorky LLvan der Worp BHHowells DW: 1,026 experimental treatments in acute stroke. Ann Neurol 59:4674772006

57

Pedata FPugliese AMCoppi EDettori IMaraula GCellai L: Adenosine A2A receptors modulate acute injury and neuroinflammation in brain ischemia.. Mediators Inflamm 2014:8051982014

58

Prasad KKrishnan PR: Fever is associated with doubling of odds of short-term mortality in ischemic stroke: an updated meta-analysis. Acta Neurol Scand 122:4044082010

59

Rodriguez PZhao JMilman BTiwari YVDuong TQ: Methylene blue and normobaric hyperoxia combination therapy in experimental ischemic stroke.. Brain Behav 6:e004782016

60

Rojas JCBruchey AKGonzalez-Lima F: Neurometabolic mechanisms for memory enhancement and neuroprotection of methylene blue. Prog Neurobiol 96:32452012

61

Ryou MGChoudhury GRLi WWinters AYuan FLiu R: Methylene blue-induced neuronal protective mechanism against hypoxia-reoxygenation stress. Neuroscience 301:1932032015

62

Saver JLGoyal MBonafe ADiener HCLevy EIPereira VM: Stent-retriever thrombectomy after intravenous t-PA vs. t-PA alone in stroke. N Engl J Med 372:228522952015

63

Saver JLStarkman SEckstein MStratton SJPratt FDHamilton S: Prehospital use of magnesium sulfate as neuroprotection in acute stroke. N Engl J Med 372:5285362015

64

Schäbitz WRLaage RVogt GKoch WKollmar RSchwab S: AXIS: a trial of intravenous granulocyte colony-stimulating factor in acute ischemic stroke. Stroke 41:254525512010

65

Scheindlin S: Something old... something blue. Mol Interv 8:2682732008

66

Schmidley JW: Free radicals in central nervous system ischemia. Stroke 21:108610901990

67

Schwab SSchwarz SSpranger MKeller EBertram MHacke W: Moderate hypothermia in the treatment of patients with severe middle cerebral artery infarction. Stroke 29:246124661998

68

Shen QDu FHuang SRodriguez PWatts LTDuong TQ: Neuroprotective efficacy of methylene blue in ischemic stroke: an MRI study.. PLoS One 8:e798332013

69

Siniscalchi AIannacchero RAnticoli SPezzella FRDe Sarro GGallelli L: Anti-inflammatory strategies in stroke: a potential therapeutic target. Curr Vasc Pharmacol 14:981052016

70

Wahlgren NGRanasinha KWRosolacci TFranke CLvan Erven PMAshwood T: Clomethiazole acute stroke study (CLASS): results of a randomized, controlled trial of clomethiazole versus placebo in 1360 acute stroke patients. Stroke 30:21281999

71

Xia YCai WThomson AWHu X: Regulatory T cell therapy for ischemic stroke: how far clinical translation?. Transl Stroke Res 7:4154192016

72

Yamaguchi TSano KTakakura KSaito IShinohara YAsano T: Ebselen in acute ischemic stroke: a placebo-controlled, double-blind clinical trial. Stroke 29:12171998

73

Yehuda SCarasso RL: Modification of d-amphetamine- or chlorpromazine-induced hypothermia by β-endorphin, MIF-I, and α-MSH: mediation by the dopaminergic system. Peptides 3:1051101982

74

Yu CYNg GLiao P: Therapeutic antibodies in stroke. Transl Stroke Res 4:4774832013

75

Zhang XRojas JCGonzalez-Lima F: Methylene blue prevents neurodegeneration caused by rotenone in the retina. Neurotox Res 9:47572006

76

Zhu ZFu YTian DSun NHan WChang G: Combination of the immune modulator fingolimod with alteplase in acute ischemic stroke: a pilot trial. Circulation 132:110411122015

TrendMD

Metrics

Metrics

All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 254 254 78
PDF Downloads 302 302 38
EPUB Downloads 0 0 0

PubMed

Google Scholar