Understanding history, and not repeating it. Neuroprotection for acute ischemic stroke: From review to preview

Grupke, Stephen; Hall, Jason F.; Dobbs, Michael; Bix, Gregory; Fraser, Justin F.

doi:10.1016/j.clineuro.2014.11.013

Cited by 87 publications

(58 citation statements)

References 76 publications

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“…The relevance of the repurposing approach in ischemic stroke is related to the fact that during the past three decades, all the clinical trials performed with neuroprotective drugs have failed due to excessive toxicity or lack of efficacy. 21,39 In this context, the use of drugs for which the human target has often been already validated, which are characterized by a well-established safety profile, will dramatically reduce the risk of clinical trial failure, thus significantly boosting the discovery of novel stroke therapeutics. 19,[40][41][42] This latter aim is further supported by the fact that azithromycin provides neuroprotection through the modulation of immune mechanisms that are recruited at later times after the acute event, allowing to extend the therapeutic time-window.…”

Section: Discussionmentioning

confidence: 99%

“…19 In fact, the use of drugs with a wellestablished safety profile and for which the target in humans has been already validated allows to drastically reduce the rate of clinical trial failure that has dominated the unsuccessful development of neuroprotective drugs in stroke during the past decades. [19][20][21] Following the concept of drug repurposing, with the aim of exerting a rational immunomodulation, we have recently validated the preclinical efficacy of azithromycin (9-deoxy9a-aza-9a-methyl-9a-homoerythromycin A), a dibasic macrolide antibiotic that accumulates in macrophages and neutrophils [22][23][24] and displays prolonged antibacterial as well as anti-inflammatory and immunomodulatory effects. 25 Acute intraperitoneal (i.p.)…”

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confidence: 99%

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Neuroprotective Properties of a Macrolide Antibiotic in a Mouse Model of Middle Cerebral Artery Occlusion: Characterization of the Immunomodulatory Effects and Validation of the Efficacy of Intravenous Administration

Amantea

Certo

Petrelli

et al. 2016

ASSAY and Drug Development Technologies

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Neuroprotective Properties of a Macrolide Antibiotic in a Mouse Model of Middle Cerebral Artery Occlusion: Characterization of the Immunomodulatory Effects and Validation of the Efficacy of Intravenous Administration

Amantea

Certo

Petrelli

et al. 2016

ASSAY and Drug Development Technologies

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“…Targeting this cascade has potential for reducing tissue injury and lengthening the therapeutic window for revascularization. However, drugs targeting the inflammatory cascade have been unsuccessful in clinical trials, notably due to adverse effects and poor central nervous system (CNS) penetration 13, 14…”

Section: Introductionmentioning

confidence: 99%

Apolipoprotein E mimetic peptide, CN‐105, improves outcomes in ischemic stroke

Kolls

Soderblom

et al. 2017

Ann Clin Transl Neurol

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ObjectiveAt present, the absence of a pharmacological neuroprotectant represents an important unmet clinical need in the treatment of ischemic and traumatic brain injury. Recent evidence suggests that administration of apolipoprotein E mimetic therapies represent a viable therapeutic strategy in this setting. We investigate the neuroprotective and anti‐inflammatory properties of the apolipoprotein E mimetic pentapeptide, CN‐105, in a microglial cell line and murine model of ischemic stroke.MethodsTen to 13‐week‐old male C57/BL6 mice underwent transient middle cerebral artery occlusion and were randomly selected to receive CN‐105 (0.1 mg/kg) in 100 μL volume or vehicle via tail vein injection at various time points. Survival, motor‐sensory functional outcomes using rotarod test and 4‐limb wire hanging test, infarct volume assessment using 2,3,5‐Triphenyltetrazolium chloride staining method, and microglial activation in the contralateral hippocampus using F4/80 immunostaining were assessed at various time points. In vitro assessment of tumor necrosis factor‐alpha secretion in a microglial cell line was performed, and phosphoproteomic analysis conducted to explore early mechanistic pathways of CN‐105 in ischemic stroke.ResultsMice receiving CN‐105 demonstrated improved survival, improved functional outcomes, reduced infarct volume, and reduced microglial activation. CN‐105 also suppressed inflammatory cytokines secretion in microglial cells in vitro. Phosphoproteomic signals suggest that CN‐105 reduces proinflammatory pathways and lower oxidative stress.Interpretation CN‐105 improves functional and histological outcomes in a murine model of ischemic stroke via modulation of neuroinflammatory pathways. Recent clinical trial of this compound has demonstrated favorable pharmacokinetic and safety profile, suggesting that CN‐105 represents an attractive candidate for clinical translation.

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“…Many of these compounds lack sufficient brain penetrance while exhibiting significant dose-limiting side effects. 27,38,39 The adverse event profiles included hallucinations, agitations, catatonia, peripheral sensory loss, nausea, and elevation in blood pressure. 40 Moreover, in the case of acute processes such as stroke or traumatic brain injuries, glutamate excitotoxicity is thought to cause harm within a narrow timeframe after which the neurotransmitter reassumes its normal function.…”

Section: Previous Strategies To Reduce the Glutamate Excitotoxicitymentioning

confidence: 99%

A novel mechanism of neuroprotection: Blood glutamate grabber

Castillo

Loza

Mirelman

et al. 2015

J Cereb Blood Flow Metab

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Glutamate excitotoxicity is a primary contributor of ischemic neuronal death and other cellular components of the neurovascular unit. Several strategies have been developed against glutamate excitotoxicity, however none of them have not shown positive results in the clinical practice so far. Nowadays, the concept of blood/brain glutamate grabbing or scavenging is well recognized as a novel and attractive protective strategy to reduce the excitotoxic effect of excess extracellular glutamate that accumulates in the brain following an ischemic stroke. The main advantage of this novel therapeutic strategy is that it occurs in the blood circulation and therefore does not affect the normal brain neurophysiology, as it has been described for other drug treatments used against glutamate excitotoxicity. In this work we report all experimental data from the beginning of our studies, focused on stroke pathology, and we describe new findings about the potential application of this therapy. Future clinical trials will allow to know the real efficacy of this novel therapeutic strategy in stroke patients.

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Understanding history, and not repeating it. Neuroprotection for acute ischemic stroke: From review to preview

Cited by 87 publications

References 76 publications

Neuroprotective Properties of a Macrolide Antibiotic in a Mouse Model of Middle Cerebral Artery Occlusion: Characterization of the Immunomodulatory Effects and Validation of the Efficacy of Intravenous Administration

Neuroprotective Properties of a Macrolide Antibiotic in a Mouse Model of Middle Cerebral Artery Occlusion: Characterization of the Immunomodulatory Effects and Validation of the Efficacy of Intravenous Administration

Apolipoprotein E mimetic peptide, CN‐105, improves outcomes in ischemic stroke

A novel mechanism of neuroprotection: Blood glutamate grabber

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