Neuroprotection for ischemic stroke: Two decades of success and failure

Cheng, Yuhui; Al-Khoury, Lama; Zivin, Justin A.

doi:10.1602/neurorx.1.1.36

Cited by 330 publications

(162 citation statements)

References 84 publications

(19 reference statements)

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“…In some trials, study agents have been tested at doses below those shown to be neuroprotective in animal models because of dose-limiting side effects, such as psychoactive effects, QT prolongation or liver function test abnormalities [28]. Two large Phase III trials of the competitive NMDA antagonist selfotel were terminated prematurely because of an apparent lack of clinical efficacy [29].…”

Section: Neuroprotective Agents In Acute Ischaemic Strokementioning

confidence: 99%

Optimising Clinical Trial Design for Proof of Neuroprotection in Acute Ischaemic Stroke: The SAINT Clinical Trial Programme

Davis

2006

Cerebrovasc Dis

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The development of effective therapies for acute ischaemic stroke has proven to be a challenging task. The only approved therapy for acute ischaemic stroke remains intravenous recombinant tissue plasminogen activator initiated within 3 h of stroke onset, following a CT scan to exclude intracerebral haemorrhage. Many other therapies have been evaluated in Phase III clinical trials, including more than 50 neuroprotective agents, but the results have either been inconclusive or negative. These trials have provided valuable lessons for the design of future studies in acute ischaemic stroke, including the importance of adequate testing in preclinical studies, time to treatment from symptom onset, target dose, patient selection, sample size and the outcome measures used. These key criteria have been captured in the Stroke Therapy Academic Industry Roundtable (STAIR) recommendations for the preclinical and clinical development of acute stroke therapies. NXY-059 is a novel free radical-trapping neuroprotectant that reduces infarct size and preserves brain function in animal models of acute ischaemic stroke. It is one of the first compounds to have progressed to Phase III clinical trials, having fulfilled the STAIR recommendations for the preclinical development of neuroprotective agents. The efficacy and safety of NXY-059 in patients with acute ischaemic stroke is currently being evaluated in the Stroke Acute Ischaemic NXY-059 Treatment (SAINT) clinical trial programme, which was designed in accordance with the STAIR clinical recommendations. The final results from the first of these studies, SAINT I, have recently been reported.

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Section: Neuroprotective Agents In Acute Ischaemic Strokementioning

confidence: 99%

Optimising Clinical Trial Design for Proof of Neuroprotection in Acute Ischaemic Stroke: The SAINT Clinical Trial Programme

Davis

2006

Cerebrovasc Dis

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“…The reduction of regional cerebral blood flow triggers a complex series of biochemical changes and metabolic reactions in the ischemic tissue, the ‘ischemic cascade’ , which lead, ultimately, to cell death [32]. Among these changes, the increased activation of glutamate receptors, intracellular accumulation of calcium ions, abnormal recruitment of inflammatory cells, and excessive production of free radicals and pathological apoptosis, all appear to play crucial roles in the ischemic penumbra zone [19]. The area of the brain which remains between the limits of ‘electric failure’ (15– 18 ml/100 g/min) and ‘energy failure’ (10–12 ml/100 g/min) because of blood flow conditions is called the ‘ischemic penumbra’ and, although it is functionally inactive, it is potentially recoverable if perfusion pressure is normalized.…”

Section: Bases For Neuroprotection and Neurorestorationmentioning

confidence: 99%

“…However, clinical trials with neuroprotective drugs have been largely negative or have shown very limited efficacy in certain subgroups of patient [13,14,15,16,17,18]. This issue has drawn extensive reviews highlighting possible causes for the discrepancies between experimental studies and clinical trials [19,20,21,22,23,24]. …”

Section: Introductionmentioning

confidence: 99%

Challenges of Neuroprotection and Neurorestoration in Ischemic Stroke Treatment

Martínez‐Vila

Irimia²

2005

Cerebrovasc Dis

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Currently, the most important therapeutic approaches in the acute phase of ischemic stroke are focused on the restoration of regional cerebral blood flow, early admission to a stroke unit and the attempt to block, using neuroprotective drugs, the biochemical and metabolic changes involved in the ‘ischemic cascade’. Treatment with rt-PA in the acute phase, although very effective, is still limited to a small number of patients and positive preclinical results of neuroprotective treatment have not, as yet, been endorsed in clinical trials. The remarkable lack of concordance between the positive results in experimental models and the negative results obtained in clinical trials has led to a change in attitude in the conduct of preclinical studies as well as to a modification of the design of clinical trials, with special attention being paid to patient selection criteria and clinical evaluation. Some neuroprotective drugs, such as citicoline, have shown some efficacy in subgroups of patients with cerebral infarction, even with a therapeutic window of up to 24 h, which would suggest a possible neurorestorative effect. Different degrees of functional recovery, weeks or months after the ischemic event, are currently observed in clinical practice and have been related to endogenous self-repair mechanisms. The growing understanding of the mechanisms involved in the phenomena of brain plasticity and their modulation, together with the possibility of restoring functional deficits by encouraging endogenous neurogenesis or by cell therapy, open up new directions in the treatment of stroke patients.

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“…Diabetic stroke rats exhibit resistance to thrombolytic reperfusion, and are susceptible to developing intracerebral hemorrhage 12, 13. Several novel therapeutics that improve functional outcome and promote neuroprotection in non‐DM stroke have failed to yield similar outcomes when tested in DM‐stroke animals as well as in human clinical trials 14, 15. Given the differential challenges of treating strokes in diabetics compared to nondiabetics, this review summarizes current knowledge and highlights of promising cell based and exosome therapy for diabetic stroke.…”

Section: Introductionmentioning

confidence: 99%

Cell-Based and Exosome Therapy in Diabetic Stroke

Venkat

Chopp

Chen

2018

Stem Cells Translational Medicine

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SummaryStroke is a global health concern and it is imperative that therapeutic strategies with wide treatment time frames be developed to improve neurological outcome in patients. Patients with diabetes mellitus who suffer a stroke have worse neurological outcomes and long‐term functional recovery than nondiabetic stroke patients. Diabetes induced vascular damage and enhanced inflammatory milieu likely contributes to worse post stroke outcomes. Diabetic stroke patients have an aggravated pathological cascade, and treatments that benefit nondiabetic stroke patients do not necessarily translate to diabetic stroke patients. Therefore, there is a critical need to develop therapeutics for stroke specifically in the diabetic population. Stem cell based therapy for stroke is an emerging treatment option with wide therapeutic time window. Cell‐based therapies for stroke promote endogenous central nervous system repair and neurorestorative mechanisms such as angiogenesis, neurogenesis, vascular remodeling, white matter remodeling, and also modulate inflammatory and immune responses at the local and systemic level. Emerging evidence suggests that exosomes and their cargo microRNA mediate cell therapy derived neurorestorative effects. Exosomes are small vesicles containing protein and RNA characteristic of its parent cell. Exosomes are transported by biological fluids and facilitate communication between neighboring and remote cells. MicroRNAs, a class of naturally occurring, small noncoding RNA sequences, contained within exosomes can regulate recipient cell's signaling pathways and alter protein expression either acting alone or in concert with other microRNAs. In this perspective article, we summarize current knowledge and highlight the promising future of cell based and exosome therapy for stroke and specifically for diabetic stroke. stem cells translational medicine 2018;7:451–455

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Neuroprotection for ischemic stroke: Two decades of success and failure

Cited by 330 publications

References 84 publications

Optimising Clinical Trial Design for Proof of Neuroprotection in Acute Ischaemic Stroke: The SAINT Clinical Trial Programme

Optimising Clinical Trial Design for Proof of Neuroprotection in Acute Ischaemic Stroke: The SAINT Clinical Trial Programme

Challenges of Neuroprotection and Neurorestoration in Ischemic Stroke Treatment

Cell-Based and Exosome Therapy in Diabetic Stroke

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