Translating promising preclinical neuroprotective therapies to human stroke trials

University of Toronto, Department of Surgery, Division of Neurosurgery, Toronto Western Research Institute Neuroprotection Laboratory, 11-414 MCl 399 Bathurst St, Toronto, ON, M5T 2S8, Canada.
Expert Review of Cardiovascular Therapy 04/2011; 9(4):433-49. DOI: 10.1586/erc.11.34
Source: PubMed


Stroke is the third leading cause of mortality and carries the greatest socioeconomic burden of disease in North America. Despite several promising therapies discovered in the preclinical setting, there have been no positive results in human stroke clinical trials to date. In this article, we review the potential causes for failure and discuss strategies that have been proposed to overcome the barrier to translation of stroke therapies. To improve the chance of success in future human stroke trials, we propose that therapies be tested in stroke models that closely resemble the human condition with molecular, imaging and functional outcomes that relate to outcomes utilized in clinical trials. These strategies include higher-order, old-world, nonhuman primate models of stroke with clinically relevant outcome measures. Although stroke neuroprotection has been looked upon pessimistically given the many failures in clinical trials to date, we propose that neuroprotection in humans is feasible and will be realized with rigorous translational science.

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    • "However, the essential physiological conditions and anatomical structures of the rodent brain are dramatically different from those in humans. Therefore, rodent studies do not always reflect human situations , and the species-specific differences in stroke are considered as potential reasons for the failure of translation from rodent studies to clinical trials (Cook and Tymianski, 2011; Hoyte et al., 2004). To bridge this biological gap, the Stroke Therapy Academic Industry Roundtable (STAIR) committee suggested that nonhuman primates (NHPs) should be used for preclinical and translational stroke research (Fisher et al., 2009; Stroke therapy academic industry round table, 1999). "
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    ABSTRACT: Purpose: We aimed to develop a nonhuman primate (NHP) stroke model for studies of secondary lesions in remote areas and to characterize its behavioral and neuroimaging features. Methods: Monkeys were either subjected to middle cerebral artery occlusion (MCAO) distal to the M1 branch (n = 17) or sham operation (n = 7). Neurological assessment and magnetic resonance imaging (MRI) were performed before and 1 week after operation. Results: After MCAO, six monkeys showed occlusion of the distal M1 segment and infarcts predominantly in the cortical and subcortical regions, without hippocampal and thalamic involvement. They had obvious neurological deficits. The other 11 monkeys showed blockage of the main trunk of the MCA, with infarcts extending into the hippocampus and thalamus, but no substantia nigra involvement. Their infarct volume were larger and neurological deficits were more severe than those after distal M1 occlusion. All sham-operated monkeys displayed normal behavior; however, MRI revealed small infarcts in three animals. Conclusions: MCAO or even sham operations might cause cerebral infarction in NHPs. Therefore, neurological assessment should be combined with MRI for screening candidate stroke models. Our model is suitable for studying secondary damage in remote regions, including the thalamus, hippocampus, and substantia nigra, after stroke.
    Full-text · Article · Jan 2015 · Restorative neurology and neuroscience
    • "The two main treatment approaches for ischemic stroke are cerebral thrombolysis and neuroprotective interventions aimed at restoration of blood flow to the ischemic tissue and limitation of irreversible neuronal injury in the setting of ischemiareperfusion , respectively. Although more than a thousand therapies were shown to be neuroprotective in the preclinical studies, the results of clinical trials have proved to be considerably less optimistic (Cook and Tymianski, 2011). The natural plant-derived neuroprotective agents could be more advantageous than the synthetic ones because of better patient compliance and improved safety profile. "
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    ABSTRACT: While the neuroprotective effect of green tea (Camellia sinensis) might be explained by the presence of amino acid L-theanine in the tea leaves, it is not known whether postischemic administration of L-theanine could also provide neuroprotection. In the present study, we investigated the neuroprotective effect of L-theanine (1 and 4 mg/kg) administered at 3, 12, and 24 h after reperfusion in the rat model of stroke. We also studied the effect of L-theanine on brain injury caused by exogenous administration of N-methyl-D-aspartate and α-amino-3-hydroxy-5-methyl-isoxazole-4-propionate/kainate receptor agonists during reperfusion. Rats were subjected to 30-min middle cerebral artery occlusion followed by 48-h reperfusion. Neurological deficit and infarct size were determined at the end of reperfusion. At 3 and 12 h, but not at 24 h of reperfusion, L-theanine substantially reduced the size of brain infarct. Neurological status was improved when L-theanine was administered 3, 12, and 24 h after reperfusion. Repeated intrastriatal injections of L-theanine at a total dose of 800 µg/kg during reperfusion prevented brain injury caused by glutamate receptor agonists. In conclusion, L-theanine at reperfusion exerts neuroprotective effect in the in vivo rat model of stroke. Local treatment with L-theanine at reperfusion prevents glutamate receptor agonist-mediated brain injury. Copyright © 2012 John Wiley & Sons, Ltd.
    No preview · Article · Sep 2013 · Phytotherapy Research
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    • "However, cost and ethical issues of primate research has made their wider use by most laboratories difficult, if not impossible. Despite, the recognition of role of primate research for translational medicine (Cook and Tymianski, 2011) without better funding, institutional change in animal facilities, and costs its use will remain limited and rodent models will continue to provide the predominant basic science research into the mechanisms of brain injury and its treatment. Perhaps confirmation in primate of a treatment found effective in rodents or other species may reduce the number of failures in clinical trial. "
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    ABSTRACT: Aneurysmal subarachnoid hemorrhage (aSAH) is a medical emergency that accounts for 5% of all stroke cases. Individuals affected are typically in the prime of their lives (mean age 50 years). Approximately 12% of patients die before receiving medical attention, 33% within 48 h and 50% within 30 days of aSAH. Of the survivors 50% suffer from permanent disability with an estimated lifetime cost more than double that of an ischemic stroke. Traditionally, spasm that develops in large cerebral arteries 3-7 days after aneurysm rupture is considered the most important determinant of brain injury and outcome after aSAH. However, recent studies show that prevention of delayed vasospasm does not improve outcome in aSAH patients. This finding has finally brought in focus the influence of early brain injury on outcome of aSAH. A substantial amount of evidence indicates that brain injury begins at the aneurysm rupture, evolves with time and plays an important role in patients' outcome. In this manuscript we review early brain injury after aSAH. Due to the early nature, most of the information on this injury comes from animals and few only from autopsy of patients who died within days after aSAH. Consequently, we began with a review of animal models of early brain injury, next we review the mechanisms of brain injury according to the sequence of their temporal appearance and finally we discuss the failure of clinical translation of therapies successful in animal models of aSAH.
    Full-text · Article · Mar 2012 · Progress in Neurobiology
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