Article

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

ABSTRACT 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.
    Restorative neurology and neuroscience 01/2015; 33(2). DOI:10.3233/RNN-140440 · 4.18 Impact Factor
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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.
    Progress in Neurobiology 03/2012; 97(1):14-37. DOI:10.1016/j.pneurobio.2012.02.003 · 10.30 Impact Factor
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    • "Involvement of multiple pathways may be part of the explanation why NMDAR antagonists have failed in clinical trials. A combination therapy using blockers of several routes of Ca 2+ -influx might be necessary to obtain neuroprotection in stroke (Szydlowska and Tymianski 2010; Cook and Tymianski 2011). Organotypical hippocampal slice cultures represent a good model for studying mechanisms underlying cell death signaling in brain ischemia. "
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    ABSTRACT: N-Methyl-D-aspartate receptors (NMDARs) are essential mediators of synaptic plasticity under normal physiological conditions. During brain ischemia, these receptors are excessively activated due to glutamate overflow and mediate excitotoxic cell death. Although organotypical hippocampal slice cultures are widely used to study brain ischemia in vitro by induction of oxygen and glucose deprivation (OGD), there is scant data regarding expression and functionality of NMDARs in such slice cultures. Here, we have evaluated the contribution of NMDARs in mediating excitotoxic cell death after exposure to NMDA or OGD in organotypical hippocampal slice cultures after 14 days in vitro (DIV14). We found that all NMDAR subunits were expressed at DIV14. The NMDARs were functional and contributed to cell death, as evidenced by use of the NMDAR antagonist MK-801 (dizocilpine). Excitotoxic cell death induced by NMDA could be fully antagonized by 10 μM MK-801, a dose that offered only partial protection against OGD-induced cell death. Very high concentrations of MK-801 (50-100 μM) were required to counteract cell death at long delays (48-72 h) after OGD. The relative high dose of MK-801 needed for long-term protection after OGD could not be attributed to down-regulation of NMDARs at the gene expression level. Our data indicate that NMDAR signaling is just one of several mechanisms underlying ischemic cell death and that prospective cytoprotective therapies must be directed to multiple targets.
    Cell and Tissue Research 09/2011; 345(3):329-41. DOI:10.1007/s00441-011-1218-2 · 3.33 Impact Factor
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