Neuroprotection for Stroke: Current Status and Future Perspectives

Abstract

Neuroprotection aims to prevent salvageable neurons from dying. Despite showing efficacy in experimental stroke studies, the concept of neuroprotection has failed in clinical trials. Reasons for the translational difficulties include a lack of methodological agreement between preclinical and clinical studies and the heterogeneity of stroke in humans compared to homogeneous strokes in animal models. Even when the international recommendations for preclinical stroke research, the Stroke Academic Industry Roundtable (STAIR) criteria, were followed, we have still seen limited success in the clinic, examples being NXY-059 and haematopoietic growth factors which fulfilled nearly all the STAIR criteria. However, there are a number of neuroprotective treatments under investigation in clinical trials such as hypothermia and ebselen. Moreover, promising neuroprotective treatments based on a deeper understanding of the complex pathophysiology of ischemic stroke such as inhibitors of NADPH oxidases and PSD-95 are currently evaluated in preclinical studies. Further concepts to improve translation include the investigation of neuroprotectants in multicenter preclinical Phase III-type studies, improved animal models, and close alignment between clinical trial and preclinical methodologies. Future successful translation will require both new concepts for preclinical testing and innovative approaches based on mechanistic insights into the ischemic cascade.

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

“…94 This is crucial, since promising treatments validated in preclinical models usually fail in clinical trials. Although the validity of the STAIR's recommendations has not been always confirmed, [95][96][97] they represent a useful guide for researchers planning preclinical stroke studies by providing directions on the selection and execution of the animal model, the fundamentals of good scientific inquiry, the choice and measurement of outcomes, and the drug/treatment administration, including the route and time-window. [98][99][100] We have previously defined the dose-response curve and the time-window for the neuroprotective effects of acute i.p.…”

Prevention and treatment of ischemic stroke in patients with atrial fibrillation

“…Promising neuroprotection that meets the Stroke Academic Industry Roundtable criteria and is based on a more profound understanding of the complex IS pathophysiology such as inhibitors of NADPH oxidases and PSD-95, hypothermia and ebselen, a seleno-organic compound with glutathione peroxidase-like activity, is nowadays intensively evaluated (30).…”

Stress as Necessary Component of Realistic Recovery in Animal Models of Experimental Stroke

“…Indeed, there is now a consensus that animal modeling of stroke, and of recovery from stroke needs to be altered to take into account the heterogeneity of human stroke, the variation between human and animal brain structures and functions, and differences in the therapeutic time window between animals and humans, to optimize its ability to preclinically assess interventions. [57][58][59][60][61] More recent theoretical approaches have highlighted the need to consider factors such as age and gender 55 as well as issues related to other clinical conditions that may be present in human stroke patients such as hypertension, diabetes, heart disease, 62 and use of concomitant medications, 63 in animal stroke models. The Stroke Therapy Academic Industry Roundtable (STAIR) recommendations, developed in 1999 in response to the failure of translation of preclinical findings and updated in 2009, provide guidelines developed to improve the quality of preclinical studies and provide standards for the development of neurorestorative interventions that would ensure that demonstrated preclinical benefits would not be lost in translation to the clinical setting.…”