Neuroprotection for Ischaemic Stroke: Translation from the Bench to the Bedside

Abstract

Neuroprotection seeks to restrict injury to the brain parenchyma following an ischaemic insult by preventing salvageable neurons from dying. The concept of neuroprotection has shown promise in experimental studies, but has failed to translate into clinical success. Many reasons exist for this including the heterogeneity of human stroke and the lack of methodological agreement between preclinical and clinical studies. Even with the proposed Stroke Therapy Academic Industry Roundtable criteria for preclinical development of neuroprotective agents for stroke, we have still seen limited success in the clinic, an example being NXY-059, which fulfilled nearly all the Stroke Therapy Academic Industry Roundtable criteria. There are currently a number of ongoing trials for neuroprotective strategies including hypothermia and albumin, but the outcome of these approaches remains to be seen. Combination therapies with thrombolysis also need to be fully investigated, as restoration of oxygen and glucose will always be the best therapy to protect against cell death from stroke. There are also a number of promising neuroprotectants in preclinical development including haematopoietic growth factors, and inhibitors of the nicotinamide adenine dinucleotide phosphate oxidases, a source of free radical production which is a key step in the pathophysiology of acute ischaemic stroke. For these neuroprotectants to succeed, essential quality standards need to be adhered to; however, these must remain realistic as the evidence that standardization of procedures improves translational success remains absent for stroke.

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

“…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…”

Importance of Preclinical Research in the Development of Neuroprotective Strategies for Ischemic Stroke

“…In particular, clinical studies have used dosing and treatment time windows not supported by preclinical studies. 20,21 Preclinical studies themselves have suffered from small sample sizes, insufficient statistical power calculations, and lack of randomization and blinding, all potentially leading to false-positive results. 25 The use of young, mostly male rodents of a similar strain does not encapsulate the heterogeneity of stroke patients, who are usually elderly with comorbidities severely impacting outcome.…”

The value of patient selection in demonstrating treatment effect in stroke recovery trials: lessons from the CHIMES study of MLC601 (NeuroAiD)

“…The reasons for this failure have been extensively discussed 24, 25, 26. Clinically, patient selection may be among the most important factors that should be considered when designing trials in stroke.…”