Pre-clinical to Clinical Translational Failures and Current Status of Clinical Trials in Stroke Therapy: A Brief Review

Abstract

: In stroke (brain ischemia), the leading cause of functional disability and mortality worldwide, despite continuous efforts both at experimental and clinical level in getting the better understanding, the only approved pharmacological treatment has been restricted to tissue plasminogen activator (tPA). Its complex pathophysiology starts with energy pump failure which ends with neuronal cell death. Ischemic cascade involves excessive glutamate release followed by raised intracellular sodium and calcium influx along with free radicals’ generation, activation of inflammatory cytokines, NO synthases, lipases, endonucleases and other apoptotic pathways leading to cell edema and death. At pre-clinical stage, several agents have tried and proven as an effective neuroprotectant in animal models of ischemia. However, these agents failed to show convincing results in terms of efficacy and safety when the trials were conducted in humans following stroke. This article highlights the various agents which have tried in the past but failed to translate into stroke therapy along with key points that are responsible for lagging of experimental success to translational failure in stroke treatment.

Combination treatment with U0126 and rt-PA prevents adverse effects of the delayed rt-PA treatment after acute ischemic stroke

“…By adding U0126 in combination with rt-PA we prevent activation of MMP-9 expression leading to BBB leakage and hemorrhagic transformation. Despite tremendous attempts over the last decades in developing new treatments for ischemic stroke none of them demonstrated efficacy and safety in clinical trials 17 , 18 . Considering that stroke is a vascular disease, neuroprotection without restoration of tissue perfusion will have a low possibility of demonstrating efficiency in treating acute ischemic stroke 19 .…”

Histone Deacetylases and Their Isoform-Specific Inhibitors in Ischemic Stroke

“…Each of these stages is the time point of possible application of anti-stroke drugs. Many compounds tested in animal and cell models with the exception of tissue plasminogen activator (tPA) or endovascular thrombectomy [11] reduced apoptotic cell counts, increased infarction size, and improved neurological deficits after stroke [12][13][14]. However, none of these drugs have been successful in clinical trials.…”

Epigenetic Regulations of Microglia/Macrophage Polarization in Ischemic Stroke

“…To date, the treatment of acute ischemic stroke still largely depends on the intravenous thrombolysis and endovascular treatment (Goyal et al, 2016;Eskey et al, 2018;Thiebaut et al, 2018). Unfortunately, many neuroprotective drugs have failed to show beneficial effects in the treatment of acute ischemic stroke (Auriel and Bornstein, 2010;Xu and Pan, 2013;Kikuchi et al, 2014;Dhir et al, 2020). Consequently, there is a pressing need to conduct further research to clarify the mechanism of ischemic brain injury and to find effective targets for the diagnosis and treatment of ischemic stroke.…”