Free Radical Trapping as a Therapeutic Approach to Neuroprotection in Stroke: Experimental and Clinical Studies with NXY-059 and Free Radical Scavengers

Abstract

There is substantial experimental evidence that free radicals are produced in the brain during ischemia, during reperfusion and during intracranial hemorrhage. Removal of pathologically produced free radicals is therefore a viable approach to neuroprotection. Four compounds with free radical scavenging activity (tirilazad, ebselen, edaravone) or free radical trapping properties (NXY-059) have been examined in experimental models of stroke and evaluated clinically as neuroprotective agents. Both experimental and clinical results are reviewed in this article. Ebselen was a modestly effective neuroprotectant in a rat transient middle cerebral artery occlusion (MCAO) model when given before the start of ischemia, but not when the insult was severe. Data from the permanent MCAO model and an embolic stroke model suggested a bell shaped dose-response curve. The weak preclinical profile may explain the lack of success in clinical trials. Preclinical data on tirilazad in animal models of acute ischemic stroke are neither comprehensive nor consistent. There was little evidence of efficacy in permanent MCAO or when the drug was given several hours post-occlusion. This may explain the negative clinical trials as these did not target patients likely to reperfuse and treatment started several hours after stroke onset. While preclinical data on subarachnoid hemorrhage demonstrated an attenuation of vasospasm the clinical data were inconsistent. There is very limited published preclinical data on edaravone but it has been approved in Japan as a neuroprotectant for the treatment of stroke. Evidence is based on a single placebo controlled trial in a relatively small number of patients. The status of possible development of edaravone outside of Japan is not known. NXY-059 has been found to be a very effective agent in transient and permanent MCAO and thromboembolic models of acute ischemic stroke. Its preclinical development has been governed by adherence with the recommendations of the Stroke Therapy Academic Industry Roundtable (STAIR) group and is now being investigated in Phase III clinical trials using a therapeutic time window and plasma concentrations that are effective in rat and primate models of stroke.

Ebselen Alters Mitochondrial Physiology and Reduces Viability of Rat Hippocampal Astrocytes

“…In this line, the seleno-organic compound ebselen, which was originally developed as an anti-inflammatory agent, has been shown to protect against damage caused by free radicals in the CNS (Pérez-Ortiz et al, 2004;Green and Ashwood, 2005;Funchal et al, 2006;Gabryel and Ma1ecki, 2006;Ghisleni et al, 2008). However, in spite of the positive effects of ebselen, certain signs were observed in response to selenium-containing compounds that could be the basis of potential damaging actions.…”

Drug metabolism and pharmacokinetics, the blood-brain barrier, and central nervous system drug discovery

“…This may change if efficacy is observed with compounds currently in clinical trial for stroke, e.g., Cerovive (NXY-059). 45 The failure of many antiexcitotoxic compounds in clinical trials was a setback to the whole field of neuroprotection research. However, with the progress in understanding the physiological, anatomical, cellular, biochemical, and molecular basis of Alzheimer's disease and Parkinson's disease, disease-modifying therapies are now a realistic prospect.…”

Neuroprotective effect of STAZN, a novel azulenyl nitrone antioxidant, in focal cerebral ischemia in rats: Dose–response and therapeutic window

“…Various neuroprotective antioxidants of diverse structures and activities also display a biphasic dose-response relationship and afford less neuroprotection at higher doses than at lower doses. Examples include ebselen in a permanent MCAO model (Green and Ashwood 2005); triliazad mesylate in cultured retina cells (Levin, Clark et al 1996); dipyrimadole, vitamin E and N-acetyl cysteine in cultured hippocampal neurons (Farinelli, Greene et al 1998); and α-phenyl butyl nitrone (PBN), azulenyl nitrone (AZN), dimethylthiourea (Castagne, Lefevre et al 1999), and BXT-51072, a glutathione peroxidase mimetic (Castagne and Clarke 2000), in axotomized retinal ganglion cells.…”

“…The successful translation of antioxidant therapy from animal models to the clinic, however, is not always straightforward (Committee. 2000;Green and Ashwood 2005). For example, although free radicals and oxidative stress are implicated in most human diseases, a recent meta-analysis of antioxidant supplements, such as vitamin E, vitamin A and β-carotene, found that antioxidant therapy did not confer benefit, but rather increased all-cause mortality in a variety of pathologies including neurological, cardiovascular, ocular, renal, endocrinological, gastrointestinal and dermatological diseases (Bjelakovic, Nikolova et al 2007).…”