Development Of Stroke Therapeutics Research Articles

Preconditioning in the Rhesus Macaque Induces a Proteomic Signature Following Cerebral Ischemia that Is Associated with Neuroprotection.

Each year, thousands of patients are at risk of cerebral ischemic injury, due to iatrogenic responses to surgical procedures. Prophylactic treatment of these patients as standard care could minimize potential neurological complications. We have shown that protection of brain tissue, in a non-human primate model of cerebral ischemic injury, is possible through pharmacological preconditioning using the immune activator D192935. We postulate that preconditioning with D192935 results in neuroprotective reprogramming that is evident in the brain following experimentally induced cerebral ischemia. We performed quantitative proteomic analysis of cerebral spinal fluid (CSF) collected post-stroke from our previously published efficacy study to determine whether CSF protein profiles correlated with induced protection. Four groups of animals were examined: naïve animals (no treatment or stroke); animals treated with vehicle prior to stroke; D192935 treated and stroked animals, further delineated into two groups, ones that were protected (small infarcts) and those that were not protected (large infarcts). We found that distinct protein clusters defined the protected and non-protected animal groups, with a 16-member cluster of proteins induced exclusively in D192935 protected animals. Seventy percent of the proteins induced in the protected animals have functions that would enhance neuroprotection and tissue repair, including several members associated with M2 macrophages, a macrophage phenotype shown to contribute to neuroprotection and repair during ischemic injury. These studies highlight the translational importance of CSF biomarkers in defining mechanism and monitoring responses to treatment in development of stroke therapeutics.

Adenosine and Stroke: Maximizing the Therapeutic Potential of Adenosine as a Prophylactic and Acute Neuroprotectant

Stroke is a leading cause of morbidity and mortality in the United States. Despite intensive research into the development of treatments that lessen the severity of cerebrovascular injury, no major therapies exist. Though the potential use of adenosine as a neuroprotective agent in the context of stroke has long been realized, there are currently no adenosine-based therapies for the treatment of cerebral ischemia and reperfusion. One of the major obstacles to developing adenosine-based therapies for the treatment of stroke is the prevalence of functional adenosine receptors outside the central nervous system. The activities of peripheral immune and vascular endothelial cells are particularly vulnerable to modulation via adenosine receptors. Many of the pathophysiological processes in stroke are a direct result of peripheral immune infiltration into the brain. Ischemic preconditioning, which can be induced by a number of stimuli, has emerged as a promising area of focus in the development of stroke therapeutics. Reprogramming of the brain and immune responses to adenosine signaling may be an underlying principle of tolerance to cerebral ischemia. Insight into the role of adenosine in various preconditioning paradigms may lead to new uses for adenosine as both an acute and prophylactic neuroprotectant.

Introduction to Cellular Therapy

Cell therapy represents a new frontier in the development of therapeutics for stroke. Aside from physical rehabilitation, few options exist to enhance recovery from stroke. Prior studies in the 1990s provided precedence for considering a cellular approach to treat neurological disorders with the pioneering work on transplantation in Parkinson disease. These trials furnished preliminary evidence for a modest benefit in young patients with a neurodegenerative disorder who underwent neural transplantation. From those initial studies, pilot work emerged on the application of cellular replacement in Huntington disease and other neurological disorders. In an entirely different area of medicine, stem cell transplantation in oncology provided support for the idea that stem cells could be administered intravenously for a range of disorders including stroke. Over the past decade, investigators accordingly began showing that intravenously injected stem cells from the bone marrow and umbilical cord could promote recovery in animal stroke models. Thus began a new area of investigation in which adult stem cells from other sources, rather than the brain, could be tested for therapeutic applications in stroke. As transplantation studies have been growing, it has also now clearly been established that the adult brain undergoes neurogenesis. Elegant work from Lindvall and Parent and others have shown that …

Translational Medicine for Stroke Drug Discovery

Over the past 20 years, an estimated $1 billion has been spent in research and development of stroke therapeutics; however, this huge investment has failed to produce a clinically efficacious drug with the exception of the thrombolytic agent Activase (tPA). This sobering reality has been the subject of numerous reflections by renowned leaders in stroke research with special focus on the most recent failed clinical trials. The validity of the neuroprotection strategy has been questioned and efforts to substantially modify the quality of stroke research have been examined. The consistent failures of the pharmaceutical industry to develop a neuroprotective drug for ischemic stroke have had a major impact on the assessment of stroke as an attractive therapeutic area for drug discovery. Many pharmaceutical companies have scaled down their stroke programs, reflecting skepticism about the prospect of contemporary stroke drug discovery strategy based on neuroprotective agents. In this article, we present a Translational Medicine perspective on critical issues that the pharmaceutical industry and the academic community encounter but often ignore during stroke therapeutic development. This Translational Medicine framework offers a systematic analysis of the possible deficiencies that likely underwrote the colossal failure of clinical trials with neuroprotective drugs. In addition, we offer a biomarker-based system that aims at providing "proof of concept" along the discovery and development pipeline, which if implemented along early preclinical and clinical development phases, might significantly reduce risks and enable success.

A Critique of SAINT II

Marc Fisher MD Kennedy Lees MD Section Editors: The neutral results of the SAINT II study1 dashed the hopes for a second ischemic stroke drug in the near future. Although this is certainly disappointing for stroke neurologists, a careful analysis of the NXY-059 development program reveals several deficiencies, which if properly addressed, might revitalize and strengthen the field of neuroprotection for acute ischemic stroke. This critique points out several potential reasons for the failure of SAINT II to replicate the positive findings of SAINT 1,2 discusses the preclinical problems with NXY-059, and provides a perspective on the development of future neuroprotective agents for acute ischemic stroke. The SAINT II trial1 investigated the efficacy of the free-radical–trapping agent, NXY-059, for the treatment of acute ischemic stroke and failed to confirm the positive results of SAINT I.2 In the latter study with 1699 patients, NXY-059 showed for the first time in a large phase III trial that a drug other than tissue plasminogen activator (t-PA) might lead to significant improvement on the modified Rankin Scale (mRS) using a novel and controversial outcome analysis (Rankin shift analysis). The larger SAINT II trial with 3306 patients not only failed to replicate improvement on the same primary end point but all secondary end points (neurological deficits on the National Institutes of Health Stroke Scale (NIHSS) at 90 days and activities of daily living on the Barthel Index at 90 days) were identical between treatment groups. Besides the obvious possibility that the drug itself was inactive, which may be considered due to the known instability of free-radical–trapping agents, several additional problems were evident. Both trials were designed, in part, as combination studies, testing the addition of NXY-059 to standard therapy compared with t-PA alone in the 3-hour time window. SAINT II gave …

Ion channels involved in stroke

Ion channels are membrane proteins that flicker open and shut to regulate the flow of ions down their electrochemical gradient across the membrane and consequently regulate cellular excitability. Every living cell expresses ion channels, as they are critical life-sustaining proteins. Ion channels are generally either activated by voltage or by ligand interaction. For each group of ion channels the channels' molecular biology and biophysics will be introduced and the pharmacology of that group of channels will be reviewed. The in vitro and in vivo literature will be reviewed and, for ion channel groups in which clinical trials have been conducted, the efficacy and therapeutic potential of the neuroprotective compounds will be reviewed. A large part of this article will deal with glutamate receptors, focusing specifically on N-methyl-D-aspartate (NMDA) receptors. Although the outcome of clinical trials for NMDA receptor antagonists as therapeutics for acute stroke is disappointing, the culmination of these failed trials was preceded by a decade of efforts to develop these agents. Sodium and calcium channel antagonists will be reviewed and the newly emerging efforts to develop therapeutics targeting potassium channels will be discussed. The future development of stroke therapeutics targeting ion channels will be discussed in the context of the failures of the last decade in hopes that this decade will yield successful stroke therapeutics.