A novel role for an established player: anemia drug erythropoietin for the treatment of cerebral hypoxia/ischemia

Abstract

Erythropoietin, a hematopoietic growth-factor possessing manifold, potent neuroprotective properties, after multiple testing in cell culture and animal studies now gradually finds its way into clinical neuroscience. The first time this took place was in 1998 with a pilot study in stroke patients, the “Göttingen EPO-Stroke-Trial”. This study was able to demonstrate that EPO is perfectly well tolerated and safe with this indication. Furthermore, the EPO-treated patients showed a significantly better outcome regarding their clinical progress as well as regarding the infarct size as observed by MRI, when compared to the placebo treated patients. At the moment a multicenter study is being carried out in Germany.

Introduction

The so-called “stroke”, meaning the sudden occlusion of one or more brain vessels resulting in an insufficient perfusion of the associated brain area, presents, together with cardiovascular diseases and cancer, the most frequent reason for death in western industrialized countries. The majority of severe disabilities in grown-ups are caused by stroke. For this reason this very heterogeneous disease with its multiple risk factors presents one of the most pressing socio-medical problems of our time.

Treatment of stroke is still limited to the optimal supportive measures (lowering of an elevated body temperature, correction of an aberrant blood-glucose level, readjusting of electrolyte-imbalances, rehydration, sufficient treatment of accompanying illnesses, optimal care, physio- and psychotherapy, counselling of the relatives, initiation of the optimal rehabilitation measures, etc.). The only treatment with which specific mechanisms of stroke pathogenesis can be addressed is the so-called lysis therapy using rTPA (recombinant tissue plasminogen activator). Further compounds with similar pharmacological profile are currently in preclinical and clinical testing. The use of lysis so far only reaches about 5% of the patients concerned (restrictions are mainly due to the short time-to-treatment window and contraindications). For all the remaining victims of stroke, no therapy exceeding the above mentioned supportive means exists.

Any therapeutic approach in stroke promising to favorably influence the course of this disease therefore merits to be followed up emphatically. This has been done in recent years with a number of substances hoped to positively influence the course of recovery after a stroke due to their neuroprotective properties. All of these studies have failed so far. Recent trials with various glutamate-antagonists as well as with magnesium may be cited as examples here [1], [2].

A small Göttingen pilot study succeeded for the first time in demonstrating an effective neuroprotective approach in human stroke in a carefully selected group of patients [3]. The compound used in this case was erythropoietin (EPO). Although the head start won with EPO was a relatively small one in this study, it anyhow turned out to be significant both in respect with the clinical course of the disease and the MRI data as well as the concentration of circulating damage markers. This result establishes a promising starting point for further research in this area. The small success with EPO has to be reproduced, dose and mode of application have to be optimized and the adoption of other add-on strategies has to be explored.