8Erythropoietin as neuroprotective and neuroregenerative treatment strategy: Comprehensive overview of 12 years of preclinical and clinical research
Introduction
Undoubtedly, there would be a tremendous need for effective neuroprotective and neuroregenerative treatment strategies. Most diseases of the nervous system are etiologically unclear, extremely heterogeneous, and non-curable, with chances being very low that within the next decades a cure will be available for any of them. Facing this disillusioning reality, and considering the enormous human and socio-economic burden to be expected with an increasingly aging society in industrialized countries, the urgent demand of neuroprotective/neuroregenerative treatment approaches becomes even more plausible. Neuroprotective treatments aim at an enduring improvement of symptoms and/or slowing of an ongoing disease process. Essentially all compounds that have been associated with a potential neuroprotective/neuroregenerative capacity target determinants of the final common pathway of many different diseases of the nervous system, e.g. apoptosis, oxidative stress, inflammation, metabolic dysfunction or compromised neuroplasticity.
Hardly any other compound has now over more than a decade attracted so much attention as candidate for neuroprotection/neuroregeneration than erythropoietin (EPO). Not many other drug candidates have triggered so many preclinical studies on entirely different disease models, investigated by multiple independent research groups worldwide, than EPO. This overwhelming amount of data on EPO, showing mostly positive results regarding neuroprotection and neuroregeneration, has also stimulated clinical research as reflected by a substantial number of ongoing clinical trials on EPO in nervous system indications (for review see1). The few thus far published clinical studies all yielded positive results or at least positive signals to be further pursued.2, *3, 4, 5, 6
Astonishingly, despite this large number of positive data, no adequate continuous support for translation of these findings into the clinic has been provided. This stagnation of further development may be the result of a number of unfortunate coincidences: (1) The EPO industry strongly protects their lucrative anemia market that, for individual producers, has already been subject to shrinkage due to expired patents and popping-up of more and more biosimilar products. (2) Recent clinical trials in the anemia/oncology field have raised concerns regarding previously established indications. (3) In the absence of sufficient patent protection, new indications are not welcome since they bear the risk of as yet undetected additional side-effects of EPO that might further endanger the presently still highly profitable business. (4) Finally, there is an absurd reluctance of public funding agencies to support trials for new indications on compounds that are already approved and in their eyes should be supported by industry. This makes investigator-initiated trial designers going in time-, money-, and energy-consuming circles that ultimately lead nowhere. Therefore, even though EPO might be the most promising agent so far to provide neuroprotection/neuroregeneration in a broad field of neurological and psychiatric diseases, less effective and less well tolerated compounds are much more likely to be developed. Hopefully, the present review, summarizing the overall positive outcomes of preclinical as well as of clinical work, will stimulate novel attempts to conduct clinical trials on EPO treatment of brain diseases.
With this review, we provide a comprehensive but compacted overview of the more than 180 preclinical studies performed since 1998. In an especially designed master table (Table 1), the main results are briefly summarized. Five extensive supplementary tables encompass all available preclinical studies, with their main contents recapitulated shortly and commented on. In addition, we present in this article a brief synopsis of the few published clinical studies dealing with EPO treatment of neuropsychiatric diseases as well as an overview of work on healthy individuals, rodents and humans, set up to gain more mechanistic insight into the potent effects of EPO on cognitive performance. These positive effects on cognition have not sufficiently been explored yet for potential application in diseases characterized by cognitive decline. Ultimately, we will give an outlook regarding the most important next steps required to move the field towards clinical development.
Section snippets
Biology of the EPO system
Since the present review deals predominantly with neuroprotection/neuroregeneration in preclinical and clinical models, the molecular and cellular effects of EPO cannot be comprehensively covered. For deeper insight into these fields, the reader is politely referred to some excellent recent reviews e.g.*7, 8, 9, 10
Human EPO is an acidic glycoprotein with a molecular mass of about 30.4 kDa. It consists of 165 amino acids which form 2 bisulphide bridges. The carbohydrate portion amounts to
Preclinical studies
EPO treatment effects reported in publications on preclinical disease models from 1998 up to April 2010 are summarized in Table 1. Diseases are presented in respective categories, ranging from cerebrovascular conditions to neuroinflammatory, neurodegenerative and traumatic brain/spinal cord diseases. The categories are further subdivided into disease models, with the main outcomes of clinical and non-clinical readouts listed. For each disease model, the number of studies, range of years when
Clinical studies
Published clinical studies on EPO in neurological and psychiatric indications are still rare even though many studies are ongoing worldwide (for review see1). In the following part of the review, we will provide a short overview of the published work.
EPO and cognition
Effects of EPO on cognition have been observed as early as around the time of its introduction to the clinic for the treatment of anemia in chronic kidney disease (for review see e.g.245, 253). At that time, improvement of cognitive performance was attributed to the EPO-induced increase in red blood cells/hemoglobin with subsequently enhanced tissue oxygenation. In fact, artificial reduction of circulating red blood cells in human volunteers to anemic levels leads to compromised cognitive
Outlook
Based on the above outlined multiple positive findings of EPO as a neuroprotective/neuroregenerative agent for the treatment of human brain diseases, it appears mandatory to further pursue these indications. This more so since alternative treatments are completely lacking. As the critical next steps for further clinical development of EPO or EPO variants, the doses, application routes and treatment schedules would have to be varied and (re-)tested in different clinical studies for the most
Conflict of interest
Hannelore Ehrenreich holds/has submitted user patents for EPO in stroke, schizophrenia and multiple sclerosis.
Acknowledgement
The work on EPO performed by the Division of Clinical Neuroscience over the last 14 years has had continuous support by the Max Planck Society and the DFG Center for Molecular Physiology of the Brain (CMPB).
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