Can EPO prevent loss of brain function in schizophrenia?

December 03, 2003

The causes and mechanisms of most brain diseases still evade scientists. A causal treatment exists for only few conditions. Therapeutic approaches at present aim predominantly at harm reduction. Harm reducing, brain function protecting measures are addressed with the term "neuroprotection". Neuroprotection is best defined as the effort to maintain / restore the highest possible integrity of cellular interactions in the brain, resulting in an overall undisturbed neural function.

Neuroprotection is a novel approach for the treatment of schizophrenia. Over the last decade it has become clear that in addition to disturbed brain development, continuous neurodegenerative processes are involved in the progression of this brain disease. Nevertheless, molecular and cellular mechanisms accounting for the various dysfunctions of schizophrenic psychosis are far from clear. Existing animal models of schizophrenia only reflect certain aspects of the human disease. Therefore, novel concepts to treating schizophrenia should be immediately translated into clinical pilot trials. This is particularly appropriate if the beneficial compounds that are suggested are safe. During early episodes of schizophrenic psychosis, a dramatic worsening of cognitive performance is often observed. More than 100 years ago, the famous psychiatrist Emil Kraepelin described these phenomena and called the disease "Dementia praecox" (premature dementia). Neuroleptic therapy, one of the major achievements of psychiatry over the last century, has prepared the ground for any further therapy aiming at influencing the course of disease: Reduction in psychotic symptoms (paranoia, delusions) through neuroleptic treatment is a prerequisite for creating a stable therapeutic interaction between patients and therapists. Neuroleptic treatment by itself, however, is unlikely to influence the neurodegenerative course of schizophrenia. Therefore, a neuroprotective add-on therapy using well-tolerated and safe compounds appears worthwhile to test.

The authors decided to use erythropoietin as a first compound with known high neuroprotective potential in men to design a proof-of-concept trial "neuroprotection in schizophrenia". Three key questions had to be clarified to prepare the ground for that trial: (1) Can erythropoietin reach the brain via an intact blood-brain barrier following intravenous application? (2) Can erythropoietin binding sites be detected in the brains of schizophrenic patients? (3) Can cognitive functioning be benefited by erythropoietin treatment in schizophrenic patients? The authors addressed these three questions successfully. Using rodent studies, immunohistochemical analysis of human post mortem brain tissue, and nuclear imaging technology in men, the authors demonstrated that: (1) peripherally applied erythropoietin efficiently penetrates into the brain, (2) erythropoietin is enriched intracranially in healthy men and more distinctly in schizophrenic patients, where binding sites are densely expressed in the hippocampus and cortex, and (3) peripherally administered erythropoietin enhances cognitive functioning in mice in the context of an aversion task involving brain circuits believed to be affected in schizophrenic humans. First results of the multicenter trial running in Germany will be available in 2004.
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Citation source: Molecular Psychiatry advance online publication, December 2003 (doi:10.1038/sj.mp.4001442)

For further information on this work, please contact Professor Hannelore Ehrenreich, MD, DVM, Max-Planck-Institute for Experimental Medicine, Hermann-Rein-Str. 3, D-37075 Goettingen, Germany, Tel: + 49 551 3899628; Fax: + 49 551 3899670, E-mail: ehrenreich@em.mpg.de

Molecular Psychiatry is published by the Nature Publishing Group. http://www.nature.com/mp

Editor: Julio Licinio, M.D.; phone: +1-310-825-7113; FAX: +1-310-206-6715; e-mail: licinio@ucla.edu

For a copy of this article, please contact Aimee Midei, Editorial Assistant, e-mail: molecularpsychiatry@mednet.ucla.edu.

PLEASE CITE MOLECULAR PSYCHIATRY AS THE SOURCE OF THIS MATERIAL.

ARTICLE: "Erythropoietin: A candidate compound for neuroprotection in schizophrenia"

AUTHORS: Hannelore Ehrenreich, Detlef Degner, Johannes Meller, Michael Brines, Martin Béhé, Martin Hasselblatt, Helge Woldt, Peter Falkai, Friederike Knerlich, Sonja Jacob, Nicolas von Ahsen, Wolfgang Maier, Wolfgang Brück, Eckart Rüther, Anthony Cerami, Wolfgang Becker and Anna-Leena Sirén

Max-Planck-Institute for Experimental Medicine and Department of Psychiatry, Department of Nuclear Medicine, Department of Clinical Chemistry, Department of Neuropathology, Georg-August-University, Goettingen, Germany; The Kenneth S. Warren Institute, Kitchawan, NY 10562, USA; Department of Psychiatry, Friedrich-Wilhelm-University, Bonn, Germany

Molecular Psychiatry

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