ORIGINAL RESEARCH ARTICLE Erythropoietin: a candidate compound for neuroprotection in schizophrenia H Ehrenreich 1 , D Degner 1 , J Meller 2 , M Brines 3 , M Be ´he ´ 2 , M Hasselblatt 1 , H Woldt 1 , P Falkai 4 , F Knerlich 1 , S Jacob 1 , N von Ahsen 5 , W Maier 4 , W Bru ¨ck 6 , E Ru ¨ ther 1 , A Cerami 3 , W Becker 2,{ and A-L Sire ´n 1 1 Max-Planck-Institute for Experimental Medicine and Department of Psychiatry, Georg-August-University, Goettingen, Germany; 2 Department of Nuclear Medicine, Georg-August-University, Goettingen, Germany; 3 The Kenneth S Warren Institute, Kitchawan, NY, USA; 4 Department of Psychiatry, Friedrich-Wilhelm-University, Bonn, Germany; 5 Department of Clinical Chemistry, Georg-August-University, Goettingen, Germany; 6 Department of Neuropathology, Georg-August-University, Goettingen, Germany Erythropoietin (EPO) is a candidate compound for neuroprotection in human brain disease capable of combating a spectrum of pathophysiological processes operational during the progression of schizophrenic psychosis. The purpose of the present study was to prepare the ground for its application in a first neuroprotective add-on strategy in schizophrenia, aiming at improvement of cognitive brain function as well as prevention/slowing of degenerative processes. Using rodent studies, primary hippocampal neurons in culture, immunohisto- chemical analysis of human post-mortem brain tissue and nuclear imaging technology in man, we demonstrate that: (1) peripherally applied recombinant human (rh) EPO penetrates into the brain efficiently both in rat and humans, (2) rhEPO is enriched intracranially in healthy men and more distinctly in schizophrenic patients, (3) EPO receptors are densely expressed in hippocampus and cortex of schizophrenic subjects but distinctly less in controls, (4) rhEPO attenuates the haloperidol-induced neuronal death in vitro, and (4) peripherally administered rhEPO enhances cognitive functioning in mice in the context of an aversion task involving cortical and subcortical pathways presumably affected in schizophrenia. These observations, together with the known safety of rhEPO, render it an interesting compound for neuroprotective add-on strategies in schizophrenia and other human diseases characterized by a progressive decline in cognitive performance. Molecular Psychiatry (2004) 9, 42–54. doi:10.1038/sj.mp.4001442 Published online 28 October 2003 Keywords: recombinant human erythropoietin; EPO; schizophrenia; clinical; rodent; SPECT Introduction The discovery of dopamine antagonists in the middle of the last century represents a major achievement for psychiatry, in general, and for the treatment of schizophrenic psychosis, in particular. 1 Dopamine antagonists delivered a new class of drugs, neurolep- tics, which are capable of reducing or eliminating psychotic symptoms. Patients tend to return ‘to normal’ with respect to their most obvious behavior and their compliance towards treatment. Underneath this ‘normalization’, however, there is a silently, slowly and nondramatically progressing deterioration of cognitive functioning. 2–5 This deterioration shows gradual differences among patients with the most severely affected individuals representing Kraepelin’s ‘dementia praecox’. 6 Brain atrophy and ventricular enlargement as morphological substrates of this continuous cognitive decline have been suspected for decades using autopsy material and imaging studies. 5,7,8 A pivotal long-term follow-up study of brain morphology in first episode schizophrenia has revealed progressive ventricular enlargement, consis- tent with a neurodegenerative process. 9 Another recent study, also based on high-resolution magnetic resonance imaging, found dynamic patterns of accel- erated gray matter loss in the brains of childhood- onset schizophrenia with earliest defects in the parietal association cortex. 10 Gray matter loss in parietal cortex is known to be strongly associated with environmental factors. 11,12 The deficits described in the study intensified and spread over 5 years of disease progression frontally to the prefrontal cortex and to temporal brain regions, indicative of ongoing Received 18 February 2003; revised 27 August 2003; accepted 17 September 2003 Correspondence: Professor Hannelore Ehrenreich, MD, DVM, Max-Planck-Institute for Experimental Medicine, Hermann- Rein-Str. 3, D-37075 Goettingen, Germany. E-mail: ehrenreich@em.mpg.de { Wolfgang Becker died at the time this work had been completed. The authors mourn the passing away of a brilliant young colleague, a kind and caring person who during his short life made invaluable contributions to his field. Molecular Psychiatry (2004) 9, 42–54 & 2004 Nature Publishing Group All rights reserved 1359-4184/04 $25.00 www.nature.com/mp