Responsible:
Prof. Hannelore Ehrenreich, MD, DVM
Division of Clinical Neuroscience
Max-Planck-Institute of Experimental Medicine
Hermann-Rein-Strasse 3
D-37075 Goettingen
Tel: ++49-551-3899-628
Fax: ++49-551-3899-670
Email: ehrenreich@em.mpg.de
 
     
 
 
 
 


Neuroprotection Schizophrenia

Where we stand and where we are going

 
 

Figure 1: Photos of group members, working predominantly on the schizophrenia projects are framed: red - basic research; yellow - clinical research

 

To limit neuronal dysfunction and death after central nervous system injury due to ischemia, trauma or degenerative disease remains a major task for neuroscience research. The Division of Clinical Neuroscience aims at identifying neuroprotective compounds that can easily and without delay be translated into therapeutic strategies in man. Neuroprotection may be defined as an attempt to maintain the highest possible integrity of cellular interactions in the brain resulting in an undisturbed neural function. Loss of brain function can be detrimental whereas loss of brain cells may not even be measurable. In fact, mere prevention of cell death can be undesired: Elimination of dysfunctional or transformed cells may contribute to the preservation of the best possible function, perhaps at the price of increased cell death. Similar considerations may apply for synaptic sprouting or electrical activity: More may not always be better. Neuroprotection may be prophylactic or therapeutic. In the first case, it means prevention of functional loss before it occurs. Identification of genetic or environmental risk factors is essential for prevention. Therapeutic neuroprotection means maintenance or amelioration of remaining function as much as possible. For clinical application of potential neuroprotective strategies, efficacy in humans and safety, also in chronic use, are of tremendous importance.

Research in the Division of Clinical Neuroscience ranges from identification to therapeutic exploitation of endogenous mechanisms of neuroprotection. Working "from bench to bedside and back again" characterizes our approach: The search for candidate neuroprotective compounds, exploration of their mechanisms of action, testing of their effectiveness in cell culture and animal models, realization of clinical pilot studies for safety, and double-blind proof-of-concept studies for efficacy.

Schizophrenia research in general, and neuroprotection in schizophrenia in particular, has been a central research focus within the Division of Clinical Neuroscience for over 10 years. This research focus fits very well into the Institute's research landscape. All departments of the Max Planck Institute of Experimental Medicine as well as the Department of Jens Frahm at the Max Planck Institute of Biophysical Chemistry are involved in schizophrenia research. This is why the "Göttingen Research Association for Schizophrenia (GRAS)" has been founded in 2004 in order to exchange expertise and move the field forward in a common effort. Among others, GRAS has defined the schizophrenia research focus in the Center for Molecular Physiology of the Brain (CMPB). The Division of Clinical Neuroscience has received funding for its schizophrenia research mainly from the MPG, but also from the BMBF, the DFG (CMPB), Lundbeck, Ortho-Biotech, as well as from private donations.

 

Development of a mouse model of the degenerative aspects of schizophrenia

Despite general agreement on the significance of the genetic predisposition, the etiology/etiologies of schizophrenic psychosis remain(s) obscure. There is, however, strong evidence for a number of co-factors (e.g. neurotrauma, drug abuse) that influence manifestations and course of schizophrenia.



Figure 2: Etiologies of schizophrenic psychosis

These findings point to a dual origin of the disease determining processes: Neurodevelopmental and neurodegenerative. Modern imaging technology has been able to demonstrate a gradual loss of cortical gray matter in early onset schizophrenia, which starts out in the parietal lobe and extends to the frontal and the temporal lobe of the brain. Although the endogenous cause of the initiation of neurodegeneration in the parietal lobe is entirely unknown, we decided to create an animal model, where an exogenous inducer of neurodegeneration (standardized neurotrauma in the form of a cryolesion) is applied through the intact skull onto the right parietal cortex of juvenile mice. We were hoping to identify general mechanisms that might contribute (independent of the initiating cause) to the progression of cortical gray matter loss in schizophrenia.



Figure 3: Parietal cortical cryolesion in juvenile mice (Sirén et al, BRAIN 2006)

Using this model we were able to show that juvenile (4 weeks old) mice that are given a discrete unilateral lesion of the parietal cortex, developed to adulthood without obvious clinical symptoms. However, when monitored 3 and 9 months after lesioning, using high resolution three-dimensional MRI and behavioral testing, the same mice display global neurodegenerative changes. Surprisingly, erythropoietin (EPO), a hematopoietic growth factor with potent neuroprotective activity, prevents behavioral abnormalities, cognitive dysfunction and brain atrophy when given for 2 weeks after acute brain injury. This demonstrates that a localized brain lesion, set at a vulnerable age, is a primary cause of delayed global neurodegeneration that can be efficiently counteracted by neuroprotection. Based on comprehensive stereological analysis, we found that early unilateral lesion causes immediate and lasting bilateral increase in the number of microglia in cingulate cortex and hippocampus, consistent with a chronic low-grade inflammatory process. Whereas the total number of neurons and astrocytes in these brain regions remain unaltered, pointing to a non-gliotic neurodegeneration (as seen in schizophrenia), the subgroup of parvalbumin-positive inhibitory GABAergic interneurons is increased bilaterally in the hippocampus, as is the expression of the GABA-synthesizing enzyme GAD67. Moreover, unilateral parietal lesion causes a decrease in the expression of synapsin1, suggesting impairment of presynaptic functions/neuroplasticity. Reduced expression of the myelin protein CNPase (cyclic nucleotide phosphodiesterase), reflecting a reduction of oligodendrocytes, may further contribute to the observed brain atrophy. Remarkably, early intervention with recombinant human EPO prevented all these neurodegenerative changes.



Figure 4: Morphology 3 and 9 months after unilateral parietal cortical lesion: Effect of early EPO (n=7-12) (Sirén et al, BRAIN 2006)



Figure 5: Behavioral follow-up 3 and 9 months after parietal cortical lesion: Effect of early EPO (Hyperactivity: Hole Board Test and Elevated Plus-Maze, n=10-19) (Sirén et al, BRAIN 2006)



Figure 6: Prepulse inhibition in parietally lesioned juvenile mice is preserved by early EPO (Startle response to acoustic stimulation; sensorimotor gating; n=11-13) (Sirén et al, BRAIN 2006)

 

Neuroprotection in schizophrenia - erythropoietin add-on trial

EPO is a candidate compound for neuroprotection also in human brain disease. It is capable of combating a spectrum of pathophysiological processes operational during the progression of schizophrenic psychosis. Based on the encouraging results obtained with EPO in our animal model of global brain atrophy, we decided to prepare the ground for the application of EPO in a first neuroprotective add-on strategy in schizophrenia, aiming at improvement of cognitive brain function as well as prevention/slowing of degenerative processes. We used rodent studies, primary hippocampal neurons in culture, immunohistochemical analysis of human postmortem brain tissue and nuclear imaging technology in man. In fact, we were able to 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 (Figure 7), (3) EPO receptors are densely expressed in hippocampus and cortex in schizophrenic subjects but distinctly less in controls (Figure 8), (4) rhEPO attenuates the haloperidol-induced neuronal death in vitro, and (5) 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, forced us to start a neuroprotective add-on trial of EPO in schizophrenia (Figure 9).



Figure 7: 111In-EPO in young male schizophrenic patients versus controls (signal ratio intracerebral / bone marrow of the skull) (Ehrenreich et al, Mol Psychiatry 2004)



Figure 8: EPO receptor expression in the brains of schizophrenic and control subjects (Ehrenreich et al, Mol Psychiatry 2004)


Figure 9: Design of the clinical trial (Ehrenreich et al, Mol Psychiatry 2006)

We hypothesized that a neuroprotective/neurotrophic add-on strategy, rhEPO in addition to stable antipsychotic medication, may be able to improve cognitive function even in chronic schizophrenic patients. Therefore, we designed a double-blind, placebo-controlled, randomized, multicenter proof-of-principle (phase II) study. Participating centers were Göttingen, Kiel, Homburg, Cologne, and Marburg. The study had a total duration of 2 years and an individual duration of 12 weeks with an additional safety visit at week 16. Of 172 patients assed for eligibility, a total of 39 chronic schizophrenic men participated in the study. They had a defined cognitive deficit, stable medication and disease state, were treated for 3 months with a weekly short intravenous infusion of 40 000 I.U. of rhEPO (n = 20) or placebo (n = 19). Main outcome measure was schizophrenia relevant cognitive function at week 12. The neuropsychological test set was applied over 2 days at baseline, 2 weeks, 4 weeks, and 12 weeks of study participation. Both, placebo and rhEPO patients improved in all evaluated categories. Patients receiving rhEPO showed a significant improvement over placebo patients in schizophrenia related cognitive performance, but no effects on psychopathology or social functioning (Figure 10).



Figure 10: Covariance analysis: Effect of erythropoietin (N=19) versus placebo (N=19) treatment on cognitive parameters in male chronic schizophrenic patients
Cognitive parameters: Sum score of RBANS subtests language - semantic fluency, attention, delayed memory, plus WCST perseveration errors. Covariate: Age. Mean±SEM presented.
Strategy: Follow-up of each individual according to his inclusion status (data expressed as % individual baseline) (Ehrenreich et al, Mol Psychiatry 2006)

Also, a significant decline in serum levels of S100B, a glial damage marker, occurred upon rhEPO. Most importantly, EPO prevented cortical gray matter loss in schizophrenia relevant brain areas like hippocampus, amygdala, nucleus accumbens, and several neocortical areas, as evaluated by MRI. The fact that rhEPO is the first compound to exert a selective and lasting beneficial effect on cognition and cortical gray matter should encourage new treatment strategies for schizophrenia. In fact, we are in the process of applying/fund-raising for a follow-up trial in acutely ill patients, undergoing the first episode of schizophrenia, where we aim at preventing cognitive decline and alterations in cortical gray matter.



 

The GRAS data collection: Investment into the future

In order to promote translational research on schizophrenia, we have decided to invest into an extensive, fundamental project that involved recruitment of over 1000 schizophrenic patients within the short time frame of less than 3 years. This cross-sectional study has provided around 3000 data points on each individual, which are presently being entered into a most comprehensive databank, the "GRAS data collection". Information on individual patients ranges from individual disease history to family history, environmental risk factors, and co-morbid disorders to neurological symptoms, cognitive function and psychopathology, to just name a few. Of all these patients, blood samples are stored for both, DNA screening and serological analyses. With the help of this data bank, GRAS members and collaborating partners will be able to perform well designed studies, based on analysis of candidate genes. These studies, hypothesis-driven or hypothesis-generating, will investigate specific genotype-phenotype relations (PGAS = phenotype-based genetic association studies) i.e. explore the relative contribution of a particular genotype to the phenotype. The data bank will not only allow identifying biological subgroups of the disease, but also defining populations with a high probability to respond to certain neuroprotective treatment approaches. Ultimately, the GRAS data collection will enable industry partners to collaborate based on information from this data bank (Figure 12).



Figure 12: Overview: State of the Cross-Sectional Schizophrenia Study ("GRAS Data Collection")

 

CMPB research focus schizophrenia

GRAS has decided to provide a specific research focus under the umbrella of the Center for Molecular Physiology of the Brain (CMPB). Within this research focus, novel strategies are applied to create more clinically relevant animal models based on genetic and environmental factors (see Figure 2). A combination of e.g. neuregulin mutants (Klaus-Armin Nave, Department of Neurogenetics) with neurotrauma or of SKCA3 mutants (Walter Stühmer, Department of Molecular Biology of Neuronal Signals) with chronic social stress, is expected to open up new avenues for exploring the interaction of genetic and environmental factors in the development of the schizophrenic phenotype. Other interesting genes are complexins (Nils Brose, Department of Molecular Neurobiology), EAG (Stühmer) or Cnp1 (Nave), all of them interchangeably combined with either psychotrauma (stress) or neurotrauma (cryolesion of the parietal cortex) (Figure 13).



Figure 13: Overview: Outline of the experimental set-up

 

Relevant publications:

Hagemeyer N, Boretius S, Ott C, Von Streitberg A, Welpinghus H, Sperling S, Frahm J, Simons M, Ghezzi P, Ehrenreich H.: Erythropoietin attenuates neurological and histological consequences of toxic demyelination in mice. Mol Med. [Epub ahead of print] (2012)
 
Steinberg S, de Jong S; Irish Schizophrenia Genomics Consortium, Andreassen OA, Werge T, Børglum AD, Mors O, Mortensen PB, Gustafsson O, Costas J, Pietiläinen OP, Demontis D, Papiol S, Huttenlocher J, Mattheisen M, Breuer R, Vassos E, Giegling I, Fraser G, Walker N, Tuulio-Henriksson A, Suvisaari J, Lönnqvist J, Paunio T, Agartz I, Melle I, Djurovic S, Strengman E; GROUP, Jürgens G, Glenthøj B, Terenius L, Hougaard DM, Orntoft T, Wiuf C, Didriksen M, Hollegaard MV, Nordentoft M, van Winkel R, Kenis G, Abramova L, Kaleda V, Arrojo M, Sanjuán J, Arango C, Sperling S, Rossner M, Ribolsi M, Magni V, Siracusano A, Christiansen C, Kiemeney LA, Veldink J, van den Berg L, Ingason A, Muglia P, Murray R, Nöthen MM, Sigurdsson E, Petursson H, Thorsteinsdottir U, Kong A, Rubino IA, De Hert M, Réthelyi JM, Bitter I, Jönsson EG, Golimbet V, Carracedo A, Ehrenreich H, Craddock N, Owen MJ, O'Donovan MC; Wellcome Trust Case Control Consortium 2, Ruggeri M, Tosato S, Peltonen L, Ophoff RA, Collier DA, St Clair D, Rietschel M, Cichon S, Stefansson H, Rujescu D, Stefansson K.: Common variants at VRK2 and TCF4 conferring risk of schizophrenia. Hum Mol Genet. 20:4076-81 (2011).
 
Ribbe K, Ackermann V, Schwitulla J, Begemann M, Papiol S, Grube S, Sperling S, Friedrichs H, Jahn O, Sillaber I, Gefeller O, Krampe H, Ehrenreich H.: Prediction of the Risk of Comorbid Alcoholism in Schizophrenia by Interaction of Common Genetic Variants in the Corticotropin-Releasing Factor System. Arch Gen Psychiatry. (2011)
 
Grube S, Gerchen MF, Adamcio B, Pardo LA, Martin S, Malzahn D, Papiol S, Begemann M, Ribbe K, Friedrichs H, Radyushkin KA, Müller M, Benseler F, Riggert J, Falkai P, Bickeböller H, Nave KA, Brose N, Stühmer W, Ehrenreich H.: A CAG repeat polymorphism of KCNN3 predicts SK3 channel function and cognitive performance in schizophrenia. EMBO Mol Med. 3,309-19 (2011)
 
Papiol S, Begemann M, Rosenberger A, Friedrichs H, Ribbe K, Grube S, Schwab MH, Jahn H, Gunkel S, Benseler F, Nave KA, Ehrenreich H. A phenotype-based genetic association study reveals the contribution of neuregulin1 gene variants to age of onset and positive symptom severity in schizophrenia. Am J Med Genet B Neuropsychiatr Genet. 156B, 340-345 (2011)
 
Ribbe K, Friedrichs H, Begemann M, Grube S, Papiol S, Kastner A, Gerchen MF, Ackermann V, Tarami A, Treitz A, Flogel M, Adler L, Aldenhoff JB, Becker-Emner M, Becker T, Czernik A, Dose M, Folkerts H, Freese R, Gunther R, Herpertz S, Hesse D, Kruse G, Kunze H, Franz M, Lohrer F, Maier W, Mielke A, Muller-Isberner R, Oestereich C, Pajonk FG, Pollmacher T, Schneider U, Schwarz HJ, Kroner-Herwig B, Havemann-Reinecke U, Frahm J, Stuhmer W, Falkai P, Brose N, Nave KA, Ehrenreich H.: The cross-sectional GRAS sample: A comprehensive phenotypical data collection of schizophrenic patients. BMC Psychiatry. 10, 91-91. (2010)
 
Begemann M, Grube S, Papiol S, Malzahn D, Krampe H, Ribbe K, Friedrichs H, Radyushkin KA, El-Kordi A, Benseler F, Hannke K, Sperling S, Schwerdtfeger D, Thanhäuser I, Gerchen MF, Ghorbani M, Gutwinski S, Hilmes C, Leppert R, Ronnenberg A, Sowislo J, Stawicki S, Stödtke M, Szuszies C, Reim K, Riggert J, Eckstein F, Falkai P, Bickeböller H, Nave KA, Brose N, Ehrenreich H: Modification of Cognitive Performance in Schizophrenia by Complexin 2 Gene Polymorphisms. Arch Gen Psychiatry. 67, 879-888 (2010).
 
Wüstenberg T, Begemann M, Bartels C, Gefeller O, Stawicki S, Hinze-Selch D, Mohr A, Falkai P, Aldenhoff JB, Knauth M, Nave KA, Ehrenreich H: Recombinant human erythropoietin delays loss of gray matter in chronic schizophrenia. Mol Psychiatry. [Epub ahead of print] (2010).
 
Brzózka MM, Radyushkin K, Wichert SP, Ehrenreich H, Rossner MJ: Cognitive and Sensorimotor Gating Impairments in Transgenic Mice Overexpressing the Schizophrenia Susceptibility Gene Tcf4 in the Brain. Biol Psychiatry. 68, 33-40 (2010).
 
Radyushkin K, El-Kordi A, Boretius S, Castaneda S, Ronnenberg A, Reim K, Bickeböller H, Frahm J, Brose N, Ehrenreich H: Complexin2 null mutation requires a 'second hit' for induction of phenotypic changes relevant to schizophrenia. Genes Brain Behav. 9, 592-604 (2010).
 
Adamcio B, Sperling S, Hagemeyer N, Walkinshaw G, Ehrenreich H: Hypoxia inducible factor stabilization leads to lasting improvement of hippocampal memory in healthy mice. Behav Brain Res. 208, 80-84 (2009).
 
El-Kordi A, Radyushkin K, Ehrenreich H: Erythropoietin improves operant conditioning and stability of cognitive performance in mice. BMC Biol. 7, 37-37 (2009).
 
Sirén A.L., Faßhauer T., Bartels C., Ehrenreich H.: Therapeutic Potential of Erythropoietin and its Structural or Functional Variants in the Nervous System. Neurotherapeutics 6, 108-127 (2009).
 
Adamcio B, Havemann-Reinecke U, Ehrenreich H Chronic psychosocial stress in the absence of social support induces pathological pre-pulse inhibition in mice. Behav Brain Res. 204, 246-249 (2009).
 
Sargin D., Hassouna I., Sperling S., Sirén A.L., Ehrenreich H.: Uncoupling of neurodegeneration and gliosis in a murine model of juvenile cortical lesion. Glia 57, 693-702 (2009).
 
Bartels C., Späte K., Krampe H., Ehrenreich H.: Recombinant human erythropoietin: Novel strategies for neuroprotective/neuroregenerative treatment of multiple sclerosis. Therapeutic Advances in Neurological Disorders 1, 193-206 (2008).
 
Adamcio B., Sargin D., Stradomska A., Medrihan L., Gertler C., Theis F., Zhang M., Muller M., Hassouna I., Hannke K., Sperling S., Radyushkin K., El-Kordi A., Schulze L., Ronnenberg A., Wolf F., Brose N., Rhee J.S., Zhang W., Ehrenreich H.: Erythropoietin enhances hippocampal long-term potentiation and memory. BMC Biol. 6, 37 (2008).
 
Brinkmann B.G., Agarwal A., Sereda M.W., Garratt A.N., Müller T., Wende H., Stassart R.M., Nawaz S., Humml C., Velanac V., Radyushkin K., Goebbels S., Fischer T.M., Franklin R.J., Lai C., Ehrenreich H., Birchmeier C., Schwab M.H., Nave K.A.: Neuregulin-1/ErbB signaling serves distinct functions in myelination of the peripheral and central nervous system. Neuron 59, 581-595 (2008).
 
Jamain S., Radyushkin K., Hammerschmidt K., Granon S., Boretius S., Varoqueaux F., Ramanantsoa N., Gallego J., Ronnenberg A., Winter D., Frahm J., Fischer J., Bourgeron T., Ehrenreich H., Brose N.: Reduced social interaction and ultrasonic communication in a mouse model of monogenic heritable autism. Proc Natl Acad Sci U S A. 105, 1710-1715 (2008).
 
Ehrenreich H., Bartels C., Sargin D., Stawicki S., Krampe H.: Recombinant human erythropoietin in the treatment of human brain disease: focus on cognition. J Ren Nutr. 18, 146-153 (2008).
 
Ehrenreich, H., Hinze-Selch, D., Stawicki, S., Aust, C., Knolle-Veentjer, S., Wilms, S., Heinz, G., Erdag , S., Jahn, H., Degner, D., Ritzen, M., Mohr, A., Wagner, M., Schneider, U., Bohn, M., Huber, M., Czernik, A., Pollmächer, T., Maier, W., Sirén, A.-L., Klosterkötter, J., Falkai, P., Rüther, E., Aldenhoff, J. B., Krampe, H.: Improvement of cognitive functions in chronic schizophrenic patients by recombinant human erythropoietin. Mol Psychiatry, 12(2): 206-220 (2007).
 
Weishaupt, J. H., Bartels, C., Polking, E., Dietrich, J., Rohde, G., Poeggeler, B., Mertens, N., Sperling, S., Bohn, M., Huther, G., Schneider, A., Bach, A., Siren, A. L., Hardeland, R., Bahr, M., Nave, K. A., Ehrenreich, H.: Reduced oxidative damage in ALS by high-dose enteral melatonin treatment. Journal of Pineal Research, 41: 313-323 (2006).
 
Sirén, A.-L., Radyushkin, K., Boretius, S., Kämmer, D., Riechers, CC, Natt, O., Sargin, D., Watanabe, T., Sperling, S., Michaelis, T., Price, J., Meyer, B., Frahm, J., Ehrenreich, H.: Global brain atrophy after unilateral parietal lesion and its prevention by erythropoietin. Brain, 129: 480-489, 2006.
 
Brettschneider J, Widl K, Ehrenreich H, Riepe M, Tumani H.: Erythropoietin in the cerebrospinal fluid in neurodegenerative diseases. Neurosci Lett. 404: 347-51, (2006).
 
Hasselblatt, M., Ehrenreich, H., Siren, A.L.: The brain erythropoietin system and its potential for therapeutic exploitation in brain disease. J Neurosurg Anesthesiol., 18:132-138, (2006).
 
Ehrenreich, H., Hasselblatt, M., Knerlich, F., von Ahsen, N., Jacob, S., Sperling, S., Woldt, H., Vehmeyer, K., Nave, K-A., Sirén, A-L..: A hematopoietic growth factor, thrombopoietin, has a proapoptotic role in the brain. PNAS, 102: 862-867, (2005).
 
Ehrenreich, H., Timner, W., Sirén, A.-L.: A novel role for an established player: anemia drug erythropoietin for the treatment of cerebral hypoxia/ischemia. Transfusion and Apheresis Science, 31: 39-44, (2004).
 
Ehrenreich, H.: Medicine. A boost for translational neuroscience. Science, 305:184-85, (2004).
 
Piazza, O., Sirén, A.-L., Ehrenreich, H.: Soccer, neurotrauma and amyotrophic lateral sclerosis: Is there a connection? Current Medical Research and Opinion, 20: 505-508, (2004).
 
Ehrenreich H, Degner D, Meller J, Brines M, Behe M, Hasselblatt M, Woldt H, Falkai P, Knerlich F, Jacob S, Von Ahsen N, Maier W, Bruck W, Ruther E, Cerami A, Becker W, Siren AL.: Erythropoietin: a candidate compound for neuroprotection in schizophrenia. Mol. Psychiatry: 9:42-54, (2004).
 
Herrmann M, Ehrenreich H.: Brain derived proteins as markers of acute stroke: Their relation to pathophysiology, outcome prediction and neuroprotective drug monitoring. Restor Neurol Neurosci.: 21: 177-190 (2003).
 
Jacob, S., Poeggeler, B., Weishaupt, JH., Siren, AL., Hardeland, R., Bahr, M., Ehrenreich, H.: Melatonin as a candidate compound for neuroprotection in amyotrophic lateral sclerosis (ALS): high tolerability of daily oral melatonin administration in ALS patients. J Pineal Res., 33: 186-7, (2003).
 
Hasselblatt, M., Stiefel, M., Rustenbeck, HH., Breiter, N., Grabbe, E., Ehrenreich, H.: The approximate planimetric method: a simple, rapid and reliable method for estimation of lesion size in acute ischemic stroke. Neuroradiology, 45: 164-5, (2003).
 
Ehrenreich, H, Hasselblatt, M, Dembowski, C, Cepek, L, Lewczuk, P, Stiefel, M, Rustenbeck, HH, Breiter, N, Jacob, S, Knerlich, F, Bohn, M, Poser, W, Rüther, E, Kochen, M, Gefeller, O, Gleiter, C, Wessel, T, de Ryck, M, Itri, L, Prange, H, Cerami, A, Brines, M, Sirén, AL: Erythropoietin therapy for acute stroke is both safe and beneficial. Molecular Medicine 8:495-505, (2002).
 
Ehrenreich H., Sirén A.-L: Neuroprotection in Schizophrenia: What does it mean? What means do we have? In: Häfner, H. (ed.) "Risk and protective factors in schizophrenia". Heidelberg: Steinkopff Darmstadt: 257-262, (2002).
 
Ehrenreich H., Sirén A.-L.: Benefits of recombinant erythropoietin on cognitive function. Erythropoiesis, 11: 35-39, (2001).
 
Sirén, A.-L. and Ehrenreich, H.: Erythropoietin - a novel concept for neuroprotection. Eur Arch Psychiatry Clin Neurosci, 251: 179-184 (2001).
 
Ehrenreich, H. and Sirén, A.-L.: Special Issue-Editorial. Neuroprotection - what does it mean? - what means do we have? Eur Arch Psychiatry Clin Neurosci, 251: 149-151 (2001).
 
Sirén, A.-L., Fratelli, M., Brines, M., Goemans, C., Casagrande, S., Lewczuk, P., Keenan, S., Gleiter, C., Pasquali, C., Capobianco, A., Mennini, T., Heumann, R., Cerami, A., Ehrenreich, H., Ghezzi, P.: Erythropoietin prevents neuronal apoptosis after cerebral ischemia and in metabolically stress. Proc. Natl., Acad. Sci. USA, 98: 4044-4049, (2001).
 
Sirén, A.-L., Knerlich, F., Poser, W., Gleiter, C.H., Brück, W., Ehrenreich, H.: Erythropoietin, and erythropoietin receptor in human ischemic/hypoxic brain. Acta Neuropathol., 101: 271-276, (2001).
 
Hasselblatt, M., Lewczuk, P., Löffler, B.-M., Kamrowski-Kruck, H., von Ahsen, N., Sirén, A.-L., Ehrenreich, H.: Role of the astrocytic ETB-receptor in the regulation of extracellular endothelin-1 during hypoxia. Glia, 34: 18-26, (2001).
 
Lewczuk, P., Hasselblatt, M., Kamrowski-Kruck, H., Heyer, A., Unzicker, C., Sirén, A.-L., Ehrenreich, H., Survival of hippocampal neurons in culture upon hypoxia: effect of erythropoietin. NeuroReport, 11: 3485-3488, (2000).
 
Sirén, A.-L., Knerlich, F., Schilling, L., Kamrowski-Kruck, H., Hahn, A., Ehrenreich, H.: Differential glial and vascular expression of endothelins and their receptors in rat brain after neurotrauma. Neurochem. Res., 25: 957-969, (2000).
 
Knerlich, F., Schilling, L., Görlach, C., Wahl, M., Ehrenreich, H., Sirén, A.-L.: Temporal profile of expression and cellular localization of inducible nitric oxide synthase, interleukin-1ß, and interleukin converting enzyme after cryogenic lesion of the rat parietal cortex. Mol Brain Res., 68: 73-87, (1999).
 
Görlach, C., Sirén, A.-L., Knerlich, F., Feger, G., Fricke, A., Schilling L., Ehrenreich, H., Wahl, M.: Delayed loss of ETB-mediated vasodilation following experimental neurotrauma in the rat. J.Cereb.Blood Flow Metab., 18: 1357-1364, (1998).