Anna-Leena Sirén

Publications of Anna-Leena Sirén

• Blocking of bradykinin receptor B1 protects from focal closed head injury in mice by reducing axonal damage and astroglia activation.

  Authors: Christiane Albert-Weissenberger, Christian Stetter, Sven G Meuth, Kerstin Göbel, Michael Bader, Anna-Leena Sirén, Christoph Kleinschnitz

  Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 05/2012;

  The two bradykinin receptors B1R and B2R are central components of the kallikrein-kinin system with different expression kinetics and binding characteristics. Activation of these receptors by kininsThe two bradykinin receptors B1R and B2R are central components of the kallikrein-kinin system with different expression kinetics and binding characteristics. Activation of these receptors by kinins triggers inflammatory responses in the target organ and in most situations enhances tissue damage. We could recently show that blocking of B1R, but not B2R, protects from cortical cryolesion by reducing inflammation and edema formation. In the present study, we investigated the role of B1R and B2R in a closed head model of focal traumatic brain injury (TBI; weight drop). Increased expression of B1R in the injured hemispheres of wild-type mice was restricted to the later stages after brain trauma, i.e. day 7 (P<0.05), whereas no significant induction could be observed for the B2R (P>0.05). Mice lacking the B1R, but not the B2R, showed less functional deficits on day 3 (P<0.001) and day 7 (P<0.001) compared with controls. Pharmacological blocking of B1R in wild-type mice had similar effects. Reduced axonal injury and astroglia activation could be identified as underlying mechanisms, while inhibition of B1R had only little influence on the local inflammatory response in this model. Inhibition of B1R may become a novel strategy to counteract trauma-induced neurodegeneration.Journal of Cerebral Blood Flow & Metabolism advance online publication, 9 May 2012; doi:10.1038/jcbfm.2012.62.

• Stiff person syndrome-associated autoantibodies to amphiphysin mediate reduced GABAergic inhibition.

  Authors: Christian Geis, Andreas Weishaupt, Stefan Hallermann, Benedikt Grünewald, Carsten Wessig, Thomas Wultsch, Andreas Reif, Nadiya Byts, Marcus Beck, Sibylle Jablonka, Michael K Boettger, Nurcan Üçeyler, Wernher Fouquet, Manfred Gerlach, Hans-Michael Meinck, Anna-Leena Sirén, Stephan J Sigrist, Klaus V Toyka, Manfred Heckmann, Claudia Sommer

  Brain : a journal of neurology. 09/2010; 133(11):3166-80.

  Synaptic inhibition is a central factor in the fine tuning of neuronal activity in the central nervous system. Symptoms consistent with reduced inhibition such as stiffness, spasms and anxiety occurSynaptic inhibition is a central factor in the fine tuning of neuronal activity in the central nervous system. Symptoms consistent with reduced inhibition such as stiffness, spasms and anxiety occur in paraneoplastic stiff person syndrome with autoantibodies against the intracellular synaptic protein amphiphysin. Here we show that intrathecal application of purified anti-amphiphysin immunoglobulin G antibodies induces stiff person syndrome-like symptoms in rats, including stiffness and muscle spasms. Using in vivo recordings of Hoffmann reflexes and dorsal root potentials, we identified reduced presynaptic GABAergic inhibition as an underlying mechanism. Anti-amphiphysin immunoglobulin G was internalized into neurons by an epitope-specific mechanism and colocalized in vivo with presynaptic vesicular proteins, as shown by stimulation emission depletion microscopy. Neurons from amphiphysin deficient mice that did not internalize the immunoglobulin provided additional evidence of the specificity in antibody uptake. GABAergic synapses appeared more vulnerable than glutamatergic synapses to defective endocytosis induced by anti-amphiphysin immunoglobulin G, as shown by increased clustering of the endocytic protein AP180 and by defective loading of FM 1-43, a styryl dye used to label cell membranes. Incubation of cultured neurons with anti-amphiphysin immunoglobulin G reduced basal and stimulated release of γ-aminobutyric acid substantially more than that of glutamate. By whole-cell patch-clamp analysis of GABAergic inhibitory transmission in hippocampus granule cells we showed a faster, activity-dependent decrease of the amplitude of evoked inhibitory postsynaptic currents in brain slices treated with antibodies against amphiphysin. We suggest that these findings may explain the pathophysiology of the core signs of stiff person syndrome at the molecular level and show that autoantibodies can alter the function of inhibitory synapses in vivo upon binding to an intraneuronal key protein by disturbing vesicular endocytosis.

• Inhibition of bradykinin receptor B1 protects mice from focal brain injury by reducing blood-brain barrier leakage and inflammation.

  Authors: Furat Raslan, Tobias Schwarz, Sven G Meuth, Madeleine Austinat, Michael Bader, Thomas Renné, Klaus Roosen, Guido Stoll, Anna-Leena Sirén, Christoph Kleinschnitz

  Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 03/2010; 30(8):1477-86.

  Kinins are proinflammatory and vasoactive peptides that are released during tissue damage and may contribute to neuronal degeneration, inflammation, and edema formation after brain injury by actingKinins are proinflammatory and vasoactive peptides that are released during tissue damage and may contribute to neuronal degeneration, inflammation, and edema formation after brain injury by acting on discrete bradykinin receptors, B1R and B2R. We studied the expression of B1R and B2R and the effect of their inhibition on lesion size, blood-brain barrier (BBB) disruption, and inflammatory processes after a focal cryolesion of the right parietal cortex in mice. B1R and B2R gene transcripts were significantly induced in the lesioned hemispheres of wild-type mice (P<0.05). The volume of the cortical lesions and neuronal damage at 24 h after injury in B1R(-/-) mice were significantly smaller than in wild-type controls (2.5+/-2.6 versus 11.5+/-3.9 mm(3), P<0.001). Treatment with the B1R antagonist R-715 1 h after lesion induction likewise reduced lesion volume in wild-type mice (2.6+/-1.4 versus 12.2+/-6.1 mm(3), P<0.001). This was accompanied by a remarkable reduction of BBB disruption and tissue inflammation. In contrast, genetic deletion or pharmacological inhibition of B2R had no significant impact on lesion formation or the development of brain edema. We conclude that B1R inhibition may offer a novel therapeutic strategy after acute brain injuries.

• Therapeutic Potential of Erythropoietin and its Structural or Functional Variants in the Nervous System.

  Authors: Anna-Leena Sirén, Theresa Faßhauer, Claudia Bartels, Hannelore Ehrenreich

  Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics. 02/2009; 6(1):108-127.

  The growth factor erythropoietin (EPO) and erythropoietin receptors (EPOR) are expressed in the nervous system. Neuronal expression of EPO and EPOR peaks during brain development and is upregulatedThe growth factor erythropoietin (EPO) and erythropoietin receptors (EPOR) are expressed in the nervous system. Neuronal expression of EPO and EPOR peaks during brain development and is upregulated in the adult brain after injury. Peripherally administered EPO, and at least some of its variants, cross the blood-brain barrier, stimulate neurogenesis, neuronal differentiation, and activate brain neurotrophic, anti-apoptotic, anti-oxidant and anti-inflammatory signaling. These mechanisms underlie their tissue protective effects in nervous system disorders. As the tissue protective functions of EPO can be separated from its stimulatory action on hematopoiesis, novel EPO derivatives and mimetics, such as asialo-EPO and carbamoylated EPO have been developed. While the therapeutic potential of the novel EPO derivatives continues to be characterized in preclinical studies, the experimental findings in support for the use of recombinant human (rh)EPO in human brain disease have already been translated to clinical studies in acute ischemic stroke, chronic schizophrenia, and chronic progressive multiple sclerosis. In this review article, we assess the studies on EPO and, in particular, on its structural or functional variants in experimental models of nervous system disorders, and we provide a short overview of the completed and ongoing clinical studies testing EPO as neuroprotective/neuroregenerative treatment option in neuropsychiatric disease.

• Erythropoietin: a multimodal neuroprotective agent.

  Authors: Nadiya Byts, Anna-Leena Sirén

  Experimental & translational stroke medicine. 01/2009; 1:4.

  The tissue protective functions of the hematopoietic growth factor erythropoietin (EPO) are independent of its action on erythropoiesis. EPO and its receptors (EPOR) are expressed in multiple brainThe tissue protective functions of the hematopoietic growth factor erythropoietin (EPO) are independent of its action on erythropoiesis. EPO and its receptors (EPOR) are expressed in multiple brain cells during brain development and upregulated in the adult brain after injury. Peripherally administered EPO crosses the blood-brain barrier and activates in the brain anti-apoptotic, anti-oxidant and anti-inflammatory signaling in neurons, glial and cerebrovascular endothelial cells and stimulates angiogenesis and neurogenesis. These mechanisms underlie its potent tissue protective effects in experimental models of stroke, cerebral hemorrhage, traumatic brain injury, neuroinflammatory and neurodegenerative disease. The preclinical data in support of the use of EPO in brain disease have already been translated to first clinical pilot studies with encouraging results with the use of EPO as a neuroprotective agent.

• Uncoupling of neurodegeneration and gliosis in a murine model of juvenile cortical lesion.

  Authors: Derya Sargin, Imam Hassouna, Swetlana Sperling, Anna-Leena Sirén, Hannelore Ehrenreich

  Glia. 12/2008;

  A small experimental cryolesion to the right parietal cortex of juvenile mice causes late-onset global brain atrophy with memory impairments, reminiscent of cognitive decline, and progressive brainA small experimental cryolesion to the right parietal cortex of juvenile mice causes late-onset global brain atrophy with memory impairments, reminiscent of cognitive decline, and progressive brain matter loss in schizophrenia. However, the cellular events underlying this global neurodegeneration are not understood. Here we show, based on comprehensive stereological analysis, 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 cyclic nucleotide phosphodiesterase, reflecting a reduction of oligodendrocytes, may further contribute to the observed brain atrophy. Remarkably, early intervention with recombinant human erythropoietin (EPO), a hematopoietic growth factor with multifaceted neuroprotective properties (intraperitoneal injection of 5000 IU/kg body weight every other day for 3 weeks), prevented all these neurodegenerative changes. To conclude, unilateral parietal lesion of juvenile mice induces a non- gliotic neurodegenerative process, susceptible to early EPO treatment. Although the detailed mechanisms remain to be defined, these profound EPO effects open new ways for prophylaxis and therapy of neuropsychiatric diseases, e.g. schizophrenia. (c) 2008 Wiley-Liss, Inc.

• Thrombopoietin inhibits nerve growth factor-induced neuronal differentiation and ERK signalling.

  Authors: Anatoly Samoylenko, Nadiya Byts, Krishnaraj Rajalingam, Nicolas von Ahsen, Ulf R Rapp, Hannelore Ehrenreich, Anna-Leena Sirén

  Cellular signalling. 02/2008; 20(1):154-62.

  Thrombopoietin (TPO), a hematopoietic growth factor regulating platelet production, and its receptor (TPOR) were recently shown to be expressed in the brain where they exert proapoptotic activity.Thrombopoietin (TPO), a hematopoietic growth factor regulating platelet production, and its receptor (TPOR) were recently shown to be expressed in the brain where they exert proapoptotic activity. Here we used PC12 cells, an established model of neuronal differentiation, to investigate the effects of TPO on neuronal survival and differentiation. These cells expressed TPOR mRNA. TPO increased cell death in neuronally differentiated PC12 cells but had no effect in undifferentiated cells. Surprisingly, TPO inhibited nerve growth factor (NGF)-induced differentiation of PC12 cells in a dose- and time-dependent manner. This inhibition was dependent on the activity of Janus kinase-2 (JAK2). Using phospho-kinase arrays and Western blot we found downregulation of the NGF-stimulated phosphorylation of the extracellular signal-regulated kinase p42ERK by TPO with no effect on phosphorylation of Akt or stress kinases. NGF-induced phosphorylation of ERK-activating kinases, MEK1/2 and C-RAF was also reduced by TPO while NGF-induced RAS activation was not attenuated by TPO treatment. In contrast to its inhibitory effects on NGF signalling, TPO had no effect on epidermal growth factor (EGF)-stimulated ERK phosphorylation or proliferation of PC12 cells. Our data indicate that TPO via activation of its receptor-bound JAK2 delays the NGF-dependent acquisition of neuronal phenotype and decreases neuronal survival by suppressing NGF-induced ERK activity.

• Exploring recombinant human erythropoietin in chronic progressive multiple sclerosis.

  Authors: Hannelore Ehrenreich, Benjamin Fischer, Christine Norra, Felix Schellenberger, Nike Stender, Michael Stiefel, Anna-Leena Sirén, Walter Paulus, Klaus-Armin Nave, Ralf Gold, Claudia Bartels

  Brain : a journal of neurology. 11/2007; 130(Pt 10):2577-88.

  The neurodegenerative aspects of chronic progressive multiple sclerosis (MS) have received increasing attention in recent years, since anti-inflammatory and immunosuppressive treatment strategiesThe neurodegenerative aspects of chronic progressive multiple sclerosis (MS) have received increasing attention in recent years, since anti-inflammatory and immunosuppressive treatment strategies have largely failed. However, successful neuroprotection and/or neuroregeneration in MS have not been demonstrated yet. Encouraged by the multifaceted neuroprotective effects of recombinant human erythropoietin (rhEPO) in experimental models, we performed an investigator-driven, exploratory open label study (phase I/IIa) in patients with chronic progressive MS. Main study objectives were (i) evaluating safety of long-term high-dose intravenous rhEPO treatment in MS, and (ii) collecting first evidence of potential efficacy on clinical outcome parameters. Eight MS patients, five randomly assigned to high-dose (48,000 IU), three to low-dose (8000 IU) rhEPO treatment, and, as disease controls, two drug-naïve Parkinson patients (receiving 48,000 IU) were followed over up to 48 weeks: A 6-week lead-in phase, a 12-week treatment phase with weekly EPO, another 12-week treatment phase with bi-weekly EPO, and a 24-week post-treatment phase. Clinical and electrophysiological improvement of motor function, reflected by a reduction in expanded disability status scale (EDSS), and of cognitive performance was found upon high-dose EPO treatment in MS patients, persisting for three to six months after cessation of EPO application. In contrast, low-dose EPO MS patients and drug-naïve Parkinson patients did not improve in any of the parameters tested. There were no adverse events, no safety concerns and a surprisingly low need of blood-lettings. This first pilot study demonstrates the necessity and feasibility of controlled trials using high-dose rhEPO in chronic progressive MS.

• Reduced oxidative damage in ALS by high-dose enteral melatonin treatment.

  Authors: Jochen H Weishaupt, Claudia Bartels, Esther Pölking, Jeannine Dietrich, Gundula Rohde, Burkhard Poeggeler, Nina Mertens, Swetlana Sperling, Matthias Bohn, Gerald Hüther, Armin Schneider, Alfred Bach, Anna-Leena Sirén, Rüdiger Hardeland, Mathias Bähr, Klaus-Armin Nave, Hannelore Ehrenreich

  Journal of pineal research. 12/2006; 41(4):313-23.

  Amyotrophic lateral sclerosis (ALS) is the collective term for a fatal motoneuron disease of different etiologies, with oxidative stress as a common molecular denominator of disease progression.Amyotrophic lateral sclerosis (ALS) is the collective term for a fatal motoneuron disease of different etiologies, with oxidative stress as a common molecular denominator of disease progression. Melatonin is an amphiphilic molecule with a unique spectrum of antioxidative effects not conveyed by classical antioxidants. In preparation of a possible future clinical trial, we explored the potential of melatonin as neuroprotective compound and antioxidant in: (1) cultured motoneuronal cells (NSC-34), (2) a genetic mouse model of ALS (SOD1(G93A)-transgenic mice), and (3) a group of 31 patients with sporadic ALS. We found that melatonin attenuates glutamate-induced cell death of cultured motoneurons. In SOD1(G93A)-transgenic mice, high-dose oral melatonin delayed disease progression and extended survival. In a clinical safety study, chronic high-dose (300 mg/day) rectal melatonin was well tolerated during an observation period of up to 2 yr. Importantly, circulating serum protein carbonyls, which provide a surrogate marker for oxidative stress, were elevated in ALS patients, but were normalized to control values by melatonin treatment. This combination of preclinical effectiveness and proven safety in humans suggests that high-dose melatonin is suitable for clinical trials aimed at neuroprotection through antioxidation in ALS.

• Cell type specific signalling by hematopoietic growth factors in neural cells.

  Authors: Nadiya Byts, Anatoly Samoylenko, Helge Woldt, Hannelore Ehrenreich, Anna-Leena Sirén

  Neurochemical research. 11/2006; 31(10):1219-30.

  Correct timing and spatial location of growth factor expression is critical for undisturbed brain development and functioning. In terminally differentiated cells distinct biological responses toCorrect timing and spatial location of growth factor expression is critical for undisturbed brain development and functioning. In terminally differentiated cells distinct biological responses to growth factors may depend on cell type specific activation of signalling cascades. We show that the hematopoietic growth factors thrombopoietin (TPO) and granulocyte colony-stimulating factor (GCSF) exert cell type specific effects on survival, proliferation and the degree of phosphorylation of Akt1, ERK1/2 and STAT3 in rat hippocampal neurons and cortical astrocytes. In neurons, TPO induced cell death and selectively activated ERK1/2. GCSF protected neurons from TPO- and hypoxia-induced cell death via selective activation of Akt1. In astrocytes, neither TPO nor GCSF had any effect on cell viability but inhibited proliferation. This effect was accompanied by activation of ERK1/2 and inhibition of STAT3 activity. A balance between growth factors, their receptors and signalling proteins may play an important role in regulation of neural cell survival.

• The brain erythropoietin system and its potential for therapeutic exploitation in brain disease.

  Authors: Martin Hasselblatt, Hannelore Ehrenreich, Anna-Leena Sirén

  Journal of neurosurgical anesthesiology. 05/2006; 18(2):132-8.

  The discovery of the broad neuroprotective potential of erythropoietin (EPO), an endogenous hematopoietic growth factor, has opened new therapeutic avenues in the treatment of brain diseases. EPOThe discovery of the broad neuroprotective potential of erythropoietin (EPO), an endogenous hematopoietic growth factor, has opened new therapeutic avenues in the treatment of brain diseases. EPO expression in the brain is induced by hypoxia. Practically all brain cells are capable of production and release of EPO and expression of its receptor. EPO exerts multifaceted protective effects on brain cells. It protects neuronal cells from noxious stimuli such as hypoxia, excess glutamate, serum deprivation or kainic acid exposure in vitro by targeting a variety of mechanisms and involves neuronal, glial and endothelial cell functions. In rodent models of ischemic stroke, EPO reduces infarct volume and improves functional outcome, but beneficial effects have also been observed in animal models of subarachnoid hemorrhage, intracerebral hemorrhage, traumatic brain injury, and spinal cord injury. EPO has a convenient therapeutic window upon ischemic stroke and favorable pharmacokinetics. Results from first therapeutic trials in humans are promising, but will need to be validated in larger trials. The safety profile and effectiveness of EPO in a wide variety of neurologic disease models make EPO a candidate compound for a potential first-line therapeutic for neurologic emergencies.

• Global brain atrophy after unilateral parietal lesion and its prevention by erythropoietin.

  Authors: Anna-Leena Sirén, Konstantin Radyushkin, Susann Boretius, Daniel Kämmer, Claas-Christian Riechers, Oliver Natt, Derya Sargin, Takashi Watanabe, Swetlana Sperling, Thomas Michaelis, Jack Price, Barbara Meyer, Jens Frahm, Hannelore Ehrenreich

  Brain : a journal of neurology. 03/2006; 129(Pt 2):480-9.

  In humans, neurotrauma is suspected to cause brain atrophy and accelerate slowly progressive neurodegenerative disorders, such as Alzheimer's disease or schizophrenia. However, a direct link betweenIn humans, neurotrauma is suspected to cause brain atrophy and accelerate slowly progressive neurodegenerative disorders, such as Alzheimer's disease or schizophrenia. However, a direct link between brain injury and subsequent delayed global neurodegeneration has remained elusive. Here we show that juvenile (4-week-old) mice that are given a discrete unilateral lesion of the parietal cortex, develop to adulthood without obvious clinical symptoms. However, when monitored 3 and 9 months after lesioning, using high-resolution three-dimensional MRI and behavioural testing, the same mice display global neurodegenerative changes. Surprisingly, erythropoietin, a haematopoietic growth factor with potent neuroprotective activity, prevents behavioural abnormalities, cognitive dysfunction and brain atrophy when given for 2 weeks after acute brain injury. This demonstrates that a localized brain lesion is a primary cause of delayed global neurodegeneration that can be efficiently counteracted by neuroprotection.

• Expression patterns of erythropoietin and its receptor in the developing spinal cord and dorsal root ganglia.

  Authors: Wolfgang Knabe, Anna-Leena Sirén, Hannelore Ehrenreich, Hans-Jürg Kuhn

  Anatomy and embryology. 11/2005; 210(3):209-19.

  Recombinant human erythropoietin (EPO) is neuroprotective in animal models of adult spinal cord injury, and reduces apoptosis in adult dorsal root ganglia after spinal nerve crush. The present workRecombinant human erythropoietin (EPO) is neuroprotective in animal models of adult spinal cord injury, and reduces apoptosis in adult dorsal root ganglia after spinal nerve crush. The present work demonstrates that spinal cord and dorsal root ganglia share dynamic expression patterns of EPO and its receptor (EPOR) during development. C57Bl mice from embryonic days (E) 8 (E8) to E19 were studied. In spinal cord and dorsal root ganglia, EPOR expression in all precursor cells preceded the expression of EPO in subsets of neurons. On E11, EPO-immunoreactive spinal motoneurons and ganglionic sensory neurons resided adjacent to EPOR-expressing radial glial cells and satellite cells, respectively. From E12 onwards, EPOR-immunoreactivity decreased in radial glial cells and, transiently, in satellite cells. Simultaneously, large-scale apoptosis of motoneurons and sensory neurons started, and subsets of neurons were labelled by antibodies against EPOR. Viable neurons expressed EPO and EPOR. Up to E12.5, apoptotic cells were EPOR-immunopositive, but variably EPO-immunonegative or EPO-immunopositive. Thereafter, EPO-immunonegative and EPOR-immunopositive apoptotic cells predominated. Our findings suggest that EPO-mediated neuron-glial and, later, neuron-neuronal interactions promote the differentiation and/or the survival of subsets of neurons and glial cells in central as well as in peripheral parts of the embryonic nervous system. Correspondingly, expression of phospho-Akt-1/protein-kinase B extensively overlapped expression sites of EPO and EPOR, but was absent from apoptotic cells. Identified other sites of EPO and/or EPOR expression include radial glial cells that transform to astrocytes, cells of the floor plate and notochord as well as neural crest-derived boundary cap cells at motor exit points and cells of the primary sympathetic chain.

• Hippocampal cannabinoid-1 receptor upregulation upon endothelin-B receptor deficiency: a neuroprotective substitution effect?

  Authors: Christian Unzicker, Heike Erberich, Gabriella Moldrich, Helge Woldt, Jan Bulla, Raphael Mechoulam, Hannelore Ehrenreich, Anna-Leena Sirén

  Neurochemical research. 11/2005; 30(10):1305-9.

  Endothelin (ETB)-receptors mediate anti-apoptotic actions. Lack of functional ETB-receptors leads to increased neuronal apoptosis in the hippocampus. The increased apoptosis must be compensated byEndothelin (ETB)-receptors mediate anti-apoptotic actions. Lack of functional ETB-receptors leads to increased neuronal apoptosis in the hippocampus. The increased apoptosis must be compensated by other mechanisms, however, as ETB-deficient rats display normal overall brain morphology. To illuminate on brain plasticity in ETB-receptor deficiency, we studied the expression and function of another neuroprotective system, the cannabinoid CB1-receptors, in ETB-deficient hippocampus. We show that CB1 expression in hippocampus increases postnatally in all rats but that the increase in CB1-receptor expression is significantly higher in ETB-deficient compared to wildtype littermates. Neuronal apoptosis decreases during brain maturation but remains on a significantly higher level in the ETB-deficient compared to wildtype dentate. When investigating survival of hippocampal neurons in culture, we found significant protection against hypoxia-induced cell death with CB1-analogs (noladin, (9-tetrahydrocannabinol) only in ETB-deficient neurons. We suggest that CB1-receptor upregulation in the ETB-mutant hippocampus reflects an attempt to compensate for the lack of ETB-receptors.

• In vitro gender differences in neuronal survival on hypoxia and in 17beta-estradiol-mediated neuroprotection.

  Authors: Andrea Heyer, Martin Hasselblatt, Nicolas von Ahsen, Heinz Häfner, Anna-Leena Sirén, Hannelore Ehrenreich

  Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 05/2005; 25(4):427-30.

  Gender differences in neuropsychiatric disease are recognized but not well understood. Investigating the survival of primary rat hippocampal neurons in culture, we found significant and invertedGender differences in neuropsychiatric disease are recognized but not well understood. Investigating the survival of primary rat hippocampal neurons in culture, we found significant and inverted gender differences on normoxia versus hypoxia. Male cells were more resistant under normoxia but more vulnerable under hypoxia than female cells. Male vulnerability pattern was acquired in cells from neonatally testosterone-primed females. Estrogens, acting via membrane receptors, had a higher neuroprotective power in male neurons, explained at least in part by the pronounced increase in estrogen receptor beta/alpha ratio during hypoxia in male cells only.

• A hematopoietic growth factor, thrombopoietin, has a proapoptotic role in the brain.

  Authors: Hannelore Ehrenreich, Martin Hasselblatt, Friederike Knerlich, Nico Von Ahsen, Sonja Jacob, Swetlana Sperling, Helge Woldt, Katalin Vehmeyer, Klaus-Armin Nave, Anna-Leena Sirén

  Proceedings of the National Academy of Sciences of the United States of America. 02/2005; 102(3):862-7.

  Central nervous and hematopoietic systems share developmental features. We report that thrombopoietin (TPO), a stimulator of platelet formation, acts in the brain as a counterpart of erythropoietinCentral nervous and hematopoietic systems share developmental features. We report that thrombopoietin (TPO), a stimulator of platelet formation, acts in the brain as a counterpart of erythropoietin (EPO), a hematopoietic growth factor with neuroprotective properties. TPO is most prominent in postnatal brain, whereas EPO is abundant in embryonic brain and decreases postnatally. Upon hypoxia, EPO and its receptor are rapidly reexpressed, whereas neuronal TPO and its receptor are down-regulated. Unexpectedly, TPO is strongly proapoptotic in the brain, causing death of newly generated neurons through the Ras-extracellular signal-regulated kinase 1/2 pathway. This effect is not only inhibited by EPO but also by neurotrophins. We suggest that the proapoptotic function of TPO helps to select for neurons that have acquired target-derived neurotrophic support.

• Erythropoietin: novel approaches to neuroprotection in human brain disease.

  Authors: Hannelore Ehrenreich, Carlotta Aust, Henning Krampe, Henriette Jahn, Sonja Jacob, Manfred Herrmann, Anna-Leena Sirén

  Metabolic brain disease. 01/2005; 19(3-4):195-206.

  With the increased life expectancy in western industrialized countries, the incidence and prevalence of brain diseases dramatically increased. Stroke and a wide spectrum of neuropsychiatric illnessesWith the increased life expectancy in western industrialized countries, the incidence and prevalence of brain diseases dramatically increased. Stroke and a wide spectrum of neuropsychiatric illnesses such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, traumatic head injury, and schizophrenia all lead to severe disability. However, targeted effective therapies for treatment of these diseases are lacking. Even more frustrating is the fact that we do not yet clearly understand the basic mechanisms underlying the disease processes in these conditions. We propose a hypothesis of loss of neuronal function via a final common deleterious pathway in this clinically very heterogeneous disease group. This review presents a novel neuroprotective concept for treatment of brain disease: Erythropoietin (EPO). EPO is a natural body-own-protein hormone that has been used for treatment of anemia for more than a decade. The neuroprotective approach using EPO in brain disease represents a totally new frontier. The "Göttingen EPO-stroke trial" represents the first effective use in man of a neuroprotective therapy in an acute brain disease while the experimental EPO therapy to combat cognitive decline in patients with schizophrenia will be introduced as an example of a neuroprotective strategy for a chronic brain disease.

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

  Authors: Hannelore Ehrenreich, Wiebke Timner, Anna-Leena Sirén

  Transfusion and apheresis science : official journal of the World Apheresis Association : official journal of the European Society for Haemapheresis. 09/2004; 31(1):39-44.

  Erythropoietin, a hematopoietic growth-factor possessing manifold, potent neuroprotective properties, after multiple testing in cell culture and animal studies now gradually finds its way intoErythropoietin, 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.

• Soccer, neurotrauma and amyotrophic lateral sclerosis: is there a connection?

  Authors: Ornella Piazza, Anna-Leena Sirén, Hannelore Ehrenreich

  Current medical research and opinion. 05/2004; 20(4):505-8.

  Trauma has long been hypothesized but never proven to be a risk factor for amyotrophic lateral sclerosis (ALS). This hypothesis may now have a renaissance due to recent reports in the lay press onTrauma has long been hypothesized but never proven to be a risk factor for amyotrophic lateral sclerosis (ALS). This hypothesis may now have a renaissance due to recent reports in the lay press on 'the Italian motoneuron mystery', i.e. the disclosure of 33 diagnosed ALS cases in a subpopulation of 24000 soccer players of the top three Italian divisions from the 1960s to 1996. Could the repetitive brain trauma that soccer players experience for controlling and advancing the ball with their heads represent an environmental risk factor for developing ALS in genetically predisposed individuals? By critically reviewing the scarce literature and 'surrounding evidence' (Medline, CDC, lay press, Italian health officials), we have looked for a potential relationship between (1) soccer and head trauma and (2) head trauma and subsequent development of amyotrophic lateral sclerosis. Whereas the brain traumatizing effect of soccer seems to be out of the question, the findings of the few retrospective studies on ALS and neurotrauma are conflicting. Taken together, however, the literature would still support the concept of soccer, head trauma, and ALS being interrelated, with high levels of athleticism/physical activity perhaps playing an additive part. To further clarify this issue, extensive prospective epidemiological investigations on ALS following neurotrauma as well as carefully designed animal studies will have to be conducted.

• Effect of endothelin-1 on astrocytic protein content.

  Authors: Martin Hasselblatt, Marion Bunte, Ralf Dringen, Arantxa Tabernero, José M Medina, Christian Giaume, Anna-Leena Sirén, Hannelore Ehrenreich

  Glia. 07/2003; 42(4):390-7.

  The astrocytic endothelin (ET) receptors, ET(A) and ET(B), modulate calcium signaling and the astrocytic gap junctional network. The nonselective ET receptor ligand ET-1 inhibits gap junctionThe astrocytic endothelin (ET) receptors, ET(A) and ET(B), modulate calcium signaling and the astrocytic gap junctional network. The nonselective ET receptor ligand ET-1 inhibits gap junction permeability, an effect that can be blocked by tolbutamide. This mechanism may play a role in pathophysiological conditions such as ischemic stroke, characterized by elevated tissue ET-1 levels and hypertrophic-appearing reactive astrocytes. Therefore, the effect of ET-1 on cellular protein content was investigated in confluent once-passaged rat astrocyte cultures under serum-free conditions, by the Lowry method. Gap junction permeability was determined by the dye transfer technique. ET-1 prevented the decrease in astrocytic protein content observed in controls. The effect of ET-1 on cellular protein content was most pronounced in cultures seeded at high density, but it was attenuated in ET(B)-deficient (sl/sl) astrocytes. This effect could be blocked by the nonselective ET antagonist LU 302872 (10 micro M), as well as by the protein synthesis inhibitor cycloheximide (10 micro M). This increase in astrocytic protein content was inhibited by the ATP-sensitive K(+) channel blocker tolbutamide, which also antagonized the ET-1-induced reduction of gap junction permeability and reversed the morphological changes observed in astrocytes upon ET-1 treatment. Cytosine arabinoside (10 micro M), a DNA synthesis blocker, inhibited the ET-1-induced BrdU uptake without affecting the ET-1-induced increase in astrocytic protein content. To conclude, ET-1 induces an increase in astrocytic protein content as well as changes in astrocyte morphology in vitro. This hypertrophic response involves uncoupling of the astrocytic gap junctional network and is not dependent on DNA synthesis.