Showing papers by "Ulrich Bogdahn published in 2015"

Structural and functional rejuvenation of the aged brain by an approved anti-asthmatic drug

Abstract: As human life expectancy has improved rapidly in industrialized societies, age-related cognitive impairment presents an increasing challenge. Targeting histopathological processes that correlate with age-related cognitive declines, such as neuroinflammation, low levels of neurogenesis, disrupted blood-brain barrier and altered neuronal activity, might lead to structural and functional rejuvenation of the aged brain. Here we show that a 6-week treatment of young (4 months) and old (20 months) rats with montelukast, a marketed anti-asthmatic drug antagonizing leukotriene receptors, reduces neuroinflammation, elevates hippocampal neurogenesis and improves learning and memory in old animals. By using gene knockdown and knockout approaches, we demonstrate that the effect is mediated through inhibition of the GPR17 receptor. This work illustrates that inhibition of leukotriene receptor signalling might represent a safe and druggable target to restore cognitive functions in old individuals and paves the way for future clinical translation of leukotriene receptor inhibition for the treatment of dementias.

Ibuprofen and Diclofenac Restrict Migration and Proliferation of Human Glioma Cells by Distinct Molecular Mechanisms.

Abstract: Background Non-steroidal anti-inflammatory drugs (NSAIDs) have been associated with anti-tumorigenic effects in different tumor entities. For glioma, research has generally focused on diclofenac; however data on other NSAIDs, such as ibuprofen, is limited. Therefore, we performed a comprehensive investigation of the cellular, molecular, and metabolic effects of ibuprofen and diclofenac on human glioblastoma cells. Methods Glioma cell lines were treated with ibuprofen or diclofenac to investigate functional effects on proliferation and cell motility. Cell cycle, extracellular lactate levels, lactate dehydrogenase-A (LDH-A) expression and activity, as well as inhibition of the Signal Transducer and Activator of Transcription 3 (STAT-3) signaling pathway, were determined. Specific effects of diclofenac and ibuprofen on STAT-3 were investigated by comparing their effects with those of the specific STAT-3 inhibitor STATTIC. Results Ibuprofen treatment led to a stronger inhibition of cell growth and migration than treatment with diclofenac. Proliferation was affected by cell cycle arrest at different checkpoints by both agents. In addition, diclofenac, but not ibuprofen, decreased lactate levels in all concentrations used. Both decreased STAT-3 phosphorylation; however, diclofenac led to decreased c-myc expression and subsequent reduction in LDH-A activity, whereas treatment with ibuprofen in higher doses induced c-myc expression and less LDH-A alteration. Conclusions This study indicates that both ibuprofen and diclofenac strongly inhibit glioma cells, but the subsequent metabolic responses of both agents are distinct. We postulate that ibuprofen may inhibit tumor cells also by COX- and lactate-independent mechanisms after long-term treatment in physiological dosages, whereas diclofenac mainly acts by inhibition of STAT-3 signaling and downstream modulation of glycolysis.

The Granulocyte-colony stimulating factor has a dual role in neuronal and vascular plasticity.

Abstract: Granulocyte-colony stimulating factor (G-CSF) is a growth factor that has originally been identified several decades ago as a hematopoietic factor required mainly for the generation of neutrophilic granulocytes, and is in clinical use for that. More recently, it has been discovered that G-CSF also plays a role in the brain as a growth factor for neurons and neural stem cells, and as a factor involved in the plasticity of the vasculature. We review and discuss these dual properties in view of the neuroregenerative potential of this growth factor.

Reduction in subventricular zone-derived olfactory bulb neurogenesis in a rat model of Huntington's disease is accompanied by striatal invasion of neuroblasts.

Abstract: Huntington’s disease (HD) is an inherited progressive neurodegenerative disorder caused by an expanded CAG repeat in exon 1 of the huntingtin gene (HTT). The primary neuropathology of HD has been attributed to the preferential degeneration of medium spiny neurons (MSN) in the striatum. Reports on striatal neurogenesis have been a subject of debate; nevertheless, it should be considered as an endogenous attempt to repair the brain. The subventricular zone (SVZ) might offer a close-by region to supply the degenerated striatum with new cells. Previously, we have demonstrated that R6/2 mice, a widely used preclinical model representing an early onset HD, showed reduced olfactory bulb (OB) neurogenesis but induced striatal migration of neuroblasts without affecting the proliferation of neural progenitor cell (NPCs) in the SVZ. The present study revisits these findings, using a clinically more relevant transgenic rat model of late onset HD (tgHD rats) carrying the human HTT gene with 51 CAG repeats and mimicking many of the neuropathological features of HD seen in patients. We demonstrate that cell proliferation is reduced in the SVZ and OB of tgHD rats compared to WT rats. In the OB of tgHD rats, although cell survival was reduced, the frequency of neuronal differentiation was not altered in the granule cell layer (GCL) compared to the WT rats. However, an increased frequency of dopamenergic neuronal differentiation was noticed in the glomerular layer (GLOM) of tgHD rats. Besides this, we observed a selective proliferation of neuroblasts in the adjacent striatum of tgHD rats. There was no evidence for neuronal maturation and survival of these striatal neuroblasts. Therefore, the functional role of these invading neuroblasts still needs to be determined, but they might offer an endogenous alternative for stem or neuronal cell transplantation strategies.

Activation of TGF-β-induced non-Smad signaling pathways during Th17 differentiation

Abstract: Although transforming growth factor-β (TGF-β) has been shown to positively regulate the development of murine T helper type 17 (Th17) cells, which of the intracellular signaling pathways are involved is controversial. We examined Smad-dependent and -independent signaling molecules downstream of the TGF-β receptor (TGFβR) involved in Th17 differentiation of naive murine CD4(+)CD62L(+) T cells. During Th17 differentiation of wild-type T cells, Smad2/3 was phosphorylated, indicating activation of the canonical Smad pathway. T cells lacking TGFβRII did not differentiate into Th17, whereas T cells treated with a TGFβRI kinase inhibitor (SB-431542) or overexpression of inhibitory Smad7 retained a low amount of Th17 polarization despite absent Smad2/3 phosphorylation. Using protein antibody arrays we found an increase of expression and phosphorylation of the following Smad-independent signaling molecules in Th17-polarized wild-type T cells: AKT1(Tyr474), AKT2 (Ser474), ERK1-p44/42 MAPK(Tyr204), mTOR(Thr2446), p38 MAPK(Thr180), Rac1/cdc42(Ser71), SAPK/JNK(Tyr185) and SP1(Thr739). Pharmacological inhibition of AKT/mammalian target of rapamycin (mTOR) signaling with rapamycin or LY294002 decreased Th17 differentiation of wild-type T cells, and completely abolished interleukin-17 production in T cells with overexpression of Smad7. Rapamycin and LY294002 also decreased induced regulatory T cell differentiation, but only had minor additive effects to Smad7 overexpression. Finally, inhibitors of mitogen-activated protein kinase (MAPK) blocked in vitro polarization of Th17 cells. Our data show that Smad-dependent and -independent intracellular pathways contribute to murine Th17 differentiation.

Low Endogenous Recanalization in Embolic Central Retinal Artery Occlusion—The Retrobulbar “Spot Sign”

Abstract: BACKGROUND AND PURPOSE Central retinal artery occlusion (CRAO) is most often indirectly diagnosed by lack of retinal perfusion. Direct embolus characterization may help to understand the natural course and low response to treatment. In a previous study we identified a hyperechoic signal within the optic nerve and in the central retinal artery (“spot sign”). METHODS In this study we performed a follow-up investigation in 7 patients with CRAO and positive spot sign indicating the embolic cause of the occlusion after a median interval of 17 months (range 11-38 months) using a battery of tests (ocular color-coded sonography, optic coherence tomography [OCT], fundoscopy, amongst others). RESULTS The spot sign persisted in all patients, none had high-grade internal carotid artery stenosis, stroke or transient ischemic attacks. Four patients were completely blind, 3 patients were able to recognize hand movements. OCT demonstrated retinal atrophy, and fundoscopy revealed only minimal arterial perfusion. CONCLUSIONS The hyperechoic spot sign may be an important predictive prognostic marker for persistent loss of vision. Its persistence may indicate calcified or cholesterol emboli and may explain the low therapeutic success rate to thrombolysis. Further studies on their origin and significance in atherosclerotic disease are warranted.

Intracranial hemorrhage: frequency, location, and risk factors identified in a TeleStroke network.

Abstract: Intracranial hemorrhages are associated with high rates of disability and mortality. Telemedicine in general provides clinical healthcare at a distance by using videotelephony and teleradiology and is used particularly in acute stroke care medicine (TeleStroke). TeleStroke considerably improves quality of stroke care (for instance, by increasing thrombolysis) and may be valuable for the management of intracranial hemorrhages in rural hospitals and hospitals lacking neurosurgical departments, given that surgical/interventional therapy is only recommended for a subgroup of patients. The aim of this study was to analyze the frequency, anatomical locations of intracranial hemorrhage, risk factors, and the proportion of patients transferred to specialized hospitals. We evaluated teleconsultations conducted between 2008 and 2010 in a large cohort of patients consecutively enrolled in the Telemedical Project for Integrated Stroke Care (TEMPiS) network. In cases in which intracranial hemorrhage was detected, all images were re-examined and analyzed with a focus on frequency, location, risk factors, and further management. Overall, 6187 patients presented with stroke-like symptoms. Intracranial hemorrhages were identified in 631 patients (10.2%). Of these, intracerebral hemorrhages were found in 423 cases (67.0%), including 174 (41.1%) in atypical locations and 227 (53.7%) in typical sites among other locations. After 14 days of hospitalization in community facilities, the mortality rate in patients with intracranial hemorrhages was 15.1% (95/631). Two hundred and twenty-three patients (35.3%) were transferred to neurological/neurosurgical hospitals for diagnostic workup or additional treatment. Community hospitals are confronted with patients with intracranial hemorrhage, whose management requires specific neurosurgical and hematological expertise with respect to hemorrhage subtype and clinical presentation. TeleStroke networks help select patients who need advanced neurological and/or neurosurgical care. The relatively low proportion of interhospital transfers shown in this study reflects a differentiated decision process on the basis of both guidelines and standard operating procedures.

Inventory of a Neurological Intensive Care Unit: Who Is Treated and How Long?

Abstract: Purpose. To characterize indications, treatment, and length of stay in a stand-alone neurological intensive care unit with focus on comparison between ventilated and nonventilated patient. Methods. We performed a single-center retrospective cohort study of all treated patients in our neurological intensive care unit between October 2006 and December 2008. Results. Overall, 512 patients were treated in the surveyed period, of which 493 could be included in the analysis. Of these, 40.8% had invasive mechanical ventilation and 59.2% had not. Indications in both groups were predominantly cerebrovascular diseases. Length of stay was 16.5 days in mean for ventilated and 3.6 days for nonventilated patient. Conclusion. Most patients, ventilated or not, suffer from vascular diseases with further impairment of other organ systems or systemic complications. Data reflects close relationship and overlap of treatment on nICU with a standardized stroke unit treatment and suggests, regarding increasing therapeutic options, the high impact of acute high-level treatment to reduce consequential complications.

Reversible Splenial Lesion Syndrome (RESLES) in a Patient with ClinicallyMild Tick-Borne Encephalitis and Hyponatremia

Abstract: Introduction: Reversible splenial lesion syndrome (RESLES) is a clinicoradiological syndrome of varied etiology, characterized by transient lesions involving the splenium of the corpus callosum (SCC). Clinical presentation is nonspecific and depends on etiology. In the case of infectious disease the syndrome is also called mild encephalitis with reversible splenial lesion (MERS). Hyponatremia is often described in patients with RESLES. Here we present a patient case of RESLES/MERS in a patient with tick-borne encephalitis (TBE) accompanied by mild hyponatremia. Case Presentation: A 46-year-old man presented with malaise, fever, headache, discrete nuchal rigidity, brain stem symptoms (disturbance of ocular movements, gait ataxia) and mild cognitive and psychomotor impairment. Cerebrospinal fluid analysis at two different time points showed a lymphocytic pleocytosis and seroconversion for anti-TBEIgM/- IgG, serum biochemical analysis a mild hyponatremia. Magnetic resonance imaging (MRI) of the brain on day four after admission revealed a distinct signal hyperintensity on T2/FLAIR sequences in the SCC associated with diffusion restriction and low apparent diffusion coefficient (ADC) values on diffusion-weighted sequences. On T1-weighted images no contrast enhancement was detectable. Until the diagnosis of TBE the patient was treated with intravenous ceftriaxone, ampicillin and acyclovir. The patient recovered completely within three weeks. The T2/FLAIR hyperintense and diffusion-restricted lesion of the SCC was completely resolved ten days after the first MRI. Conclusion: TBE accompanied by hyponatremia may lead to RESLES/MERS, a clinicoradiological syndrome with reversible non-enhancing lesion of the SCC and excellent prognosis. Neuroradiological findings in RESLES are very similar to findings described in patients with osmotic demyelination syndromes like central pontine myelinolysis or extrapontine myelinolysis.

MUNIX – ein viel versprechender Biomarker bei der ALS

Abstract: Um den bislang unaufhaltsamen Verlust motorischer Nervenzellen bei der amyotrophen Lateralsklerose (ALS) quantitativ zu erfassen, sind sog. MUNE-Verfahren (von engl.: motor unit number estimation) eingesetzt worden. Diese scheinen den Verlauf einer ALS besser abzubilden als klinische Scores oder neurophysiologische Standardverfahren, sind dafur aber sehr zeitaufwandig. Letzteres ist bei einem neuen Verfahren nicht der Fall, dem MUNIX (von engl.: motor unit number index). Das Funktionsprinzip von MUNIX ist intuitiv nicht unmittelbar eingangig. Hier wird daher versucht, die Funktion von MUNIX moglichst verstandlich zu beschreiben. Der Einsatz von MUNIX bei Patienten mit ALS hat gezeigt, dass MUNIX ahnlich sensitiv wie MUNE den Verlauf der Erkrankung abbildet. Es ist aber noch unklar, ob MUNIX tatsachlich die Anzahl von Vorderhornzellen wiedergibt oder ob andere Einflusse, wie z. B. eine Pyramidenbahnlasion, die MUNIX-Werte nicht wesentlich beeinflussen.

Safety and Feasibility of G-CSF Compassionate use in ALS Patients (P6.009)

Abstract: OBJECTIVE: G-CSF may compensate rapid neuronal loss in ALS. Therefore we initiated long-term compassionate use of G-CSF in ALS patients. BACKGROUND: Granulocyte-colony-stimulating factor (G-CSF) is a long-term established and safe hematopoietic growth factor. It is neuroprotective, increases neurogenesis and induces neuronal differentiation. Despite evidence for efficacy in ALS animal models, multiple small trials with G-CSF in patients delivered inconclusive results. Functional improvement might have been missed due to inadequate application and duration of treatment with short follow up. DESIGN/METHODS: 23 ALS patients (15 male, 8 female, mean age 51,4 yrs. (±13.2), mean ALS-FRS-r at start 36.75 (± 6.84)) were treated with G-CSF 5-10 μg/kg BW s.c. plus standard treatment incl. Riluzole. Application modes were individually adapted with (1) G-CSF for five consecutive days every four weeks (mean: 26.3 treatment months (8 - 49)) or (2) G-CSF twice a week (mean 23.2 treatment months (8 - 31)). Monthly control visits with clinical exams, ALSFRS-r, clinical chemistry, blood smears, bone marrow function were performed. RESULTS: Compliance was excellent, aside from mild to moderate bone pain in all patients, application modes were well tolerated. Both modes of delivery resulted in hematopoietic stem cell mobilization and biomarker modulation. We found no evidence of premalignant changes in bone marrow differentiation. In retrospective analysis a significant decrease in ALS progression rate - ALS-FRS-r - and clinical relevant prolongation of overall survival in comparison to the current Pro-ACT database, indicate high safety of prolonged G-CSF treatment. CONCLUSIONS: Long-term administration of G-CSF in ALS patients is safe and feasible. Compliance of outpatient regimens is excellent. A prospective trial is very urgently needed. Disclosure: Dr. Khomenko has nothing to disclose. Dr. Baldaranov has nothing to disclose. Dr. Johannesen has nothing to disclose. Dr. Kobor has nothing to disclose. Dr. Blume has nothing to disclose. Dr. Bruun has nothing to disclose. Dr. Grassinger has nothing to disclose. Dr. Kammermaier has nothing to disclose. Dr. Ludolph has nothing to disclose. Dr. Deppe has nothing to disclose. Dr. Schuierer has nothing to disclose. Dr. Schulte-Mattler has nothing to disclose. Dr. Friede has nothing to disclose. Dr. Laage has nothing to disclose. Dr. Schneider has nothing to disclose. Dr. Bogdahn has nothing to disclose.

Introspection: a curious case of lens luxation.

Abstract: Incidental magnetic resonance imaging finding of a luxated lens in a 76-year-old patient’s work up for transient ischemic attack (Fig 1). Further history revealed sudden loss of vision in the right eye to movement perception after surgery for abdominal aortic aneurysm 6 months ago. Lens luxation is a common complication in Marfan’s syndrome,1 connective tissue abnormalities, trauma—and even more so in Terrier breeds.2 The dark appearance of the lens in T2 turbo-spin-echo is related to the protein concentration of the lens and the proton binding to the lens protein. Orbital sonography was performed (Fig 2) with a linear transducer positioned on the upper lid of the closed eye.3 The lens floats freely in the vitreous body according to its position of the head. Lens replacement would be the therapy of choice.