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Duda S.,Hannover Medical School | Dreyer L.,Leibniz University of Hanover | Behrens P.,Leibniz University of Hanover | Wienecke S.,Leibniz University of Hanover | And 4 more authors.
BioMed Research International

We report on the performance of composite nerve grafts with an inner 3D multichannel porous chitosan core and an outer electrospun polycaprolactone shell. The inner chitosan core provided multiple guidance channels for regrowing axons. To analyze the in vivo properties of the bare chitosan cores, we separately implanted them into an epineural sheath. The effects of both graft types on structural and functional regeneration across a 10 mm rat sciatic nerve gap were compared to autologous nerve transplantation (ANT). The mechanical biomaterial properties and the immunological impact of the grafts were assessed with histological techniques before and after transplantation in vivo. Furthermore during a 13-week examination period functional tests and electrophysiological recordings were performed and supplemented by nerve morphometry. The sheathing of the chitosan core with a polycaprolactone shell induced massive foreign body reaction and impairment of nerve regeneration. Although the isolated novel chitosan core did allow regeneration of axons in a similar size distribution as the ANT, the ANT was superior in terms of functional regeneration. We conclude that an outer polycaprolactone shell should not be used for the purpose of bioartificial nerve grafting, while 3D multichannel porous chitosan cores could be candidate scaffolds for structured nerve grafts. © 2014 Sven Duda et al. Source

Scheiblich H.,University of Veterinary Medicine Hannover | Bicker G.,University of Veterinary Medicine Hannover | Bicker G.,Center for Systems Neuroscience Hanover
Developmental neurobiology

Clearance of infected and apoptotic neuronal corpses during inflammatory conditions is a fundamental process to create a favorable environment for neuronal recovery. Microglia are the resident immune cells and the predominant phagocytic cells of the CNS, showing a multitude of cellular responses upon activation. Here, we investigated in functional assays how the CO generating enzyme heme oxygenase 1 (HO-1) influences BV-2 microglial migration, clearance of debris, and neurite outgrowth of human NT2 neurons. Stimulation of HO-1 activity attenuated microglial migration in a scratch wound assay, and phagocytosis in a cell culture model of acute inflammation comprising lipopolysaccharide (LPS)-activated microglia and apoptosis-induced neurons. Application of a CO donor prevented the production of NO during LPS stimulation, and reduced microglial migration and engulfment of neuronal debris. LPS-activated microglia inhibited neurite elongation of human neurons without requiring direct cell-cell surface contact. The inhibition of neurite outgrowth was totally reversed by application of exogenous CO or increased internal CO production through supply of the substrate hemin to HO. Our results point towards a vital cytoprotective role of HO-1/CO signaling after microglial activation. In addition, they support a therapeutic potential of CO releasing chemical agents in the treatment of excessive inflammatory conditions in the CNS. © 2014 Wiley Periodicals, Inc. Source

Podrygajlo G.,University of Veterinary Medicine Hannover | Podrygajlo G.,Center for Systems Neuroscience Hanover | Wiegreffe C.,Albert Ludwigs University of Freiburg | Wiegreffe C.,University of Ulm | And 3 more authors.
Developmental Dynamics

Postmitotic neurons were generated from the human NT2 teratocarcinoma cell line in a novel cell aggregate differentiation procedure. Approximately a third of the differentiated neurons expressed cell markers related to cholinergic neurotransmission. To examine whether this human cell model system can be directed toward a motoneuronal fate, postmitotic neurons were co-cultured with mouse myotubes. Outgrowing neuronal processes established close contact with the myotubes and formed neuromuscular junction-like structures that bound α-bungarotoxin. To determine how grafted precursor cells and neurons respond to embryonic nerve tissue, NT2 cells at different stages of neural development were injected into chick embryo neural tube and brain. Grafted NT2 neurons populated both parts of the nervous system, sometimes migrating away from the site of injection. The neural tube appeared to be more permissive for neurite extensions than the brain. Moreover, extending neurites of spinal grafts were approaching the ventral roots, thus resembling motoneuronal projections. © 2009 Wiley-Liss, Inc. Source

Tegenge M.A.,University of Veterinary Medicine Hannover | Tegenge M.A.,Center for Systems Neuroscience Hanover | Tegenge M.A.,Johns Hopkins University | Bohnel H.,University of Gottingen | And 3 more authors.
Cellular and Molecular Neurobiology

Botulinum neurotoxins (BoNTs) internalize into nerve terminals and block the release of neurotransmitters into the synapse. BoNTs are widely used as a therapeutic agent for treatment of movement disorders and recently gained more attention as a biological weapon. Consequently, there is strong interest to develop a cell-based assay platform to screen the toxicity and bioactivity of the BoNTs. In this study, we present an in vitro screening assay for BoNT/A based on differentiated human embryonal carcinoma stem (NT2) cells. The human NT2 cells fully differentiated into mature neurons that display immunoreactivity to cytoskeletal markers (βIII-tubulin and MAP2) and presynaptic proteins (synapsin and synaptotagmin I). We showed that the human NT2 cells undergo a process of exo-endocytotic synaptic vesicle recycling upon depolarization with high K + buffer. By employing an antibody directed against light chain of BoNT/A, we detected internalized toxin as a punctate staining along the neurites of the NT2 neurons. Using well-established methods of synaptic vesicle exocytosis assay (luminal synaptotagmin I and FM1-43 imaging) we show that preincubation with BoNT/A resulted in a blockade of vesicle release from human NT2 neurons in a dose-dependent manner. Moreover, this blocking effect of BoNT/A was abolished by pre-adsorbing the toxin with neutralizing antibody. In a proof of principle, we demonstrate that our cell culture assay for vesicle release is sensitive to BoNT/A and the activity of BoNT/A can be blocked by specific neutralizing antibodies. Overall our data suggest that human NT2 neurons are suitable for large scale screening of botulinum bioactivity. © Springer Science+Business Media, LLC 2012. Source

Hansmann F.,University of Veterinary Medicine Hannover | Hansmann F.,Center for Systems Neuroscience Hanover | Herder V.,University of Veterinary Medicine Hannover | Herder V.,Center for Systems Neuroscience Hanover | And 3 more authors.
Journal of Comparative Pathology

This report is the first description of a spinal epidermoid cyst (EC) in a SJL mouse and gives an overview on the occurrence of ECs in animals including dogs, horses, mice and rats. The EC was not detected grossly and the mouse did not display clinical signs or an altered rotarod performance. Microscopically, there was an oval cyst lined by stratified squamous epithelium that was attached to the dorsolateral meninges and caused moderate compression of the adjacent lumbar spinal cord. ECs in mice and rats are mainly located in the caudal part of the spinal cord with a variable, strain-dependent occurrence. ECs in mice and rats are not associated with clinical signs and can be interpreted as incidental findings. © 2011 Elsevier Ltd. Source

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