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Interleukin-1 Receptor Antagonist Promotes Survival of Ventral Horn Neurons and Suppresses Microglial Activation in Mouse Spinal Cord Slice Cultures
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
2014 (English)In: Journal of Neuroscience Research, ISSN 0360-4012, E-ISSN 1097-4547, Vol. 92, no 11, 1457-1465 p.Article in journal (Refereed) Published
Abstract [en]

Secondary damage after spinal cord injury (SCI) induces neuronal demise through neurotoxicity and inflammation, and interleukin (IL)-1 beta is a key inflammatory mediator. We hypothesized that IL-1 beta is released in spinal cord slice cultures (SCSC) and aimed at preventing the potentially neurotoxic effects of IL-1 beta by using interleukin-1 receptor antagonist (IL1RA). We hypothesized that IL1RA treatment enhances neuronal survival and suppresses microglial activation. SCSC were cultured up to 8 days in vitro (DIV) in the presence of IL1RA or without, either combined with trophic support using neurotrophin (NT)-3 or not. Four groups were studied: negative control, IL1RA, NT-3, and IL1RA1NT-3. IL-1 beta concentrations in supernatants were measured by ELISA. SCSC were immunohistochemically stained for NeuN and a-neurofilament, and microglial cells were visualized with isolectin B-4. After 8 DIV, ventral horn neurons were significantly more numerous in the IL1RA, NT-3, and IL1RA1NT-3 groups compared with negative controls. Activated microglial cells were significantly less numerous in the IL1RA, NT-3, and IL1RA1NT-3 groups compared with negative controls. Axons expanded into the collagen matrix after treatment with IL1RA, NT-3, or IL1RA1NT-3, but not in negative controls. IL-1 beta release from cultures peaked after 6 hr and was lowest in the IL1RA1NT-3 group. We conclude that IL-1 beta is released in traumatized spinal cord tissue and that IL1RA could exert its neuroprotective actions by blocking IL-1-receptors. IL1RA thereby sustains neuronal survival irrespective of the presence of additional trophic support. Microglial activation is suppressed in the presence of IL1RA, suggesting decreased inflammatory activity. IL1RA treatment approaches may have substantial impact following SCI.

Place, publisher, year, edition, pages
2014. Vol. 92, no 11, 1457-1465 p.
Keyword [en]
interleukin-1, neuroinflammation, neuroprotection
National Category
Neurology Neurosciences
Identifiers
URN: urn:nbn:se:uu:diva-231972DOI: 10.1002/jnr.23429ISI: 000340534900005OAI: oai:DiVA.org:uu-231972DiVA: diva2:747079
Available from: 2014-09-15 Created: 2014-09-12 Last updated: 2017-12-05Bibliographically approved
In thesis
1. Neuroprotection in the Injured Spinal Cord: Novel Strategies using Immunomodulation, Stem cell Transplantation and Hyaluronic acid Hydrogel carriers
Open this publication in new window or tab >>Neuroprotection in the Injured Spinal Cord: Novel Strategies using Immunomodulation, Stem cell Transplantation and Hyaluronic acid Hydrogel carriers
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The overall aim of this thesis was to establish strategies to minimize secondary damage to the injured spinal cord. Secondary damage that follows spinal cord injury (SCI) involves inflammatory and excitotoxic pathways. Regulation of these pathways using immunomodulatory and neuroprotective substances potentially protects the injured spinal cord from further damage. We also developed and studied resorbable biomaterials to be used as carriers for potential neuroprotectants to the injured spinal cord.

We used transversal spinal cord slice cultures (SCSCs) derived from postnatal mice as a model. SCSCs were maintained on different biomaterials and were studied after treatment with immunomodulatory and/or neurotrophic factors. They were further excitotoxically injured and subsequently treated with interleukin-1 receptor antagonist (IL1RA) or by neural crest stem cell (NCSC)-transplantation.

The results show that biocompatible and resorbable hydrogels based on hyaluronic acid (HA) preserved neurons in SCSCs to a much higher extent than a conventional collagen-based biomaterial or standard polyethylene terephthalate (PET) membrane inserts. Glial activation was limited in the cultures maintained on HA-based hydrogel. The anti-inflammatory factor IL1RA protected SCSCs from degenerative mechanisms that occur during in vitro incubation, and IL1RA also protected SCSCs from excitotoxic injury induced by N-Methyl-d-Aspartate (NMDA). IL1RA specifically protected neurons that resided in the ventral horn, while other neuronal populations such as dorsal horn neurons and Renshaw cells did not respond to treatment. Finally, transplantation of NCSCs onto excitotoxically injured SCSCs protected from neuronal loss, apoptosis and glial activation, while NCSCs remained undifferentiated.

The results presented in this thesis indicate that carriers based on HA seem to be more suitable than conventional collagen-based biomaterials since they enhance neuronal survival per se. The observed neuroprotection is likely due to biomechanical properties of HA. IL1RA protects SCSCs from spontaneous degeneration and from NMDA-induced injury, suggesting that excitotoxic mechanisms can be modulated through anti-inflammatory pathways. Different neuronal populations are affected by IL1RA to various degrees, suggesting that a combination of different neuroprotectants should be used in treatment strategies after SCI. Finally, NCSCs seem to protect SCSCs from excitotoxic injury through paracrine actions, since they remain undifferentiated and do not migrate into the tissue during in vitro incubation.

It seems that combinations of neuroprotectants and carrier substances should be considered rather than one single strategy when designing future treatments for SCI. Incorporation of neuroprotectants such as IL1RA combined with stem cells in injectable biocompatible carriers based on HA is the final goal of our group in the treatment of SCI.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2015. 59 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1106
Keyword
Hyaluronic Acid-based hydrogel, motorneurons, microglial cells, Interleukin-1 Receptor Antagonist, Renshaw cells, excitotoxicity, neuroinflammation, Neural Crest Stem Cells
National Category
Medical and Health Sciences
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-251477 (URN)978-91-554-9255-7 (ISBN)
Public defence
2015-06-12, Grönwallsalen, Akademiska sjukhuset, Akademiska sjukhuset ing.70, Uppsala, 09:00 (English)
Opponent
Supervisors
Available from: 2015-06-04 Created: 2015-04-19 Last updated: 2016-04-21

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Schizas, NikosAndersson, BrittmarieHilborn, JönsHailer, Nils P.

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