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Summary Statement

Spinal cord injury is characterised by an inflammatory cascade that leads to neuronal death by neurotoxicity. In a model of spinal cord damage we successfully preserved the number of ventral horn neurons by treatment with interleukin-1 receptor antagonist (IL1RA) and neurotrophin (NT)-3.

Introduction

Secondary damage after spinal cord injury (SCI) is characterised by activation of microglial cells that release neurotoxic agents. This results in apoptotic death of neurons that survived the initial trauma. Interleukin (IL)-1 is one of the most prominent mediators of neurotoxicity. Organotypic spinal cord slice cultures (OSCSC) are a useful in vitro model of spinal cord injury. We have previously shown that OSCSC degenerate substantially during in vitro incubation under standard conditions. Our aim was to treat OSCSC with the putatively neuroprotective agents IL-1 receptor antagonist (IL1RA) and neurotrophin (NT)-3 and to evaluate neuronal and microglial populations as well as axonal preservation. We hypothesised that treatment with the above substances would enhance neuronal survival and suppress microglial activation.


Orthopaedic Proceedings
Vol. 94-B, Issue SUPP_XXXVII | Pages 89 - 89
1 Sep 2012
Ackermann P Schizas N Bring D Li J Andersson T Fahlgren A Aspenberg P
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Introduction

Traumatized musculoskeletal tissue often exhibits prolonged time to healing, mostly due to low blood flow and innervation. Intermittent Pneumatic Compression (IPC) increases blood flow and decreases thromboembolic event after orthopedic surgery,[1] however little is known about healing effects.[2] We hypothesized that IPC could stimulate tissue repair: 1.) blood flow 2.) nerve ingrowth 3.) tissue proliferation and during immobilisation enhance 4.) biomechanical tissue properties.

Methods

Study 1: In 104 male Sprague Dawley (SD) rats the right Achilles tendon was ruptured and the animals freely mobilized. Half the group received daily IPC-treatment, using a pump and cuff over the hindpaw that inflates/deflates cyclicly, 0–55mmHg (Biopress SystemTM, Flexcell Int.), and the other half received sham-treatment. Healing was assessed at 1,3,6 weeks by perfusion-analysis with laser doppler scanner (Perimed, Sweden), histology and biomechanical testing.

Study 2: 48 male SD-rats were ruptured as above. Three groups of each 16 rats were either mobilized, immobilized or immobilized with IPC treatment. Immobilization was performed by plaster cast. Healing was assessed at 2 weeks with histology and biomechanical testing.


Orthopaedic Proceedings
Vol. 93-B, Issue SUPP_II | Pages 133 - 134
1 May 2011
Ackermann P Schizas N Oystein L Frihagen F Engebretsen L Bahr R
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Introduction: Tendinopathy entails pain and degenerative tissue proliferation such as tenocyte transformation and increased numbers of sensory nerves and microvessels. Pain and tissue proliferation are suggested to be modulated via nerve transmitters, including substance P (SP) and glutamate, both detected in tendinopathy. Substance P and glutamate are known to activate glutamate receptors in a variety of pain conditions and additionally to be implicated in cell transformation. However, the presence of different glutamate receptors, eg. ionotropic (NMDA) and metabotropic (mGlu), and whether they are up- or downregulated in tendinopathy is still unknown. In this study we assessed the

presence,

the tissue density and

the co-existence of different glutamate receptors together with glutamate in tendinopathic biopsies and controls.

Methods: All procedures were conducted with local ethical committee approval and patient consent. Human patellar tendon biopsies of tendinopathic patients (n=10) and controls (n=8) were single- and double-stained immunohistochemically for glutamate, glutamate receptors NMDAR1, mGluR1, mGluR5 and mGluR6,7, the nerve marker PGP9.5 and SP and assessed subjectively and semi-quantitatively with image analysis. Images were taken using an epifluorescence microscope with camera and were subjectively assessed by two independent observers blinded with regard to the identity of the slides. Tenocyte density and morphologic characteristics were assessed. Non-parametric Mann-Whitney U-tests for independent samples were used, and the level for significance was set at p< 0.05.

Results: Of the glutamate receptors tested all except mGluR1 was identified in the tendons, however only NMDAR1 was found significantly altered between both groups. The chronic painful tendons exhibited a significant elevation of NMDAR1 (9-fold) and also of glutamate (10-fold). This up-regulation of NMDAR1 and glutamate was found to be co-localized on sensory nerve fibers, blood vessels as well as on transformed tenocytes. None of the controls exhibited neuronal co-existence of glutamate with NMDAR1.

Conclusions: This study establishes for the first time that patients with tendinopathy exhibit an elevation of peripheral glutamate receptor NMDAR1, morphologically co-localized with increased glutamate expression. The up-regulated NMDAR1/glutamate system may represent hyper-excitability of the cells – leading to cell proliferative effects observed as angiogenesis, tenocyte transformation, and nerve sprouting. Moreover, the neuronal co-existence of glutamate and NMDAR1 observed in painful tendinosis, but not seen in any of the controls, strongly suggests a role in pain signalling. Future studies will focuse on interventional approaches to investigate if modulation of NMDAR1 pathways can ameliorate the symptoms of tendinopathic patients.