Selected Combination of Neurotrophins Potentiate Neuroprotection and Functional Recovery Following Spinal Cord Injury in
The possibility that a combination of neurotrophins induces long-lasting neuroprotection of the cord following spinal cord injury (SCI) was examined in a rat model. The SCI was performed by making a unilateral incision into the right dorsal horn of the T1
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Abstract The possibility that a combination of neurotrophins induces long-lasting neuroprotection of the cord following spinal cord injury (SCI) was examined in a rat model. The SCI was performed by making a unilateral incision into the right dorsal horn of the T10-11 segments and the animals were allowed to survive 5 h after trauma. Different combination of neurotrophins, i.e., BDNF in combination with GDNF, NT-3, or NGF was applied topically over the traumatized spinal cord and motor dysfunction, blood-spinal cord barrier (BSCB) breakdown, edema formation, and cell injury were examined. Topical application of BDNF in combination with GDNF and NGF 30 min (but not 60 or 90 min) at high concentrations (0.5 µg each) after SCI significantly improved motor function and reduced BSCB breakdown, edema formation, and cell injury at 5 h. However, concurrent application of BDNF, IGF-1, and GDNF (but not with NT-3 or NGF) even 60 or 90 min after trauma induced a significant reduction in motor dysfunction and spinal cord pathology. These observations suggest that a combination of neurotrophins may have added therapeutic value in the treatment of SCI, not reorted earlier. Keywords Spinal cord injury • BDNF • IGF-1 • GDNF • blood–spinal cord barrier • edema • motor function • spinal cord pathology
Introduction Spinal cord injury (SCI) is a serious clinical problem that induces lifelong disabilities for the victims and places a huge burden on society (see (5,6,11)). Although our knowledge
H.S. Sharma () Laboratory of Cerebrovascular Research, Department of Surgical Sciences, Anaesthesiology and Intensive Care Medicine, University Hospital, Frödingsgatan 12:28, Uppsala, SE-75421, Sweden e-mail: [email protected]
on the basic mechanisms of the pathophysiology of SCI has expanded tremendously in the last decades (2,3,5,6), suitable and effective therapeutic approaches to enhance neuroprotection and/or neurorepair are still not worked out. Thus, further studies in SCI are needed to enhance neuro repair mechanisms in order to improve the quality of life of trauma victims. Experimental studies in SCI suggest that neurotrophins could play important roles in the repair mechanisms of the spinal cord following injury (2,3,5–10). Thus, dysregulation of neurotrophin receptors and/or alerted expression of neurotrophins in spinal cord motoneurons following injury are quite common (see (12) for review). This indicates that therapeutic intervention using neurotrophic factors may influence recovery following SCI by enhancing neuroregeneration or neurorepair processes. One of the important goals for the treatment of SCI with neurotrophins is to thwart the propagation of spinal cord pathology to the uninjured portion of the cord and to rescue damaged nerve cells and axons in order to improve functional outcome (10–15). Another therapeutic aim of SCI is to find a suitable combination of neurotrophins that can help to achieve neuroprotection and neurorepair even when applied at longer time intervals after the initial injury (7–10,12–15). Ke
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