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Treatment for autonomic dysreflexia using trkA-IgG after spinal cord injury

Treatment for autonomic dysreflexia using trkA-IgG after spinal cord injury

Society for Neuroscience Abstracts 26(1-2): Abstract No -864 4

We have devised a strategy for treatment of autonomic dysreflexia (episodic hypertension) after spinal cord injury (SCI) using a fusion protein (trkA-IgG) containing the specific trkA receptor for nerve growth factor (NGF). We hypothesize that using trkA-IgG to sequester NGF in the injured spinal cord will prevent inappropriate growth of small-diameter primary afferent fibres in the dorsal horn of the spinal cord, therefore blocking the onset of autonomic dysreflexia after SCI. In vitro, trkA-IgG was produced using a baculovirus expression vector containing complementary DNA encoding the NGF binding domain of rat trkA fused to the Fc portion of human IgG. The trkA-IgG was secreted by spodoptera frugiperda (Sf9) insect cells infected with the baculovirus construct, then purified by affinity column and dialysis. Specific binding of the trkA-IgG to NGF was verified by dot blots and optical biosensor technology (Biacore): preliminary data indicate that after trkA-IgG immobilization onto a protein A chip, NGF bound to trkA-IgG at KD = 4.26x10-11M. Functional inhibition of NGF-induced neurite sprouting by trkA-IgG was confirmed using rat pheochromocytoma (PC12) cell culture assays. In vivo, the spinal cords of female Wistar rats were injured by 50 gram clip compression at the 4th thoracic level. Using an intrathecal catheter and Alzet osmotic pump, trkA-IgG (2.14mug/day) or non-immune control IgG (2.14mug/day) mixed with Pontamine sky blue dye was administered to the spinal cord caudal to the injury site. Penetration of the trkA-IgG and control IgG was confirmed by distribution of dye throughout the spinal cord. At 14 days post-injury, the effects of trkA-IgG versus control IgG on mean arterial pressure (MAP) and heart rate (HR) responses to colon distension and skin stimulation were compared. After infusion of control IgG, MAP typically increased by 40 mm Hg and HR decreased by 80 bpm following colon distension, with similar responses to stimulation of skin dermatomes near the lesion site. In contrast, small changes in MAP (uparw15 mm Hg) and HR (dwnarw10 bpm) were observed following trkA-IgG treatment. The degree of inflammation was also assessed using cresyl violet stain in transverse sections (30 mum) of the spinal cord at the 10th thoracic level. Neither the physical presence of the catheter, nor the trkA-IgG or control IgG, provoked an apparent inflammatory response in the spinal cord. These results indicate that treatment with trkA-IgG effectively reduces the magnitude of autonomic dysreflexia and causes no spinal cord inflammation after injury. Funding: Ontario Neurotrauma Foundation, Ontario Heart and Stroke Foundation.

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Accession: 035980180

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