Background: Individually, immunomodulatory therapy and chondroitinases have demonstrated neuroprotective and potential neuroregenerative effects following spinal cord injury.
Objective: To investigate the therapeutic potential of combined immunomodulatory and CS-GAG degradation therapy in spinal cord injury.
Methods: A combined immunomodulatory treatment using 1) liposome-encapsulated clodronate (selectively depletes peripheral macrophages), and 2) rolipram (a selective type 4 phosphodiesterase inhibitor), along with the CSPG-glycosaminoglycan (GAG) degrading enzyme, chondroitinase ABC (ChABC), was assessed for its potential to promote axonal re-growth and improve locomotor recovery following mid-thoracic spinal cord hemisection injury in adult rats.
Results: We demonstrate combined treatment with liposomal clodronate, rolipram, and ChABC attenuates macrophage accumulation at the site of injury, reduces axonal die-back of injured dorsal column axons, and produced the greatest improvement in locomotor recovery at six weeks post-injury compared to controls, and non-combined therapy. Anterograde and retrograde tracing revealed that delivery of clodronate, rolipram, and ChABC did not promote substantial axonal re-generation through the site of injury, although the treatment did limit the extent of axonal die-back. Histological assessments revealed that combined treatment with clodronate/ rolipram and/or ChABC resulted in a significant reduction in lesion size and cystic cavitation, as compared to injured controls. Combined clodronate, rolipram, and ChABC treatment reduced the accumulation of macrophages within the injured spinal cord seven weeks after injury.
Conclusion: The present data suggest that delivery of an immunomodulatory therapy consisting of clodronate and rolipram, in combination with ChABC, reduces axonal injury and enhances neuroprotection, plasticity, and hindlimb functional recovery after hemisection spinal cord injury in adult rats.
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