A combination immunomodulatory treatment promotes neuroprotection and locomotor recovery after contusion SCI

Abstract

The present study assessed the ability of a combined immunomodulatory treatment using (1) selective depletion of peripheral macrophages with liposomal-encapsulated clodronate, and (2) rolipram, a type 4 phosphodiesterase (PDE4) inhibitor, to promote neuroprotection and improve locomotor recovery following experimental contusion SCI. We demonstrate that delivery of either liposomal clodronate or rolipram alone promotes neuroprotection, enhances myelinated tissue sparing, and improves hindlimb functional recovery. Combined treatment with liposomal clodronate and rolipram produced the greatest improvement in locomotor recovery (inter-limb coordination, paw placement, and toe clearance), at 4weeks post-injury (2.9 points). Retrograde tracing revealed substantial axonal sparing and/or sprouting from several brainstem motor nuclei, and hindlimb motor cortex. The combined treatment with these two drugs promoted the greatest amount of axonal sparing (3- to 4-fold increase compared to controls). Histological assessments revealed that combined treatment with clodronate/ rolipram resulted in a significant reduction in lesion volume (51%) and lesion area at the injury epicenter (45%), and significantly increased the extent of myelinated tissue sparing. Immunohistochemical studies showed a qualitative reduction in the accumulation of ED-1+ macrophages within the injured spinal cord 5weeks after injury. Our results demonstrate robust neuroprotection and improved hindlimb locomotor function using a combined immunomodulatory treatment strategy consisting of liposomal clodronate and rolipram. The present data suggest that clinical trials with acute delivery of combination immunomodulatory therapies may be warranted. This article is part of a Special Issue entitled "Interaction between repair, disease, & inflammation."