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 chondroitin sulfate-glycosaminoglycan 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 chondroitin sulfate proteoglycan-glycosaminoglycan-degrading enzyme, chondroitinase ABC (ChABC), was assessed for its potential to promote axonal regrowth and improve locomotor recovery following midthoracic spinal cord hemisection injury in adult rats.
RESULTS: We demonstrate that 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 produces the greatest improvement in locomotor recovery at 6 weeks postinjury compared with controls and noncombined therapy. Anterograde and retrograde tracing revealed that delivery of clodronate, rolipram, and ChABC did not promote substantial axonal regeneration 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 in comparison with injured controls. Combined clodronate, rolipram, and ChABC treatment reduced the accumulation of macrophages within the injured spinal cord 7 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.
ABBREVIATIONS: ChABC, chondroitinase ABC
CS-GAG, chondroitin sulfate glycosaminoglycan
CSPG, chondroitin sulfate proteoglycan
DMSO, dimethyl sulfoxide
EC, eriochrome cyanine
NIH, National Institutes of Health
PBS, phosphate-buffered saline
SEM, standard error of the mean
‡Center for Spine Health, Department of Neurological Surgery, Cleveland Clinic, Cleveland, Ohio;
§Department of Neuroscience, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio;
¶Southeastern Brain and Spine, Lumberton North Carolina;
‖Department of Cell Biology & Immunology, Faculty of Medicine, Free University Medical Center, Amsterdam, Netherlands;
#Arizona Neurosurgery and Spine Specialists, Phoenix Arizona;
**Department of Neurological Surgery, Case Western Reserve University School of Medicine, Cleveland, Ohio;
‡‡ MetroHealth Medical Center, Cleveland, Ohio
Correspondence: Michael P. Steinmetz, MD, Case Western Reserve School of Medicine, The MetroHealth System, 2500 MetroHealth Dr, Cleveland, OH 44109. E-mail: email@example.com
* These authors contributed equally to this work.
Received September 26, 2013
Accepted May 02, 2014