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Effects of an Immunomodulatory Therapy and Chondroitinase After Spinal Cord Hemisection Injury

Grosso, Matthew J. MD*,‡,§; Matheus, Virgilio MD*,¶; Clark, Megan MS; van Rooijen, Nico PhD; Iannotti, Christopher A. MD, PhD#; Steinmetz, Michael P. MD**,‡‡

doi: 10.1227/NEU.0000000000000447

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

i.p., intraperitoneal

NIH, National Institutes of Health

PBS, phosphate-buffered saline

PFA, paraformaldehyde

SEM, standard error of the mean

Author Information

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:

* These authors contributed equally to this work.

Received September 26, 2013

Accepted May 02, 2014

Copyright © by the Congress of Neurological Surgeons