Combining peripheral nerve grafts and chondroitinase promotes functional axonal regeneration in the chronically injured spinal cord.
Because there currently is no treatment for spinal cord injury, most patients are living with long-standing injuries. Therefore, strategies aimed at promoting restoration of function to the chronically injured spinal cord have high therapeutic value. For successful regeneration, long-injured axons must overcome their poor intrinsic growth potential as well as the inhibitory environment of the glial scar established around the lesion site. Acutely injured axons that regenerate into growth-permissive peripheral nerve grafts (PNGs) reenter host tissue to mediate functional recovery if the distal graft-host interface is treated with chondroitinase ABC (ChABC) to cleave inhibitory chondroitin sulfate proteoglycans in the scar matrix. To determine whether a similar strategy is effective for a chronic injury, we combined grafting of a peripheral nerve into a highly relevant, chronic, cervical contusion site with ChABC treatment of the glial scar and glial cell line-derived neurotrophic factor (GDNF) stimulation of long-injured axons. We tested this combination in two grafting paradigms: (1) a peripheral nerve that was grafted to span a chronic injury site or (2) a PNG that bridged a chronic contusion site with a second, more distal injury site. Unlike GDNF-PBS treatment, GDNF-ChABC treatment facilitated axons to exit the PNG into host tissue and promoted some functional recovery. Electrical stimulation of axons in the peripheral nerve bridge induced c-Fos expression in host neurons, indicative of synaptic contact by regenerating fibers. Thus, our data demonstrate, for the first time, that administering ChABC to a distal graft interface allows for functional axonal regeneration by chronically injured neurons.
Tom
Veronica J
VJ
Department of Neurobiology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19129, USA.
Sandrow-Feinberg
Harra R
HR
Miller
Kassi
K
Santi
Lauren
L
Connors
Theresa
T
Lemay
Michel A
MA
Houlé
John D
JD
D000818:Animals; D002574:Cervical Vertebrae / Q000601:surgery; D019765:Chondroitin ABC Lyase / Q000627:therapeutic use*; D002908:Chronic Disease / Q000628:therapy; D002921:Cicatrix / Q000188:drug therapy / Q000378:metabolism / Q000517:prevention & control; D004195:Disease Models, Animal; D005260:Female; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000494:pharmacology / Q000627:therapeutic use; D020439:Growth Cones / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure; D009416:Nerve Regeneration / Q000187:drug effects / Q000502:physiology*; D010525:Peripheral Nerves / Q000637:transplantation*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology; D013116:Spinal Cord / Q000187:drug effects / Q000503:physiopathology / Q000601:surgery; D013119:Spinal Cord Injuries / Q000188:drug therapy / Q000601:surgery / Q000628:therapy*; D016378:Tissue Transplantation / Q000379:methods*; D016896:Treatment Outcome
D051100:Glial Cell Line-Derived Neurotrophic Factor; D019765:Chondroitin ABC Lyase