title: Dose-dependent beneficial and detrimental effects of ROCK inhibitor Y27632 on axonal sprouting and functional recovery after rat spinal cord injury.
abstract: Axonal regeneration within the injured central nervous system (CNS) is hampered by multiple inhibitory molecules in the glial scar and the surrounding disrupted myelin. Many of these inhibitors stimulate, either directly or indirectly, the Rho intracellular signaling pathway, providing a strong rationale to target it following spinal cord injuries. In this study, we infused either control (PBS) or a ROCK inhibitor, Y27632 (2 mM or 20 mM, 12 microl/day for 14 days) into the intrathecal space of adult rats starting immediately after a cervical 4/5 dorsal column transection. Histological analysis revealed that high dose-treated animals displayed significantly more axon sprouts in the grey matter distal to injury compared to low dose-treated rats. Only the high dose regimen stimulated sprouting of the dorsal ascending axons along the walls of the lesion cavity. Footprint analysis revealed that the increased base of support normalized significantly faster in control and high dose-treated animals compared to low dose animals. Forepaw rotation angle, and the number of footslips on a horizontal ladder improved significantly more by 6 weeks in high dose animals compared to the other two groups. In a food pellet reaching test, high dose animals performed significantly better than low dose animals, which failed to recover. There was no evidence of mechanical allodynia in any treatment group; however, the slightly shortened heat withdrawal times normalized only with the high dose treatment. Collectively, our data support beneficial effects of high dose Y27632 treatment but indicate that low doses might be detrimental.
authors.affiliation: ICORD (International Collaboration On Repair Discoveries), University of British Columbia, 2469-6270 University Blvd., Vancouver, British Columbia, Canada V6T 1Z4.
authors.forename: Carmen C M
authors.initials: CC
authors.lastname: Chan
authors.forename: Kourosh
authors.initials: K
authors.lastname: Khodarahmi
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.forename: Darren
authors.initials: D
authors.lastname: Sutherland
authors.forename: Loren W
authors.initials: LW
authors.lastname: Oschipok
authors.forename: John D
authors.initials: JD
authors.lastname: Steeves
authors.forename: Wolfram
authors.initials: W
authors.lastname: Tetzlaff
mesh_terms: D051339:Actin Depolymerizing Factors / Q000378:metabolism; D000577:Amides / Q000008:administration & dosage*; D000704:Analysis of Variance; D000818:Animals; D001369:Axons / Q000187:drug effects* / Q000502:physiology; D001522:Behavior, Animal; D001710:Biotin / Q000031:analogs & derivatives / Q000378:metabolism; D015153:Blotting, Western / Q000379:methods; D002772:Cholera Toxin / Q000378:metabolism; D003911:Dextrans / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D007150:Immunohistochemistry / Q000379:methods; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D043263:Myosin-Light-Chain Phosphatase / Q000378:metabolism / Q000494:pharmacology; D009416:Nerve Regeneration / Q000187:drug effects; D010147:Pain Measurement / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011597:Psychomotor Performance / Q000187:drug effects; D011725:Pyridines / Q000008:administration & dosage*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D020127:Recovery of Function / Q000187:drug effects*; D045442:Rotarod Performance Test / Q000379:methods; D013119:Spinal Cord Injuries / Q000134:cerebrospinal fluid / Q000188:drug therapy* / Q000503:physiopathology*; D054460:rho-Associated Kinases
chemical_list: D051339:Actin Depolymerizing Factors; D000577:Amides; D003911:Dextrans; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D011725:Pyridines; C076397:biotinylated dextran amine; C108830:Y 27632; D001710:Biotin; D002772:Cholera Toxin; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D043263:Myosin-Light-Chain Phosphatase