PMID- 19651108 OWN - NLM STAT- MEDLINE DCOM- 20091216 LR - 20220408 IS - 1872-6240 (Electronic) IS - 0006-8993 (Linking) VI - 1295 DP - 2009 Oct 27 TI - Treatment of rat spinal cord injury with a Rho-kinase inhibitor and bone marrow stromal cell transplantation. PG - 192-202 LID - 10.1016/j.brainres.2009.07.087 [doi] AB - In light of reports that the administration of fasudil, a Rho-kinase inhibitor, improved rats locomotor abilities following spinal cord injury, we hypothesized that combining fasudil with another type of therapy, such as stem cell transplantation, might further improve the level of locomotor recovery. Bone marrow stromal cells (BMSCs) are readily available for stem cell therapy. In the present study, we examined whether fasudil combined with BMSC transplantation would produce synergistic effects on recovery. Adult female Sprague-Dawley rats were subjected to spinal cord contusion injury at the T10 vertebral level using an IH impactor (200 Kdyn). Immediately after contusion, they were administrated fasudil intrathecally for 4 weeks. GFP rat-derived BMSCs (2.5x10(6)) were injected into the lesion site 14 days after contusion. Locomotor recovery was assessed for 9 weeks with BBB scoring. Sensory tests were conducted at 8 weeks. Biotinylated dextran amine (BDA) was injected into the sensory-motor cortex at 9 weeks. In addition to an untreated control group, the study also included a fasudil-only group and a BMSC-only group in order to compare the effects of combined therapy vs. single-agent therapy. Animals were perfused transcardially 11 weeks after contusion, and histological examinations were performed. The combined therapy group showed statistically better locomotor recovery than the untreated control group at 8 and 9 weeks after contusion. Neither of the two single-agent treatments improved open field locomotor function. Sensory tests showed no statistically significant difference by treatment. Histological and immunohistochemical studies provided some supporting evidence for better locomotor recovery following combined therapy. The average area of the cystic cavity was significantly smaller in the fasudil+BMSC group than in the control group. The number of 5-HT nerve fibers was significantly higher in the fasudil+BMSC group than in the control group on the rostral side of the lesion site. BDA-labeled fibers on the caudal side of the lesion epicenter were observed only in the fasudil+BMSC group. On the other hand, only small numbers of GFP-labeled grafted cells remained 9 weeks after transplantation, and these were mainly localized at the site of injection. Double immunofluorescence studies showed no evidence of differentiation of grafted BMSCs into glial cells or neurons. The Rho-kinase inhibitor fasudil combined with BMSC transplantation resulted in better locomotor recovery than occurred in the untreated control group. However, the data failed to demonstrate significant synergism from combined therapy compared with the levels of recovery following single-agent treatment. FAU - Furuya, Takeo AU - Furuya T AD - Department of Orthopaedic Surgery, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan. FAU - Hashimoto, Masayuki AU - Hashimoto M FAU - Koda, Masao AU - Koda M FAU - Okawa, Akihiko AU - Okawa A FAU - Murata, Atsushi AU - Murata A FAU - Takahashi, Kazuhisa AU - Takahashi K FAU - Yamashita, Toshihide AU - Yamashita T FAU - Yamazaki, Masashi AU - Yamazaki M LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20090803 PL - Netherlands TA - Brain Res JT - Brain research JID - 0045503 RN - 0 (Neuronal Tract-Tracers) RN - 0 (Protein Kinase Inhibitors) RN - 84477-87-2 (1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine) RN - Q0CH43PGXS (fasudil) SB - IM MH - 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/*analogs & derivatives/therapeutic use MH - Analysis of Variance MH - Animals MH - Bone Marrow Cells MH - *Bone Marrow Transplantation MH - Cell Differentiation MH - Cells, Cultured MH - Combined Modality Therapy MH - Female MH - Fluorescent Antibody Technique MH - Infusion Pumps, Implantable MH - Injections, Spinal MH - Male MH - Microinjections MH - Motor Activity/drug effects MH - Nerve Regeneration/drug effects/*physiology MH - Neuroglia/drug effects/pathology MH - Neuronal Tract-Tracers MH - Neurons/drug effects/pathology MH - Pain Threshold/drug effects MH - Protein Kinase Inhibitors/therapeutic use MH - Pyramidal Tracts/pathology MH - Random Allocation MH - Rats MH - Rats, Sprague-Dawley MH - Rats, Transgenic MH - Recovery of Function/*physiology MH - Spinal Cord Injuries/pathology/*therapy MH - Stromal Cells/cytology MH - *Thoracic Vertebrae/pathology EDAT- 2009/08/05 09:00 MHDA- 2009/12/17 06:00 CRDT- 2009/08/05 09:00 PHST- 2009/03/20 00:00 [received] PHST- 2009/07/24 00:00 [revised] PHST- 2009/07/25 00:00 [accepted] PHST- 2009/08/05 09:00 [entrez] PHST- 2009/08/05 09:00 [pubmed] PHST- 2009/12/17 06:00 [medline] AID - S0006-8993(09)01584-4 [pii] AID - 10.1016/j.brainres.2009.07.087 [doi] PST - ppublish SO - Brain Res. 2009 Oct 27;1295:192-202. doi: 10.1016/j.brainres.2009.07.087. Epub 2009 Aug 3.