Local Delivery of High-Dose Chondroitinase ABC in the Sub-Acute Stage Promotes Axonal Outgrowth and Functional Recovery after Complete Spinal Cord Transection.
Chondroitin sulfate proteoglycans (CSPGs) are glial scar-associated molecules considered axonal regeneration inhibitors and can be digested by chondroitinase ABC (ChABC) to promote axonal regeneration after spinal cord injury (SCI). We previously demonstrated that intrathecal delivery of low-dose Ch...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2015-01-01
|
| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC4579094?pdf=render |
| _version_ | 1819135967972294656 |
|---|---|
| author | Chu-Hsun Cheng Chi-Te Lin Meng-Jen Lee May-Jywan Tsai Wen-Hung Huang Ming-Chao Huang Yi-Lo Lin Ching-Jung Chen Wen-Cheng Huang Henrich Cheng |
| author_facet | Chu-Hsun Cheng Chi-Te Lin Meng-Jen Lee May-Jywan Tsai Wen-Hung Huang Ming-Chao Huang Yi-Lo Lin Ching-Jung Chen Wen-Cheng Huang Henrich Cheng |
| author_sort | Chu-Hsun Cheng |
| collection | DOAJ |
| description | Chondroitin sulfate proteoglycans (CSPGs) are glial scar-associated molecules considered axonal regeneration inhibitors and can be digested by chondroitinase ABC (ChABC) to promote axonal regeneration after spinal cord injury (SCI). We previously demonstrated that intrathecal delivery of low-dose ChABC (1 U) in the acute stage of SCI promoted axonal regrowth and functional recovery. In this study, high-dose ChABC (50 U) introduced via intrathecal delivery induced subarachnoid hemorrhage and death within 48 h. However, most SCI patients are treated in the sub-acute or chronic stages, when the dense glial scar has formed and is minimally digested by intrathecal delivery of ChABC at the injury site. The present study investigated whether intraparenchymal delivery of ChABC in the sub-acute stage of complete spinal cord transection would promote axonal outgrowth and improve functional recovery. We observed no functional recovery following the low-dose ChABC (1 U or 5 U) treatments. Furthermore, animals treated with high-dose ChABC (50 U or 100 U) showed decreased CSPGs levels. The extent and area of the lesion were also dramatically decreased after ChABC treatment. The outgrowth of the regenerating axons was significantly increased, and some partially crossed the lesion site in the ChABC-treated groups. In addition, retrograde Fluoro-Gold (FG) labeling showed that the outgrowing axons could cross the lesion site and reach several brain stem nuclei involved in sensory and motor functions. The Basso, Beattie and Bresnahan (BBB) open field locomotor scores revealed that the ChABC treatment significantly improved functional recovery compared to the control group at eight weeks after treatment. Our study demonstrates that high-dose ChABC treatment in the sub-acute stage of SCI effectively improves glial scar digestion by reducing the lesion size and increasing axonal regrowth to the related functional nuclei, which promotes locomotor recovery. Thus, our results will aid in the treatment of spinal cord injury. |
| first_indexed | 2024-12-22T10:27:30Z |
| format | Article |
| id | doaj.art-80f659395d2a4a2b8a8481160e6abe43 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-22T10:27:30Z |
| publishDate | 2015-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-80f659395d2a4a2b8a8481160e6abe432022-12-21T18:29:25ZengPublic Library of Science (PLoS)PLoS ONE1932-62032015-01-01109e013870510.1371/journal.pone.0138705Local Delivery of High-Dose Chondroitinase ABC in the Sub-Acute Stage Promotes Axonal Outgrowth and Functional Recovery after Complete Spinal Cord Transection.Chu-Hsun ChengChi-Te LinMeng-Jen LeeMay-Jywan TsaiWen-Hung HuangMing-Chao HuangYi-Lo LinChing-Jung ChenWen-Cheng HuangHenrich ChengChondroitin sulfate proteoglycans (CSPGs) are glial scar-associated molecules considered axonal regeneration inhibitors and can be digested by chondroitinase ABC (ChABC) to promote axonal regeneration after spinal cord injury (SCI). We previously demonstrated that intrathecal delivery of low-dose ChABC (1 U) in the acute stage of SCI promoted axonal regrowth and functional recovery. In this study, high-dose ChABC (50 U) introduced via intrathecal delivery induced subarachnoid hemorrhage and death within 48 h. However, most SCI patients are treated in the sub-acute or chronic stages, when the dense glial scar has formed and is minimally digested by intrathecal delivery of ChABC at the injury site. The present study investigated whether intraparenchymal delivery of ChABC in the sub-acute stage of complete spinal cord transection would promote axonal outgrowth and improve functional recovery. We observed no functional recovery following the low-dose ChABC (1 U or 5 U) treatments. Furthermore, animals treated with high-dose ChABC (50 U or 100 U) showed decreased CSPGs levels. The extent and area of the lesion were also dramatically decreased after ChABC treatment. The outgrowth of the regenerating axons was significantly increased, and some partially crossed the lesion site in the ChABC-treated groups. In addition, retrograde Fluoro-Gold (FG) labeling showed that the outgrowing axons could cross the lesion site and reach several brain stem nuclei involved in sensory and motor functions. The Basso, Beattie and Bresnahan (BBB) open field locomotor scores revealed that the ChABC treatment significantly improved functional recovery compared to the control group at eight weeks after treatment. Our study demonstrates that high-dose ChABC treatment in the sub-acute stage of SCI effectively improves glial scar digestion by reducing the lesion size and increasing axonal regrowth to the related functional nuclei, which promotes locomotor recovery. Thus, our results will aid in the treatment of spinal cord injury.http://europepmc.org/articles/PMC4579094?pdf=render |
| spellingShingle | Chu-Hsun Cheng Chi-Te Lin Meng-Jen Lee May-Jywan Tsai Wen-Hung Huang Ming-Chao Huang Yi-Lo Lin Ching-Jung Chen Wen-Cheng Huang Henrich Cheng Local Delivery of High-Dose Chondroitinase ABC in the Sub-Acute Stage Promotes Axonal Outgrowth and Functional Recovery after Complete Spinal Cord Transection. PLoS ONE |
| title | Local Delivery of High-Dose Chondroitinase ABC in the Sub-Acute Stage Promotes Axonal Outgrowth and Functional Recovery after Complete Spinal Cord Transection. |
| title_full | Local Delivery of High-Dose Chondroitinase ABC in the Sub-Acute Stage Promotes Axonal Outgrowth and Functional Recovery after Complete Spinal Cord Transection. |
| title_fullStr | Local Delivery of High-Dose Chondroitinase ABC in the Sub-Acute Stage Promotes Axonal Outgrowth and Functional Recovery after Complete Spinal Cord Transection. |
| title_full_unstemmed | Local Delivery of High-Dose Chondroitinase ABC in the Sub-Acute Stage Promotes Axonal Outgrowth and Functional Recovery after Complete Spinal Cord Transection. |
| title_short | Local Delivery of High-Dose Chondroitinase ABC in the Sub-Acute Stage Promotes Axonal Outgrowth and Functional Recovery after Complete Spinal Cord Transection. |
| title_sort | local delivery of high dose chondroitinase abc in the sub acute stage promotes axonal outgrowth and functional recovery after complete spinal cord transection |
| url | http://europepmc.org/articles/PMC4579094?pdf=render |
| work_keys_str_mv | AT chuhsuncheng localdeliveryofhighdosechondroitinaseabcinthesubacutestagepromotesaxonaloutgrowthandfunctionalrecoveryaftercompletespinalcordtransection AT chitelin localdeliveryofhighdosechondroitinaseabcinthesubacutestagepromotesaxonaloutgrowthandfunctionalrecoveryaftercompletespinalcordtransection AT mengjenlee localdeliveryofhighdosechondroitinaseabcinthesubacutestagepromotesaxonaloutgrowthandfunctionalrecoveryaftercompletespinalcordtransection AT mayjywantsai localdeliveryofhighdosechondroitinaseabcinthesubacutestagepromotesaxonaloutgrowthandfunctionalrecoveryaftercompletespinalcordtransection AT wenhunghuang localdeliveryofhighdosechondroitinaseabcinthesubacutestagepromotesaxonaloutgrowthandfunctionalrecoveryaftercompletespinalcordtransection AT mingchaohuang localdeliveryofhighdosechondroitinaseabcinthesubacutestagepromotesaxonaloutgrowthandfunctionalrecoveryaftercompletespinalcordtransection AT yilolin localdeliveryofhighdosechondroitinaseabcinthesubacutestagepromotesaxonaloutgrowthandfunctionalrecoveryaftercompletespinalcordtransection AT chingjungchen localdeliveryofhighdosechondroitinaseabcinthesubacutestagepromotesaxonaloutgrowthandfunctionalrecoveryaftercompletespinalcordtransection AT wenchenghuang localdeliveryofhighdosechondroitinaseabcinthesubacutestagepromotesaxonaloutgrowthandfunctionalrecoveryaftercompletespinalcordtransection AT henrichcheng localdeliveryofhighdosechondroitinaseabcinthesubacutestagepromotesaxonaloutgrowthandfunctionalrecoveryaftercompletespinalcordtransection |