Spinal central effects of peripherally applied botulinum neurotoxin A in comparison between its subtypes A1 and A2
Because of its unique ability to exert long-lasting synaptic transmission blockade, botulinum neurotoxin A (BoNT/A) is used to treat a wide variety of disorders involving peripheral nerve terminal hyperexcitability. However, it has been a matter of debate whether this toxin has central or peripheral...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2014-06-01
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| Series: | Frontiers in Neurology |
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| Online Access: | http://journal.frontiersin.org/Journal/10.3389/fneur.2014.00098/full |
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| author | Hidetaka eKoizumi Satoshi eGoto Satoshi eGoto Shinya eOkita Ryoma eMorigaki Ryoma eMorigaki Norio eAkaike Yasushi eTorii Yasushi eTorii Tetsuhiro eHarakawa Akihiro eGinnaga Ryuji eKaji |
| author_facet | Hidetaka eKoizumi Satoshi eGoto Satoshi eGoto Shinya eOkita Ryoma eMorigaki Ryoma eMorigaki Norio eAkaike Yasushi eTorii Yasushi eTorii Tetsuhiro eHarakawa Akihiro eGinnaga Ryuji eKaji |
| author_sort | Hidetaka eKoizumi |
| collection | DOAJ |
| description | Because of its unique ability to exert long-lasting synaptic transmission blockade, botulinum neurotoxin A (BoNT/A) is used to treat a wide variety of disorders involving peripheral nerve terminal hyperexcitability. However, it has been a matter of debate whether this toxin has central or peripheral sites of action. We employed a rat model in which BoNT/A1 or BoNT/A2 was unilaterally injected into the gastrocnemius muscle. On time-course measurements of compound muscle action potential (CMAP) amplitudes after injection of BoNT/A1 or BoNT/A2 at doses ranging from 1.7 U to 13.6 U, CMAP amplitude for the ipsilateral hind leg was markedly decreased on the 1st day, and this muscle flaccidity persisted up to the 14th day. Of note, both BoNT/A1 and BoNT/A2 administrations also resulted in decreased CMAP amplitudes for the contralateral leg in a dose-dependent manner ranging from 1.7 to 13.6 U, and this muscle flaccidity increased until the 4th day and then slowly recovered. Immunohistochemical results revealed that BoNT/A-cleaved SNAP-25 (synaptosomal-associated protein of 25 kDa) appeared in the bilateral ventral and dorsal horns 4 days after injection of BoNT/A1 (10 U) or BoNT/A2 (10 U), although there seemed to be a wider spread of BoNT/A-cleaved SNAP-25 associated with BoNT/A1 than BoNT/A2 in the contralateral spinal cord. This suggests that the catalytically active BoNT/A1 and BoNT/A2 were axonally transported via peripheral motor and sensory nerves to the spinal cord, where they spread through a transcytosis (cell-to-cell trafficking) mechanism. Our results provide evidence for the central effects of intramuscularly administered BoNT/A1 and BoNT/A2 in the spinal cord, and a new insight into the clinical effects of peripheral BoNT/A applications. |
| first_indexed | 2024-12-10T04:07:39Z |
| format | Article |
| id | doaj.art-49734534ed624a5f97084ff1eea688e5 |
| institution | Directory Open Access Journal |
| issn | 1664-2295 |
| language | English |
| last_indexed | 2024-12-10T04:07:39Z |
| publishDate | 2014-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Neurology |
| spelling | doaj.art-49734534ed624a5f97084ff1eea688e52022-12-22T02:02:48ZengFrontiers Media S.A.Frontiers in Neurology1664-22952014-06-01510.3389/fneur.2014.0009886235Spinal central effects of peripherally applied botulinum neurotoxin A in comparison between its subtypes A1 and A2Hidetaka eKoizumi0Satoshi eGoto1Satoshi eGoto2Shinya eOkita3Ryoma eMorigaki4Ryoma eMorigaki5Norio eAkaike6Yasushi eTorii7Yasushi eTorii8Tetsuhiro eHarakawa9Akihiro eGinnaga10Ryuji eKaji11Department of Clinical Neuroscience, University of TokushimaDepartment of Motor Neuroscience, University of TokushimaParkinson's Disease and Dystonia Research Center, Tokushima UniversityParkinson's Disease and Dystonia Research Center, Tokushima UniversityDepartment of Motor Neuroscience, University of TokushimaParkinson's Disease and Dystonia Research Center, Tokushima UniversityResearch Division for Life Science, Kumamoto Health Science UniversityThe Chemo-Sero-Therapeutic Research Institute (KAKETSUKEN)Graduate School of Medicine, Osaka UniversityThe Chemo-Sero-Therapeutic Research Institute (KAKETSUKEN)The Chemo-Sero-Therapeutic Research Institute (KAKETSUKEN)Department of Clinical Neuroscience, University of TokushimaBecause of its unique ability to exert long-lasting synaptic transmission blockade, botulinum neurotoxin A (BoNT/A) is used to treat a wide variety of disorders involving peripheral nerve terminal hyperexcitability. However, it has been a matter of debate whether this toxin has central or peripheral sites of action. We employed a rat model in which BoNT/A1 or BoNT/A2 was unilaterally injected into the gastrocnemius muscle. On time-course measurements of compound muscle action potential (CMAP) amplitudes after injection of BoNT/A1 or BoNT/A2 at doses ranging from 1.7 U to 13.6 U, CMAP amplitude for the ipsilateral hind leg was markedly decreased on the 1st day, and this muscle flaccidity persisted up to the 14th day. Of note, both BoNT/A1 and BoNT/A2 administrations also resulted in decreased CMAP amplitudes for the contralateral leg in a dose-dependent manner ranging from 1.7 to 13.6 U, and this muscle flaccidity increased until the 4th day and then slowly recovered. Immunohistochemical results revealed that BoNT/A-cleaved SNAP-25 (synaptosomal-associated protein of 25 kDa) appeared in the bilateral ventral and dorsal horns 4 days after injection of BoNT/A1 (10 U) or BoNT/A2 (10 U), although there seemed to be a wider spread of BoNT/A-cleaved SNAP-25 associated with BoNT/A1 than BoNT/A2 in the contralateral spinal cord. This suggests that the catalytically active BoNT/A1 and BoNT/A2 were axonally transported via peripheral motor and sensory nerves to the spinal cord, where they spread through a transcytosis (cell-to-cell trafficking) mechanism. Our results provide evidence for the central effects of intramuscularly administered BoNT/A1 and BoNT/A2 in the spinal cord, and a new insight into the clinical effects of peripheral BoNT/A applications.http://journal.frontiersin.org/Journal/10.3389/fneur.2014.00098/fullSpinal CordBotulinum NeurotoxinCentral effectsSNAP-25Axonal transport. |
| spellingShingle | Hidetaka eKoizumi Satoshi eGoto Satoshi eGoto Shinya eOkita Ryoma eMorigaki Ryoma eMorigaki Norio eAkaike Yasushi eTorii Yasushi eTorii Tetsuhiro eHarakawa Akihiro eGinnaga Ryuji eKaji Spinal central effects of peripherally applied botulinum neurotoxin A in comparison between its subtypes A1 and A2 Frontiers in Neurology Spinal Cord Botulinum Neurotoxin Central effects SNAP-25 Axonal transport. |
| title | Spinal central effects of peripherally applied botulinum neurotoxin A in comparison between its subtypes A1 and A2 |
| title_full | Spinal central effects of peripherally applied botulinum neurotoxin A in comparison between its subtypes A1 and A2 |
| title_fullStr | Spinal central effects of peripherally applied botulinum neurotoxin A in comparison between its subtypes A1 and A2 |
| title_full_unstemmed | Spinal central effects of peripherally applied botulinum neurotoxin A in comparison between its subtypes A1 and A2 |
| title_short | Spinal central effects of peripherally applied botulinum neurotoxin A in comparison between its subtypes A1 and A2 |
| title_sort | spinal central effects of peripherally applied botulinum neurotoxin a in comparison between its subtypes a1 and a2 |
| topic | Spinal Cord Botulinum Neurotoxin Central effects SNAP-25 Axonal transport. |
| url | http://journal.frontiersin.org/Journal/10.3389/fneur.2014.00098/full |
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