Botulinum Neurotoxin Chimeras Suppress Stimulation by Capsaicin of Rat Trigeminal Sensory Neurons In Vivo and In Vitro
Chimeras of botulinum neurotoxin (BoNT) serotype A (/A) combined with /E protease might possess improved analgesic properties relative to either parent, due to inheriting the sensory neurotropism of the former with more extensive disabling of SNAP-25 from the latter. Hence, fusions of /E protease li...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-02-01
|
| Series: | Toxins |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2072-6651/14/2/116 |
| _version_ | 1797476308338343936 |
|---|---|
| author | Caren Antoniazzi Mariia Belinskaia Tomas Zurawski Seshu Kumar Kaza J. Oliver Dolly Gary W. Lawrence |
| author_facet | Caren Antoniazzi Mariia Belinskaia Tomas Zurawski Seshu Kumar Kaza J. Oliver Dolly Gary W. Lawrence |
| author_sort | Caren Antoniazzi |
| collection | DOAJ |
| description | Chimeras of botulinum neurotoxin (BoNT) serotype A (/A) combined with /E protease might possess improved analgesic properties relative to either parent, due to inheriting the sensory neurotropism of the former with more extensive disabling of SNAP-25 from the latter. Hence, fusions of /E protease light chain (LC) to whole BoNT/A (LC/E-BoNT/A), and of the LC plus translocation domain (H<sub>N</sub>) of /E with the neuronal acceptor binding moiety (H<sub>C</sub>) of /A (BoNT/EA), created previously by gene recombination and expression in <i>E. coli</i>., were used. LC/E-BoNT/A (75 units/kg) injected into the whisker pad of rats seemed devoid of systemic toxicity, as reflected by an absence of weight loss, but inhibited the nocifensive behavior (grooming, freezing, and reduced mobility) induced by activating TRPV1 with capsaicin, injected at various days thereafter. No sex-related differences were observed. c-Fos expression was increased five-fold in the trigeminal nucleus caudalis ipsi-lateral to capsaicin injection, relative to the contra-lateral side and vehicle-treated controls, and this increase was virtually prevented by LC/E-BoNT/A. In vitro, LC/E-BoNT/A or /EA diminished CGRP exocytosis from rat neonate trigeminal ganglionic neurons stimulated with up to 1 µM capsaicin, whereas BoNT/A only substantially reduced the release in response to 0.1 µM or less of the stimulant, in accordance with the /E protease being known to prevent fusion of exocytotic vesicles. |
| first_indexed | 2024-03-09T20:56:01Z |
| format | Article |
| id | doaj.art-f8c450e2c352418793501911c8d10c07 |
| institution | Directory Open Access Journal |
| issn | 2072-6651 |
| language | English |
| last_indexed | 2024-03-09T20:56:01Z |
| publishDate | 2022-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Toxins |
| spelling | doaj.art-f8c450e2c352418793501911c8d10c072023-11-23T22:21:38ZengMDPI AGToxins2072-66512022-02-0114211610.3390/toxins14020116Botulinum Neurotoxin Chimeras Suppress Stimulation by Capsaicin of Rat Trigeminal Sensory Neurons In Vivo and In VitroCaren Antoniazzi0Mariia Belinskaia1Tomas Zurawski2Seshu Kumar Kaza3J. Oliver Dolly4Gary W. Lawrence5International Centre for Neurotherapeutics, Dublin City University, Collins Avenue, D09 V209 Dublin, IrelandInternational Centre for Neurotherapeutics, Dublin City University, Collins Avenue, D09 V209 Dublin, IrelandInternational Centre for Neurotherapeutics, Dublin City University, Collins Avenue, D09 V209 Dublin, IrelandInternational Centre for Neurotherapeutics, Dublin City University, Collins Avenue, D09 V209 Dublin, IrelandInternational Centre for Neurotherapeutics, Dublin City University, Collins Avenue, D09 V209 Dublin, IrelandInternational Centre for Neurotherapeutics, Dublin City University, Collins Avenue, D09 V209 Dublin, IrelandChimeras of botulinum neurotoxin (BoNT) serotype A (/A) combined with /E protease might possess improved analgesic properties relative to either parent, due to inheriting the sensory neurotropism of the former with more extensive disabling of SNAP-25 from the latter. Hence, fusions of /E protease light chain (LC) to whole BoNT/A (LC/E-BoNT/A), and of the LC plus translocation domain (H<sub>N</sub>) of /E with the neuronal acceptor binding moiety (H<sub>C</sub>) of /A (BoNT/EA), created previously by gene recombination and expression in <i>E. coli</i>., were used. LC/E-BoNT/A (75 units/kg) injected into the whisker pad of rats seemed devoid of systemic toxicity, as reflected by an absence of weight loss, but inhibited the nocifensive behavior (grooming, freezing, and reduced mobility) induced by activating TRPV1 with capsaicin, injected at various days thereafter. No sex-related differences were observed. c-Fos expression was increased five-fold in the trigeminal nucleus caudalis ipsi-lateral to capsaicin injection, relative to the contra-lateral side and vehicle-treated controls, and this increase was virtually prevented by LC/E-BoNT/A. In vitro, LC/E-BoNT/A or /EA diminished CGRP exocytosis from rat neonate trigeminal ganglionic neurons stimulated with up to 1 µM capsaicin, whereas BoNT/A only substantially reduced the release in response to 0.1 µM or less of the stimulant, in accordance with the /E protease being known to prevent fusion of exocytotic vesicles.https://www.mdpi.com/2072-6651/14/2/116botulinum neurotoxinsexocytosiscalcitonin gene-related peptidemigrainenociceptiontrigeminal ganglion |
| spellingShingle | Caren Antoniazzi Mariia Belinskaia Tomas Zurawski Seshu Kumar Kaza J. Oliver Dolly Gary W. Lawrence Botulinum Neurotoxin Chimeras Suppress Stimulation by Capsaicin of Rat Trigeminal Sensory Neurons In Vivo and In Vitro Toxins botulinum neurotoxins exocytosis calcitonin gene-related peptide migraine nociception trigeminal ganglion |
| title | Botulinum Neurotoxin Chimeras Suppress Stimulation by Capsaicin of Rat Trigeminal Sensory Neurons In Vivo and In Vitro |
| title_full | Botulinum Neurotoxin Chimeras Suppress Stimulation by Capsaicin of Rat Trigeminal Sensory Neurons In Vivo and In Vitro |
| title_fullStr | Botulinum Neurotoxin Chimeras Suppress Stimulation by Capsaicin of Rat Trigeminal Sensory Neurons In Vivo and In Vitro |
| title_full_unstemmed | Botulinum Neurotoxin Chimeras Suppress Stimulation by Capsaicin of Rat Trigeminal Sensory Neurons In Vivo and In Vitro |
| title_short | Botulinum Neurotoxin Chimeras Suppress Stimulation by Capsaicin of Rat Trigeminal Sensory Neurons In Vivo and In Vitro |
| title_sort | botulinum neurotoxin chimeras suppress stimulation by capsaicin of rat trigeminal sensory neurons in vivo and in vitro |
| topic | botulinum neurotoxins exocytosis calcitonin gene-related peptide migraine nociception trigeminal ganglion |
| url | https://www.mdpi.com/2072-6651/14/2/116 |
| work_keys_str_mv | AT carenantoniazzi botulinumneurotoxinchimerassuppressstimulationbycapsaicinofrattrigeminalsensoryneuronsinvivoandinvitro AT mariiabelinskaia botulinumneurotoxinchimerassuppressstimulationbycapsaicinofrattrigeminalsensoryneuronsinvivoandinvitro AT tomaszurawski botulinumneurotoxinchimerassuppressstimulationbycapsaicinofrattrigeminalsensoryneuronsinvivoandinvitro AT seshukumarkaza botulinumneurotoxinchimerassuppressstimulationbycapsaicinofrattrigeminalsensoryneuronsinvivoandinvitro AT joliverdolly botulinumneurotoxinchimerassuppressstimulationbycapsaicinofrattrigeminalsensoryneuronsinvivoandinvitro AT garywlawrence botulinumneurotoxinchimerassuppressstimulationbycapsaicinofrattrigeminalsensoryneuronsinvivoandinvitro |