Details
| Originalsprache | Englisch |
|---|---|
| Seiten (von - bis) | 232-245 |
| Seitenumfang | 14 |
| Fachzeitschrift | Neurochemistry international |
| Jahrgang | 90 |
| Publikationsstatus | Veröffentlicht - 1 Nov. 2015 |
Abstract
Previous studies revealed a peripheral nerve regeneration (PNR)(1) promoting activity of Clostridium botulinum C3(2) exoenzyme or a 26(mer) C-terminal peptide fragment covering amino acids 156-181 (C3(156-181)),(3) when delivered as one-time injection at the lesion site. The current study was performed to 1) investigate if prolonged availability of C3 and C3(156-181) at the lesion site can further enhance PNR in vivo and to 2) elucidate effects of C3 and C3(156-181) on Schwann cells (SCs)(4)in vitro. For in vivo studies, 10 mm adult rat sciatic nerve gaps were reconstructed with the epineurial pouch technique or autologous nerve grafts. Epineurial pouches were filled with a hydrogel containing i) vehicle, ii) 40 μM C3 or iii) 40 μM C3(156-181). Sensory and motor functional recovery was monitored over 12 weeks and the outcome of PNR further analyzed by nerve morphometry. In vitro, we compared gene expression profiles (microarray analysis) and neurotrophic factor expression (western blot analysis) of untreated rat neonatal SCs with those treated with C3 or C3(156-181) for 72 h. Effects on neurotrophic factor expression levels were proven in adult human SCs. Unexpectedly, prolonged delivery of C3 and C3(156-181) at the lesion site did not increase the outcome of PNR. Regarding the potential mechanism underlying their previously detected PNR promoting action, however, 6 genes were found to be commonly altered in SCs upon treatment with C3 or C3(156-181). We demonstrate significant down-regulation of genes involved in glutamate uptake (Eaac1,(5)Grin2a(6)) and changes in neurotrophic factor expression (increase of FGF-2(7) and decrease of NGF(8)). Our microarray-based expression profiling revealed novel C3-regulated genes in SCs possibly involved in the axonotrophic (regeneration promoting) effects of C3 and C3(156-181). Detection of altered neurotrophic factor expression by C3 or C3(156-181) treated primary neonatal rat SCs and primary adult human SCs supports this hypothesis.
ASJC Scopus Sachgebiete
- Neurowissenschaften (insg.)
- Zelluläre und Molekulare Neurowissenschaften
- Biochemie, Genetik und Molekularbiologie (insg.)
- Zellbiologie
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in: Neurochemistry international, Jahrgang 90, 01.11.2015, S. 232-245.
Publikation: Beitrag in Fachzeitschrift › Artikel › Forschung › Peer-Review
}
TY - JOUR
T1 - C3-induced release of neurotrophic factors from Schwann cells - potential mechanism behind its regeneration promoting activity
AU - Rohrbeck, Astrid
AU - Stahl, Frank
AU - Höltje, Markus
AU - Hettwer, Timo
AU - Lindner, Patrick
AU - Hagemann, Sandra
AU - Pich, Andreas
AU - Haastert-Talini, Kirsten
N1 - Funding information: The authors would like to thank Silvana Taubeler-Gerling, Maike Wesemann, Jennifer Metzen of the Institute of Neuroanatomy for their excellent technical assistance. This study was supported by DFG grant to MH ( HO 3249/2-1 ).
PY - 2015/11/1
Y1 - 2015/11/1
N2 - Previous studies revealed a peripheral nerve regeneration (PNR)(1) promoting activity of Clostridium botulinum C3(2) exoenzyme or a 26(mer) C-terminal peptide fragment covering amino acids 156-181 (C3(156-181)),(3) when delivered as one-time injection at the lesion site. The current study was performed to 1) investigate if prolonged availability of C3 and C3(156-181) at the lesion site can further enhance PNR in vivo and to 2) elucidate effects of C3 and C3(156-181) on Schwann cells (SCs)(4)in vitro. For in vivo studies, 10 mm adult rat sciatic nerve gaps were reconstructed with the epineurial pouch technique or autologous nerve grafts. Epineurial pouches were filled with a hydrogel containing i) vehicle, ii) 40 μM C3 or iii) 40 μM C3(156-181). Sensory and motor functional recovery was monitored over 12 weeks and the outcome of PNR further analyzed by nerve morphometry. In vitro, we compared gene expression profiles (microarray analysis) and neurotrophic factor expression (western blot analysis) of untreated rat neonatal SCs with those treated with C3 or C3(156-181) for 72 h. Effects on neurotrophic factor expression levels were proven in adult human SCs. Unexpectedly, prolonged delivery of C3 and C3(156-181) at the lesion site did not increase the outcome of PNR. Regarding the potential mechanism underlying their previously detected PNR promoting action, however, 6 genes were found to be commonly altered in SCs upon treatment with C3 or C3(156-181). We demonstrate significant down-regulation of genes involved in glutamate uptake (Eaac1,(5)Grin2a(6)) and changes in neurotrophic factor expression (increase of FGF-2(7) and decrease of NGF(8)). Our microarray-based expression profiling revealed novel C3-regulated genes in SCs possibly involved in the axonotrophic (regeneration promoting) effects of C3 and C3(156-181). Detection of altered neurotrophic factor expression by C3 or C3(156-181) treated primary neonatal rat SCs and primary adult human SCs supports this hypothesis.
AB - Previous studies revealed a peripheral nerve regeneration (PNR)(1) promoting activity of Clostridium botulinum C3(2) exoenzyme or a 26(mer) C-terminal peptide fragment covering amino acids 156-181 (C3(156-181)),(3) when delivered as one-time injection at the lesion site. The current study was performed to 1) investigate if prolonged availability of C3 and C3(156-181) at the lesion site can further enhance PNR in vivo and to 2) elucidate effects of C3 and C3(156-181) on Schwann cells (SCs)(4)in vitro. For in vivo studies, 10 mm adult rat sciatic nerve gaps were reconstructed with the epineurial pouch technique or autologous nerve grafts. Epineurial pouches were filled with a hydrogel containing i) vehicle, ii) 40 μM C3 or iii) 40 μM C3(156-181). Sensory and motor functional recovery was monitored over 12 weeks and the outcome of PNR further analyzed by nerve morphometry. In vitro, we compared gene expression profiles (microarray analysis) and neurotrophic factor expression (western blot analysis) of untreated rat neonatal SCs with those treated with C3 or C3(156-181) for 72 h. Effects on neurotrophic factor expression levels were proven in adult human SCs. Unexpectedly, prolonged delivery of C3 and C3(156-181) at the lesion site did not increase the outcome of PNR. Regarding the potential mechanism underlying their previously detected PNR promoting action, however, 6 genes were found to be commonly altered in SCs upon treatment with C3 or C3(156-181). We demonstrate significant down-regulation of genes involved in glutamate uptake (Eaac1,(5)Grin2a(6)) and changes in neurotrophic factor expression (increase of FGF-2(7) and decrease of NGF(8)). Our microarray-based expression profiling revealed novel C3-regulated genes in SCs possibly involved in the axonotrophic (regeneration promoting) effects of C3 and C3(156-181). Detection of altered neurotrophic factor expression by C3 or C3(156-181) treated primary neonatal rat SCs and primary adult human SCs supports this hypothesis.
KW - ADP Ribose Transferases/pharmacology
KW - Animals
KW - Botulinum Toxins/pharmacology
KW - Brain-Derived Neurotrophic Factor/metabolism
KW - Cells, Cultured
KW - Coculture Techniques
KW - Female
KW - Glial Cell Line-Derived Neurotrophic Factor
KW - Mice
KW - Nerve Growth Factor/metabolism
KW - Nerve Regeneration/drug effects
KW - Rats
KW - Schwann Cells/cytology
KW - Sciatic Nerve/drug effects
KW - Schwann cells
KW - Gene expression
KW - Microarray
KW - C3 exoenzyme
KW - Peripheral nerve regeneration
KW - Mass spectrometry
UR - http://www.scopus.com/inward/record.url?scp=84946397271&partnerID=8YFLogxK
U2 - 10.1016/j.neuint.2015.09.007
DO - 10.1016/j.neuint.2015.09.007
M3 - Article
C2 - 26417907
VL - 90
SP - 232
EP - 245
JO - Neurochemistry international
JF - Neurochemistry international
SN - 0197-0186
ER -