Intraneural application of botulinum neurotoxin a improves motoneuron innervation and functional recovery after femoral nerve reconstruction in rats

Medientyp: E-Book; Hochschulschrift

Titel: Intraneural application of botulinum neurotoxin a improves motoneuron innervation and functional recovery after femoral nerve reconstruction in rats

Beteiligte: Irintchev, Marcel [VerfasserIn]; Guntinas-Lichius, Orlando [AkademischeR BetreuerIn]; Axer, Hubertus [AkademischeR BetreuerIn]; Angelov, Dojčin N. [AkademischeR BetreuerIn]

Körperschaft: Friedrich-Schiller-Universität Jena

Erschienen: Jena, [2020]

Umfang: 1 Online-Ressource (41 Seiten); Illustrationen, Diagramme

Sprache: Englisch

DOI: 10.22032/dbt.40493

Identifikator:

Schlagwörter: Nervenregeneration > Botulinus-A-Toxin > Motoneuron

Entstehung:

Hochschulschrift: Dissertation, Friedrich-Schiller-Universität Jena, 2020

Anmerkungen: Kumulative Dissertation, enthält Zeitschriftenaufsätze
Tag der Verteidigung: 07.01.2020
Zusammenfassungen in deutscher und englischer Sprache

Beschreibung: Axonal injuries to motoneurons of adult mammals cause, among other responses, loss of synaptic terminals from their cell bodies and dendrites. This “synaptic stripping” is largely, but not always completely reversed after successful axonal regeneration and muscle reinnervation. Long-lasting deficits in, e.g., cholinergic and glutamatergic afferent terminals, correlate negatively with degree of functional recovery in rats suggesting that persistent partial deafferentation of motoneurons may be a factor limiting functional recovery after peripheral nerve injury. AimsTo further explore the idea that functional recovery is partially linked to restoration of synaptic inputs to regenerated motoneurons, we pursued to modulate the deafferentation of motoneurons following nerve section/suture and monitor the effects of this manipulation on the outcome of peripheral nerve regeneration. Two neuroactive molecules, botulinum neurotoxin A (BoNT) and brain-derived neurotrophic factor (BDNF), known for their ability to influence synaptic inputs to neurons, were selected as manipulation tools. Drug solutions were applied to the proximal stump of the freshly cut femoral nerve of rats to achieve drug uptake and transport to the neuronal perikarya and possibly transcytosis to afferent synapses. The experiments were performed in adult (10-week-old) female Wistar rats which received either BoNT (N = 17), BDNF (N = 15) or bovine serum albumin treatment (BSA, control, N = 13). After drug application, the femoral nerve was surgically reconstructed and functional recovery was monitored over a 5-month period using an established gait analysis protocol. Other outcome measures were quality of endplate reinnervation (occurrence of abnormal polyinnervation assessed morphologically) and numbers of cholinergic, GABA/glycinergic and glutamatergic synaptic terminals in the femoral motor nucleus in the spinal cord (assessed using stereological approaches). Application of BoNT, but not BDNF, resulted in a marked, as compared with BSA, improvement of motor recovery at 2 to 20 weeks after injury. At two months, BoNT-treated rats had an attenuated loss of perisomatic cholinergic terminals compared with the other two treatments. Analysis of individual animal data revealed significant linear correlations between functional parameters and numbers of cholinergic terminals. Quality of endplate reinnervation was not affected by treatment with BoNT or BDNF. The effect of BoNT on synaptic terminals is possibly related to transcytosis of BoNT into perisomatic nerve terminals as suggested by immunohistochemical analysis of cleaved SNAP-25. In turn, better preservation of modulatory cholinergic terminals, which are crucial for normal motoneuron excitability, might underlie enhanced recovery of function in BoNT-treated rats. The findings support the idea that persistent partial deafferentation of axotomized motoneurons is a factor contributing to deficient functional recovery after nerve injury. Intraneural application of drugs appears to be a promising way to analyze causal relationships between synaptic plasticity and restoration of function. In addition, it is thinkable that the described drug application approach may evolve into a clinically feasible therapy if further controlled animal experiments provide convincing evidence for its safety and efficacy.

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