Background & Aims
A recently published randomized, double-blind, placebo-controlled trial showed that two administrations of a botulinum toxin/A (BoNT/A) had significant and sustained analgesic effects against peripheral neuropathic pain1. Two-thirds of the study participants suffered from post-traumatic or postsurgical neuropathic pain. Treatment was particularly efficacious in participants with preserved nociceptive input. While the mechanism driving the observed effect is under discussion and not clearly identified yet2, Adler et al. discussed broadly preclinical observations suggesting BoNT/A could influence inflammation, accelerate neuroregeneration and improve functional recovery after injury to peripheral nerves3. To better understand the effect of BoNT/A in analgesia and neuroregeneration, we tested treatment effects of BoNT/A (NT 201, IncobotulinumtoxinA, Xeomin®) in rats in 2 different CCI models measuring functional, behavioural, and histological endpoints.
Methods
(A) 56-day sciatic CCI rat model with analysis of functional and histological readouts. Effects of 2 applications of NT 201 in the lesion site of CCI rats on day 0 and day 21 were compared with effects observed in vehicle treated CCI rats and in sham animals. Sciatic Functional Index (SFI) measurement and compound muscle action potential (CMAP) recording were performed on day 3, 35, and 56. Tissue was harvested and analyzed after hematoxylin-eosin (H&E) staining, toluidine blue staining, and immunofluorescent staining.
(B) 42-day CCI rat model of the infraorbital nerve (ION) with measurement of pain related behavior. Effects of one application of NT 201 in the whisker pad of ION-CCI rats on mechanical sensitivity were compared with effects observed in vehicle treated ION-CCI rats and in sham animals.
The studies were performed at HD Bioscience (HDB) (Shanghai, China) which has full AAALAC accreditation.
Results
(A) In the group treated with NT 201 the two endpoints SFI and onset latency in CMAP were significantly decreased on day 56 in comparison to the control group treated with vehicle. Tissue analysis revealed reduction of immune cell influx following treatment with NT 201. Analysis of toluidine blue staining employing g-ratio analyses showed that NT 201 treatment might promote re-myelination.
(B) Pain thresholds of all NT 201 treatment groups were significantly increased compared to the model group after one day of application (14 days after ION-CCI), and the elevation remained significant until study end when a dose-dependent effect was observed (42 days after ION-CCI).
Conclusions
(A) NT 201 treatment showed significant effects in a rat sciatic CCI which suggest a motor restorative and neuroprotective role of NT 201 during nerve damaging conditions. Due to effects on lymphocyte influx and myelin growth at the lesion it seems likely that anti-inflammatory and trophic processes on Schwann-cells are involved in the respective mode of action. These results stand in line with mechanisms suggested by Adler et al.3 and results observed in a mouse model by Marinelli et al.4 testing another BoNT/A.
(B) NT 201 treatment showed significant and dose dependent effects in a rat ION-CCI which suggest an analgesic role of NT 201 in neuropathic pain conditions involving the trigeminal system. The outcome stands in line with results observed in rat study by Wu et al.5 testing another BoNT/A in a different design which was not optimized to show dose-response effects.
References
1 Attal N. et al, Safety and efficacy of repeated injections of botulinum toxin A in peripheral neuropathic pain (BOTNEP): a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2016; 15(6): 555
2 Matak I. et al, Mechanisms of Botulinum Toxin Type A Action on Pain. Toxins. 2019; 5:11(8):459
3 Adler M. et al, Preclinical Evidence for the Role of Botulinum Neurotoxin A (BoNT/A) in the Treatment of Peripheral Nerve Injury, Microorganisms. 2022; 10(5):886
4 Marinelli S. et al, Botulinum neurotoxin type A counteracts neuropathic pain and facilitates functional recovery after peripheral nerve injury in animal models. Neuroscience. 2010;171(1):316
5 Wu C. et al, Central antinociceptive activity of peripherally applied botulinum toxin type A in lab rat model of trigeminal neuralgia. Springerplus. 2016 Apr 11:5:431
Poster Authors
Jens Nagel
PhD
Merz Therapeutics GmbH, Frankfurt
Lead Author
Wojciech Danysz
Prof.
Merz Therapeutics GmbH, Frankfurt
Lead Author
Klaus Fink
Prof.
Merz Therapeutics GmbH, Frankfurt
Lead Author
Maarten Ruitenberg
PhD
Merz Therapeutics GmbH, Frankfurt
Lead Author
Andreas Gravius
PhD
Merz Therapeutics GmbH, Frankfurt
Lead Author
Topics
- Treatment/Management: Pharmacology: Monoclonal Antibodies, Biologics, and Biosimilars