Abstract
In the motor system, botulinum toxin type A (BoNT/A) actions were classically attributed to its well-known peripheral anticholinergic actions in neuromuscular junctions. However, the enzymatic activity of BoNT/A, assessed by the detection of cleaved synaptosomal-associated protein 25 (SNAP-25), was recently detected in motor and sensory regions of the brainstem and spinal cord after toxin peripheral injection in rodents. In sensory regions, the function of BoNT/A activity is associated with its antinociceptive effects, while in motor regions we only know that BoNT/A activity is present. Is it possible that BoNT/A presence in central motor nuclei is without any function? In this brief review, we analyze this question. Limited data available in the literature warrant further investigations of BoNT/A actions in motor nervous system.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Antonucci F, Rossi C, Gianfranceschi L, Rossetto O, Caleo M (2008) Long distance retrograde effects of botulinum neurotoxin A. J Neurosci 28:3689–3696. doi:10.1523/jneurosci.0375-08.2008
Aoki KR, Francis J (2011) Update on antinociceptive mechanism hypothesis of botulinum toxin A. J Parkinsonism Relat Disord 117:S27–S33. doi:10.1016/j.parkreldis.2011.06.013
Aymard C, Mazzocchio R, Marchand-Pauvert V (2013) Central effects of botulinum toxin A: depression of spinal recurrent inhibition after injection of calf muscles in stroke patients. Ann Phys Rehab Med 56(S1):e396–e397. doi:10.1016/j.rehab.2013.07.1016
Bach-Rojecky L, Lacković Z (2009) Central origin of the antinociceptive action of botulinum toxin type A. Pharmacol Biochem Behav 94:234–238. doi:10.1016/j.pbb.2009.08.012
Bach-Rojecky L, Relja M, Lacković Z (2005) Botulinum toxin type A in experimental neuropathic pain. J Neural Transm (Vienna) 112(2):215–219. doi:10.1007/s00702-004-0265-1
Bach-Rojecky L, Dominis M, Lacković Z (2008) Lack of anti-inflammatory effect of botulinum toxin type A in experimental models of inflammation. Fundam Clin Pharmacol 22(5):503–509. doi:10.1111/j.1472-8206.2008.00615.x
Bach-Rojecky L, Šalković-Petrišić M, Lacković Z (2010) Botulinum toxin type A reduces pain supersensitivity in experimental diabetic neuropathy: bilateral effects after unilateral injection. Eur J Pharmacol 633:10–14. doi:10.1016/j.ejphar.2010.01.020
Black J, Dolly O (1986) Interaction of 125I-labeled botulinum neurotoxins with nerve terminals. I. Ultrastructural autoradiographic localization and quantitation of distinct membrane acceptors for types A and B on motor nerves. J Cell Biol 103:521–534
Blasi J, Chapman ER, Link E, Binz T, Yamasaki S, De Camilli P, Südhof TC, Niemann H, Jahn R (1993) Botulinum neurotoxin A selectively cleaves the synaptic protein SNAP-25. Nature 365:160–163
Bomba-Warczak E, Vevea JD, Brittain JM, Figueroa-Bernier A, Tepp WH, Johnson EA, Yeh FL, Chapman ER (2016) Interneuronal transfer and distal action of tetanus toxin and botulinum neurotoxins A and D in central neurons. Cell Rep. doi:10.1016/j.celrep.2016.06.104 (Epub ahead of print)
Caleo M, Antonucci F, Restani L, Mazzocchio R (2009) A reappraisal of the central effects of botulinum neurotoxin type A: by what mechanism? J Neurochem 109:15–24. doi:10.1111/j.1471-4159.2009.05887.x
Caron G, Marqueste T, Decherchi P (2015) Long-term effects of botulinum toxin complex type A injection on mechano- and metabo-sensitive afferent fibers originating from gastrocnemius muscle. PLoS ONE 10:e0140439
Cullheim S, Kellerth JO (1978) A morphological study of the axons and recurrent axon collaterals of cat alpha-motoneurones supplying different hind-limb muscles. J Physiol 281:285–299
Currà A, Trompetto C, Abbruzzese G, Berardelli A (2004) Central effects of botulinum toxin type A: evidence and supposition. Mov Disord 19(Suppl 8):S60–S64
Drinovac Vlah V, Bach-Rojecky L, Lacković Z (2016) Antinociceptive action of botulinum toxin type A in carrageenan-induced mirror pain. J Neural Transm (Vienna). doi:10.1007/s00702-016-1605-7
Favre-Guilmard C, Auguet M, Chabrier PE (2009) Different antinociceptive effects of botulinum toxin type A in inflammatory and peripheral polyneuropathic rat models. Eur J Pharmacol 617:48–53. doi:10.1016/j.ejphar.2009.06.047
Filipović B, Matak I, Bach-Rojecky L, Lacković Z (2012) Central action of peripherally applied botulinum toxin type a on pain and dural protein extravasation in rat model of trigeminal neuropathy. PLoS One 7:e29803. doi:10.1371/journal.pone.0029803
Filippi GM, Errico P, Santarelli R, Bagolini B, Manni E (1993) Botulinum A toxin effects on rat jaw muscle spindles. Acta Otolaryngol 113:400–404
Gómez-Pinilla F, Ying Z, Roy RR, Hodgson J, Edgerton VR (2004) Afferent input modulatesneurotrophins and synaptic plasticity in the spinal cord. J Neurophysiol 92:3423–3432. doi:10.1152/jn.00432.2004
Gracies JM (2004) Physiological effects of botulinum toxin in spasticity. Mov Disord 19(Suppl 8):S120–S128. doi:10.1002/mds.20065
Habermann E (1974) 125I-labeled neurotoxin from Clostridium botulinum A: preparation, binding to synaptosomes and ascent to the spinal cord. Naunyn Schmiedebergs Arch Pharmacol 281:47–56
Hubbard K, Beske P, Lyman M, McNutt P (2015) Functional evaluation of biological neurotoxins in networked cultures of stem cell-derived central nervous system neurons. J Vis Exp. doi:10.3791/52361
Humm AM, Pabst C, Lauterburg T, Burgunder JM (2000) Enkephalin and aFGF are differentially regulated in rat spinal motoneurons after chemodenervation with botulinum toxin. Exp Neurol 161:361–372. doi:10.1006/exnr.1999.7268
Jung HH, Lauterburg T, Burgunder JM (1997) Expression of neurotransmitter genes in rat spinal motoneurons after chemodenervation with botulinum toxin. Neuroscience 78:469–479
Kaňovský P, Rosales RL (2011) Debunking the pathophysiological puzzle of dystonia–with special reference to botulinum toxin therapy. Parkinsonism Relat Disord 17(Suppl 1):S11–S14. doi:10.1016/j.parkreldis.2011.06.018
Koizumi H, Goto S, Okita S, Morigaki R, Akaike N, Torii Y, Harakawa T, Ginnaga A (2014) Kaji R (2014) Spinal central effects of peripherally applied botulinum neurotoxin a in comparison between its subtypes A1 and A2. Front Neurol 5:98. doi:10.3389/fneur.2014.00098
Lacković Z, Filipović B, Matak I, Helyes Z (2016) Activity of botulinum toxin type A in cranial dura: implications for treatment of migraine and other headaches. Br J Pharmacol 173:279–291. doi:10.1111/bph.13366.
Luvisetto S, Marinelli S, Lucchetti F, Marchi F, Cobianchi S, Rossetto O, Montecucco C, Pavone F (2006) Botulinum neurotoxins and formalin-induced pain: central vs. peripheral effects in mice. Brain Res 1082:124–131. doi:10.1016/j.brainres.2006.01.117
Luvisetto S, Marinelli S, Cobianchi S, Pavone F (2007) Anti-allodynic efficacy of botulinum neurotoxin A in a model of neuropathic pain. Neuroscience 145(1):1–4. doi:10.1016/j.neuroscience.2006.12.004
Luvisetto S, Gazerani P, Cianchetti C, Pavone F (2015) Botulinum toxin type A as a therapeutic agent against headache and related disorders. Toxins (Basel) 7:3818–3844. doi:10.3390/toxins7093818
Marchand-Pauvert V, Aymard C, Giboin LS, Dominici F, Rossi A, Mazzocchio R (2013) Beyond muscular effects: depression of spinal recurrent inhibition after botulinum neurotoxin A. J Physiol 591:1017–1029. doi:10.1113/jphysiol.2012.239178
Marinelli S, Vacca V, Ricordy R, Uggenti C, Tata AM, Luvisetto S (2012) The analgesic effect on neuropathic pain of retrogradely transported botulinum neurotoxin A involves Schwann cells and astrocytes. PLoS One 7(10):e47977. doi:10.1371/journal.pone.0047977
Mariotti R, Bentivoglio M (1996) Botulinum toxin induces nitric oxide synthase activity in motoneurons. Neurosci Lett 219:25–28
Matak I, Lacković Z (2014) Botulinum toxin A, brain and pain. Prog Neurobiol 119–120:39–59. doi:10.1016/j.pneurobio.2014.06.001
Matak I, Bach-Rojecky L, Filipović B, Lacković Z (2011) Behavioral and immunohistochemical evidence for central antinociceptive activity of botulinum toxin A. Neuroscience 186:201–207. doi:10.1016/j.neuroscience.2011.04.026
Matak I, Riederer P, Lacković Z (2012) Botulinum toxin’s axonal transport from periphery to the spinal cord. Neurochem Int 61:236–239. doi:10.1016/j.neuint.2012.05.001
Mazzocchio R, Caleo M (2015) More than at the neuromuscular synapse: actions of botulinum neurotoxin A in the central nervous system. Neuroscientist 21:44–61. doi:10.1177/1073858414524633
Mika J, Rojewska E, Makuch W, Korostynski M, Luvisetto S, Marinelli S, Pavone F, Przewlocka B (2011) The effect of botulinum neurotoxin A on sciatic nerve injury-induced neuroimmunological changes in rat dorsal root ganglia and spinal cord. Neuroscience 175:358–366. doi:10.1016/j.neuroscience.2010.11.040
Moreno-López B, de la Cruz RR, Pastor AM, Delgado-García JM (1997) Effects of botulinum neurotoxin type A on abducens motoneurons in the cat: alterations of the discharge pattern. Neuroscience 81:437–455
Nevrly M, Hluštík P, Otruba P, Opavský R, Hok P, Kaňovský P (2014) 28. Modulation of cerebral sensorimotor circuits during botulinum toxin treatment of cervical dystonia. Clin Neurophysiol 125(5):e33. doi:10.1016/j.clinph.2013.12.066
Opavský R, Hluštík P, Otruba P, Kaňovský P (2011) Sensorimotor network in cervical dystonia and the effect of botulinum toxin treatment: a functional MRI study. J Neurol Sci 306:71–75. doi:10.1016/j.jns.2011.03.040
Pastor AM, Moreno-López B, De La Cruz RR, Delgado-García JM (1997) Effects of botulinum neurotoxin type A on abducens motoneurons in the cat: ultrastructural and synaptic alterations. Neuroscience 81:457–478
Pavone F, Luvisetto S (2010) Botulinum neurotoxin for pain management: insights from animal models. Toxins (Basel) 2:2890–2913. doi:10.3390/toxins2122890
Restani L, Antonucci F, Gianfranceschi L, Rossi C, Rossetto O, Caleo M (2011) Evidence for anterograde transport and transcytosis of botulinum neurotoxin A (BoNT/A). J Neurosci 31:15650–15659. doi:10.1523/JNEUROSCI.2618-11.2011
Restani L, Novelli E, Bottari D, Leone P, Barone I, Galli-Resta L, Strettoi E, Caleo M (2012a) Botulinum neurotoxin A impairs neurotransmission following retrograde transynaptic transport. Traffic 13:1083–1089. doi:10.1111/j.1600-0854.2012.01369.x
Restani L, Giribaldi F, Manich M, Bercsenyi K, Menendez G, Rossetto O, Caleo M, Schiavo G (2012b) Botulinum neurotoxins A and E undergo retrograde axonal transport in primary motor neurons. PLoS Pathog 8(12):e1003087. doi:10.1371/journal.ppat.1003087
Rosales RL, Dressler D (2010) On muscle spindles, dystonia and botulinum toxin. Eur J Neurol 17(Suppl 1):71–80. doi:10.1111/j.1468-1331.2010.03056.x
Rosales RL, Arimura K, Takenaga S, Osame M (1996) Extrafusal and intrafusal muscle effects in experimental botulinum toxin-A injection. Muscle Nerve 19:488–496
Scherf JM, Hu X, Tepp WH, Ichtchenko K, Johnson EA, Pellett S (2014) Analysis of gene expression in induced pluripotent stem cell-derived human neurons exposed to botulinum neurotoxin A subtype 1 and a type A atoxic derivative. PLoS One 9:e111238. doi:10.1371/journal.pone.0111238
Tyler HR (1963) Botulinus toxin: effect on the central nervous system of man. Science 139:847–848
Wang T, Martin S, Papadopulos A, Harper CB, Mavlyutov TA, Niranjan D, Glass NR, Cooper-White JJ, Sibarita JB, Choquet D, Davletov B, Meunier FA (2015) Control of autophagosome axonal retrograde flux by presynaptic activity unveiled using botulinum neurotoxin type A. J Neurosci 35:6179–6194. doi:10.1523/JNEUROSCI.3757-14.2015
Wiegand H, Erdmann G, Wellhoner HH (1976) 125I-labelled botulinum A neurotoxin: pharmacokinetics in cats after intramuscular injection. Naunyn Schmiedebergs Arch Pharmacol 292:161–165
Wohlfarth K, Schubert M, Rothe B, Elek J, Dengler R (2001) Remote F-wave changes after local botulinum toxin application. Clin Neurophysiol 112:636–640
Wu C, Xie N, Lian Y, Xu H, Chen C, Zheng Y, Chen Y, Zhang H (2016) Central antinociceptive activity of peripherally applied botulinum toxin type A in lab rat model of trigeminal neuralgia. Springerplus 5:431. doi:10.1186/s40064-016-2071-2
Zhang X, Verge VM, Wiesenfeld-Hallin Z, Piehl F, Hökfelt T (1993) Expression of neuropeptides and neuropeptide mRNAs in spinal cord after axotomy in the rat, with special reference to motoneurons and galanin. Exp Brain Res 93:450–461
Acknowledgments
This work was supported by Project No. HR.3.2.01-0178 (to Ivica Matak) and project of Croatian National Foundation (HRZZ) No. O-1259-2015 (to Zdravko Lacković).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Matak, I., Lacković, Z. & Relja, M. Botulinum toxin type A in motor nervous system: unexplained observations and new challenges. J Neural Transm 123, 1415–1421 (2016). https://doi.org/10.1007/s00702-016-1611-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00702-016-1611-9