{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T12:10:53Z","timestamp":1791461453793,"version":"4.3.4"},"reference-count":105,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2025,1,17]],"date-time":"2025-01-17T00:00:00Z","timestamp":1737072000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Institute of Advanced Sciences and the Maryada Foundation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Botulinum toxin (BoNT), the most potent substance known to humans, likely evolved not to kill but to serve other biological purposes. While its use in cosmetic applications is well known, its medical utility has become increasingly significant due to the intricacies of its structure and function. The toxin\u2019s structural complexity enables it to target specific cellular processes with remarkable precision, making it an invaluable tool in both basic and applied biomedical research. BoNT\u2019s potency stems from its unique structural features, which include domains responsible for receptor recognition, membrane binding, internalization, and enzymatic cleavage. This division of labor within the toxin\u2019s structure allows it to specifically recognize and interact with synaptic proteins, leading to precise cleavage at targeted sites within neurons. The toxin\u2019s mechanism of action involves a multi-step process: recognition, binding, and catalysis, ultimately blocking neurotransmitter release by cleaving proteins like SNAP-25, VAMP, and syntaxin. This disruption in synaptic vesicle fusion causes paralysis, typically in peripheral neurons. However, emerging evidence suggests that BoNT also affects the central nervous system (CNS), influencing presynaptic functions and distant neuronal systems. The evolutionary history of BoNT reveals that its neurotoxic properties likely provided a selective advantage in certain ecological contexts. Interestingly, the very features that make BoNT a potent toxin also enable its therapeutic applications, offering precision in treating neurological disorders like dystonia, spasticity, and chronic pain. In this review, we highlight the toxin\u2019s structural, functional, and evolutionary aspects, explore its clinical uses, and identify key research gaps, such as BoNT\u2019s central effects and its long-term cellular impact. A clear understanding of these aspects could facilitate the representation of BoNT as a unique scientific paradigm for studying neuronal processes and developing targeted therapeutic strategies.<\/jats:p>","DOI":"10.3390\/ijms26020777","type":"journal-article","created":{"date-parts":[[2025,1,20]],"date-time":"2025-01-20T12:32:52Z","timestamp":1737376372000},"page":"777","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["Botulinum Toxin: A Comprehensive Review of Its Molecular Architecture and Mechanistic Action"],"prefix":"10.3390","volume":"26","author":[{"given":"Raj","family":"Kumar","sequence":"first","affiliation":[{"name":"Botulinum Research Center, Institute of Advanced Sciences, Dartmouth, MA 02747, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bal Ram","family":"Singh","sequence":"additional","affiliation":[{"name":"Botulinum Research Center, Institute of Advanced Sciences, Dartmouth, MA 02747, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1016\/j.resmic.2014.09.007","article-title":"Historical and current perspectives on Clostridium botulinum diversity","volume":"166","author":"Smith","year":"2015","journal-title":"Res. Microbiol."},{"key":"ref_2","first-page":"1","article-title":"Genetic diversity within Clostridium botulinum serotypes, botulinum neurotoxin gene clusters and toxin subtypes","volume":"364","author":"Hill","year":"2013","journal-title":"Curr. Top. Microbiol. Immunol."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Goparlakrishnakone, P. (2015). Evolutionary traits of toxins. Biological Toxins and Bioterrorism, Springer.","DOI":"10.1007\/978-94-007-6645-7"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1082","DOI":"10.1101\/gr.6282807","article-title":"Genome sequence of a proteolytic (Group I) Clostridium botulinum strain Hall A and comparative analysis of the clostridial genomes","volume":"17","author":"Sebaihia","year":"2007","journal-title":"Genome Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1128\/jb.165.1.21-27.1986","article-title":"Cloning, nucleotide sequencing and expression of tetanus toxin fragment C in Eschericia coli","volume":"165","author":"Fairweather","year":"1986","journal-title":"J. Bacteriol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Hill, K.K., Xie, G., Foley, B.T., Smith, T.J., Munk, A.C., Bruce, D., Smith, L.A., Brettin, T.S., and Detter, J.C. (2009). Recombination and insertion events involving the botulinum neurotoxin complex genes in Clostridium botulinum types A, B, E and F and Clostridium butyricumtype E strains. BMC Biol., 7.","DOI":"10.1186\/1741-7007-7-66"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1023\/A:1022590514771","article-title":"A Protease-Resistant Novel Hemagglutinin Purified from Type A Clostridium botulinum","volume":"17","author":"Fu","year":"1998","journal-title":"J Protein Chem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1007\/s10930-013-9465-6","article-title":"Molecular composition and extinction coefficient of native botulinum neurotoxin complex produced by Clostridium botulinum hall A strain","volume":"32","author":"Bryant","year":"2013","journal-title":"Protein J."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1589","DOI":"10.1128\/iai.64.5.1589-1594.1996","article-title":"Molecular composition of Clostridium botulinum type A progenitor toxins","volume":"64","author":"Inoue","year":"1996","journal-title":"Infect. Immun."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1475","DOI":"10.1099\/mic.0.27801-0","article-title":"Characterization of the interaction between subunits of the botulinum toxin complex produced by serotype D through tryptic susceptibility of the isolated components and complex forms","volume":"151","author":"Suzuki","year":"2005","journal-title":"Microbiology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1007\/s10930-008-9151-2","article-title":"Subunit stoichiometry of the Clostridium botulinum type A neurotoxin complex determined using denaturing capillary electrophoresis","volume":"27","author":"Lietzow","year":"2008","journal-title":"Protein J."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1126\/science.1214270","article-title":"Botulinum neurotoxin is shielded by NTNHA in an interlocked complex","volume":"335","author":"Gu","year":"2012","journal-title":"Science"},{"key":"ref_13","first-page":"21","article-title":"Assembly and function of the botulinum neurotoxin progenitor complex","volume":"364","author":"Gu","year":"2013","journal-title":"Curr. Top. Microbiol. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Lee, K., Gu, S., Jin, L., Le, T.T.N., Cheng, L.W., Strotmeier, J., Kruel, A.M., Yao, G., Perry, K., and Rummel, A. (2013). Structure of a bimodular botulinum neurotoxin complex provides insights into its oral toxicity. PLOS Pathog., 9.","DOI":"10.1371\/journal.ppat.1003690"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"5630","DOI":"10.1073\/pnas.1222139110","article-title":"Molecular assembly of botulinum neurotoxin progenitor complexes","volume":"110","author":"Benefield","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Nowakowska, M.B., Douillard, F.P., and Lindstr\u00f6m, M. (2019). Looking for the X Factor in Bacterial Pathogenesis: Association of orfX-p47 Gene Clusters with Toxin Genes in Clostridial and Non-Clostridial Bacterial Species. Toxins, 12.","DOI":"10.3390\/toxins12010019"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1099\/00221287-147-4-811","article-title":"Clostridium botulinum type A haemagglutinin positive progenitor toxin (HA+-PTX) binds to oligosaccharides containing Galb1-4GlcNAc through one subcomponent of haemagglutinin (HA1)","volume":"147","author":"Inoue","year":"2001","journal-title":"Microbiology"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2533","DOI":"10.1099\/00221287-145-9-2533","article-title":"Characterization of haemagglutinin activity of Clostridium botulinum type C and D 16S toxins, and one subcomponent of haemagglutinin (HA1)","volume":"145","author":"Inoue","year":"1999","journal-title":"Microbiology"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1529","DOI":"10.1099\/mic.0.26805-0","article-title":"Molecular characterization of binding subcomponents of Clostridium botulinum type C progenitor toxin for intestinal epithelial cells and erythrocytes","volume":"150","author":"Fujinaga","year":"2004","journal-title":"Microbiolo"},{"key":"ref_20","first-page":"35617","article-title":"Crystal structure of Clostridium botulinum whole hemagglutinin reveals a huge riskelion-shaped molecular complex","volume":"288","author":"Amatsu","year":"2013","journal-title":"Microbiology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1023\/A:1020691215056","article-title":"Molecular properties of a hemagglutinin purified from type A Clostridium botulinum","volume":"18","author":"Sharma","year":"1999","journal-title":"J. Protein Chem."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Ghosal, K.J., Patel, K., Singh, B.R., and Hale, M.L. (2018). Role of critical elements in botulinum neurotoxin complex in toxin routing across intestinal and bronchial barriers. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0199524"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3781","DOI":"10.1002\/1873-3468.12889","article-title":"Crystal structures of OrfX2 and P47 from a Botulinum neurotoxin OrfX-type gene cluster","volume":"591","author":"Gustafsson","year":"2017","journal-title":"FEBS Lett."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1002\/1873-3468.14576","article-title":"Crystal structures of OrfX1, OrfX2 and the OrfX1-OrfX3 complex from the orfX gene cluster of botulinum neurotoxin E1","volume":"597","author":"Gao","year":"2023","journal-title":"FEBS Lett."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1128\/iai.17.3.491-496.1977","article-title":"Intestinal absorption of botulinum toxins of different molecular sizes in rats","volume":"17","author":"Sugii","year":"1977","journal-title":"Infect. Immun."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"910","DOI":"10.1128\/iai.16.3.910-914.1977","article-title":"Correlation between oral toxicity and in vitro stability of Clostridium botulinum type A and B toxins of different molecular sizes","volume":"16","author":"Sugii","year":"1977","journal-title":"Infect. Immun."},{"key":"ref_27","first-page":"375","article-title":"Receptor-mediated transcytosis of botulinum neurotoxin A through intestinal cell monolayers","volume":"10","author":"Couesnon","year":"2007","journal-title":"Cell. Microbiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1016\/j.bbrc.2004.04.183","article-title":"The receptor and transporter for internalization of Clostridium botulinum type C progenitor toxin into HT-29 cells","volume":"319","author":"Nishikawa","year":"2004","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1111\/j.1462-5822.2008.01253.x","article-title":"Differential entry of botulinum neurotoxin A into neuronal and intestinal cells","volume":"11","author":"Couesnon","year":"2009","journal-title":"Cell. Microbiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"21950","DOI":"10.1074\/jbc.273.34.21950","article-title":"Binding and transcytosis of botulium neurotoxin by polarized human colon carcinoma cells","volume":"273","author":"Maksymowych","year":"1998","journal-title":"J. Biol. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Phan, Q.T., Myers, C.L., Fu, Y., Sheppard, D.C., Yeaman, M.R., Welch, W.H., Ibrahim, A.S., Edwards, J.E., and Filler, S.G. (2007). Als3 is a Candida albicans invasin that binds to cadherins and induces endocytosis by host cells. PLoS Biol., 5.","DOI":"10.1371\/journal.pbio.0050064"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"34","DOI":"10.4161\/cam.5.1.13574","article-title":"The botulinum toxin complex meets E-cadherin on the way to its destination","volume":"5","author":"Sugawar","year":"2010","journal-title":"Cell Adhes. Migr."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1126\/science.277.5328.949","article-title":"Conversion by Payer\u2019s patche lymphocyte of human enterocytes into M cells that transport bacteria","volume":"277","author":"Kerneis","year":"1997","journal-title":"Science"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2177","DOI":"10.1099\/0022-1317-83-9-2177","article-title":"Poliovirus transcytosis through M-like cells","volume":"83","author":"Ouzilou","year":"2002","journal-title":"J. Gen. Virol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1504\/TBJ.2010.039113","article-title":"Differential entry of Botulinum neurotoxin A into neuronal and intestinal cells: An ultrastructural approach","volume":"1","author":"Couesnon","year":"2011","journal-title":"Botulinum J."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Connan, C., Voillequin, M., Chavez, C.V., Mazuet, C., Leveque, C., Vitry, S., Vandewalle, A., and Popoff, M.R. (2017). Botulinum neurotoxin type B uses a distinct entry pathway mediated by CDC42 into intestinal cells versus neuronal cells. Cell. Microbiol., 19.","DOI":"10.1111\/cmi.12738"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.toxicon.2017.10.020","article-title":"Translocation and dissemination of botulinum neurotoxin from the intestinal tract","volume":"147","author":"Fujinaga","year":"2018","journal-title":"Toxicon"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3689","DOI":"10.1523\/JNEUROSCI.0375-08.2008","article-title":"Long-distance retrograde effects of botulinum neurotoxin A","volume":"28","author":"Antonucci","year":"2008","journal-title":"J. Neurosci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"15650","DOI":"10.1523\/JNEUROSCI.2618-11.2011","article-title":"Evidence for anterograde transport and transcytosis of botulinum neurotoxin a (BoNT\/A)","volume":"31","author":"Restani","year":"2011","journal-title":"J. Neurosci."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Restani, L., Giribaldi, F., Manich, M., Bercsenyi, K., Menendez, G., Rossetto, O., Caleo, M., and Schiavo, G. (2012). Botulinum neurotoxins A and E undergo retrograde axonal transport in primary motor neurons. PLoS Pathog., 8.","DOI":"10.1371\/journal.ppat.1003087"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.toxicon.2013.02.014","article-title":"The life history of a botulinum toxin molecule","volume":"68","author":"Simpson","year":"2013","journal-title":"Toxicon"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1152\/physrev.2000.80.2.717","article-title":"Neurotoxins affecting neuroexocytosis","volume":"80","author":"Schiavo","year":"2000","journal-title":"Physiol. Rev."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1146\/annurev.biochem.051908.125345","article-title":"Botulinum neurotoxin: A marvel of protein design","volume":"79","author":"Montal","year":"2010","journal-title":"Annu. Rev. Biochem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"6876","DOI":"10.1523\/JNEUROSCI.22-16-06876.2002","article-title":"Complex gangliosides at the neuromuscular junction are membrane receptors for autoantibodies and botulinum neurotoxin","volume":"22","author":"Bullens","year":"2002","journal-title":"J. Neurosci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"32815","DOI":"10.1074\/jbc.M205258200","article-title":"Botulinum neurotoxin A activity is dependent upon the presence of specific gangliosides in neuroblastoma cells expressing synaptotagmin I","volume":"277","author":"Yowler","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.bbadis.2005.04.005","article-title":"Different response of the knockout mice lacking \u03b2-series gangliosides against botulinum and tetanus toxins","volume":"1741","author":"Kitamura","year":"2005","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1073\/pnas.0609713104","article-title":"Identification of the protein receptor binding site of botulinum neurotoxins B and G proves the double-receptor concept","volume":"104","author":"Rummel","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"35164","DOI":"10.1074\/jbc.M507596200","article-title":"Binding of Clostridium botulinum type C and D neurotoxins to ganglioside and phospholipid: Novel insights into the receptor for clostridial neurotoxins","volume":"280","author":"Tsukamoto","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1152\/physrev.00033.2013","article-title":"Sialic acids in the brain: Gangliosides and polysialic acid in nervous system development, stability, disease, and regeneration","volume":"94","author":"Schnaar","year":"2014","journal-title":"Physiol. Rev."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1016\/bs.pmbts.2018.03.001","article-title":"Gangliosides in axon stability and regeneration","volume":"156","author":"Lopez","year":"2018","journal-title":"Prog. Mol. Biol. Trans. Sci."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.toxicon.2020.02.006","article-title":"Neuronal selectivity of botulinum neurotoxins","volume":"178","author":"Poulain","year":"2020","journal-title":"Toxicon"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"10498","DOI":"10.1016\/S0021-9258(17)34087-5","article-title":"Identification of protein receptor for Clostridium botulinum type B neurotoxin in rat brain synaptosomes","volume":"269","author":"Nishiki","year":"1994","journal-title":"J. Biol. Chem."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2011","DOI":"10.1016\/j.febslet.2006.02.074","article-title":"The synaptic vesicle protein 2C mediates the uptake of botulinum neurotoxin A into phrenic nerves","volume":"580","author":"Mahrhold","year":"2006","journal-title":"FEBS Lett."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"5226","DOI":"10.1091\/mbc.e08-07-0765","article-title":"Glycosylated SV2A and SV2B mediate the entry of botulinum neurotoxin E into neurons","volume":"19","author":"Dong","year":"2008","journal-title":"Mol. Biol. Cell"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1942","DOI":"10.1111\/j.1471-4159.2009.06298.x","article-title":"Botulinum neurotoxins C, E and F bind ganglioside via a conserved binding site prior to stimulation-deendent uptake with botulinum neurotoxin F utilisig the three isoforms of SV2 as second receptor","volume":"110","author":"Rummel","year":"2009","journal-title":"J. Neurochem."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Peng, L., Tepp, W.H., Johnson, E.A., and Dong, M. (2011). Botulinum neurotoxin D uses synaptic vesicle protein SV2 and gangliosides as receptors. PLos Pathog., 7.","DOI":"10.1371\/journal.ppat.1002008"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"30865","DOI":"10.1074\/jbc.M403945200","article-title":"Synaptotagmins I and II act as nerve cell receptors for botulinum neurotoxin G","volume":"279","author":"Rummel","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"40806","DOI":"10.1074\/jbc.M112.404244","article-title":"Botulinum neurotoxin serotype C associates with dual ganglioside receptors to facilitate cell entry","volume":"287","author":"Karalewitz","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Wang, J., Meng, J., Nugent, M., Tang, M., and Dolly, J.O. (2017). Neuronal entry and high neurotoxicity of botulinum neurotoxin A require its N-terminal binding sub-domain. Sci. Rep., 7.","DOI":"10.1038\/srep44474"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1007\/s12035-013-8423-9","article-title":"Botulinum neurotoxin type A is internalized and translocated from small synaptic vesicles at the neuromuscular junction","volume":"48","author":"Colasante","year":"2013","journal-title":"Mol. Neurobiol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"18098","DOI":"10.1073\/pnas.1908051116","article-title":"Gangliosides interact with synaptotagmin to form the high-affinity receptor complex for botulinum neurotoxin B","volume":"116","author":"Flores","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/0304-3940(96)12557-X","article-title":"Binding of botulinum type B neurotoxin to Chinese hamster ovary cells transfected with rat synaptotagmin II cDNA","volume":"208","author":"Nishiki","year":"1996","journal-title":"Neurosci. Lett."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1293","DOI":"10.1083\/jcb.200305098","article-title":"Synaptotagmins I and II mediate entry of botulinum neurotoxin B into cells","volume":"162","author":"Dong","year":"2003","journal-title":"J. Cell Biol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"2058","DOI":"10.1038\/ncomms3058","article-title":"Structure of dual receptor binding to botulinum neurotoxin B","volume":"4","author":"Berntsson","year":"2013","journal-title":"Nat. Commun."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"NS20180058","DOI":"10.1042\/NS20180058","article-title":"Therapeutic use of botulinum toxin in pain treatment","volume":"2","author":"Kumar","year":"2018","journal-title":"Neuronal Signal."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"H2627","DOI":"10.1152\/ajpheart.00477.2002","article-title":"Botulinum neurotoxin A attenuates release of norepinephrine but not NPY from vasoconstrictor neurons","volume":"283","author":"Morris","year":"2002","journal-title":"Am. J. Physiol. Circ. Physiol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1016\/j.jaad.2004.07.030","article-title":"Sweat gland morphology and periglandular innervation in essential palmar hyperhidrosis before and after treatment with intradermal botulinum toxin","volume":"51","author":"Swartling","year":"2004","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1124\/pr.116.012658","article-title":"Biological actions of botulinum neurotoxins","volume":"69","author":"Pirazzini","year":"2017","journal-title":"Pharmacol. Rev."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"2617","DOI":"10.1046\/j.1460-9568.1998.00270.x","article-title":"Presynaptic protein interactions in vivo: Evidence from botulinum A, C, D and E action at frog neuromuscular junction","volume":"10","author":"Raciborska","year":"1998","journal-title":"Eur. J. Neurosci."},{"key":"ref_70","first-page":"684","article-title":"Microarray analysis of diffentially regulated genes in neuronal and epithelial cell lines upon exposure to type A botulinum neurotoxin","volume":"405","author":"Thirunavukkarasu","year":"2011","journal-title":"BBRC"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1011","DOI":"10.1111\/bjd.16080","article-title":"The non-neuronal and neuromuscular effects of botulinum toxin: An opportunity for a deadly molecule to treat disease in skin and beyond","volume":"178","author":"Grando","year":"2018","journal-title":"Br. J. Dermatol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.1086\/444507","article-title":"Botulism","volume":"41","author":"Sobel","year":"2005","journal-title":"Clin. Infect. Dis."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.toxicon.2017.10.010","article-title":"The binding of botulinum neurotoxins to different peripheral neurons","volume":"147","author":"Rossetto","year":"2018","journal-title":"Toxicon"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1124\/pr.116.012658","article-title":"Botulinum Neurotoxins: Biology, Pharmacology, and Toxicology","volume":"69","author":"Pirazzini","year":"2017","journal-title":"Pharmacol. Rev."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1097\/PHM.0b013e318168d36c","article-title":"Influence of botulinum toxin type A treatment of elbow flexor spasticity on hemiparetic gait","volume":"87","author":"Esquenazi","year":"2008","journal-title":"Am. J. Phys. Med. Rehabil."},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Weise, D., Weise, C.M., and Naumann, M. (2019). Central effects of botulinum neurotoxin\u2014Evidence from Human studies. Toxins, 11.","DOI":"10.3390\/toxins11010021"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1016\/S0896-6273(04)00077-7","article-title":"SNAP-25 modulation of calcium dynamics underlies differences in GABAergic and glutamatergic responsiveness to depolarization","volume":"41","author":"Verderio","year":"2004","journal-title":"Neuron"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1315","DOI":"10.1016\/j.toxicon.2010.07.015","article-title":"Effects of A2 type botulinum toxin on spontaneous miniature and evoked transmitter release from the rat spinal excitatory and inhibitory synapses","volume":"56","author":"Akaike","year":"2010","journal-title":"Toxicon"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.1111\/j.1600-0854.2012.01369.x","article-title":"Botulinum neurotoxin a impairs neurotransmission following retrograde transynaptic transport","volume":"13","author":"Restani","year":"2012","journal-title":"Traffic"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.toxicon.2017.10.027","article-title":"Direct central nervous system effects of botulinum neurotoxin","volume":"147","author":"Caleo","year":"2018","journal-title":"Toxicon"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1251","DOI":"10.1097\/01.wnr.0000230500.03330.01","article-title":"White matter abnormalities in dystonia normalize after botulinum toxin treatment","volume":"17","author":"Blood","year":"2006","journal-title":"NeuroReport"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1016\/j.nbd.2014.10.013","article-title":"Dynamic cortical gray matter volume changes after botulinum toxin in cervical dystonia","volume":"73","author":"Delnooz","year":"2015","journal-title":"Neurobiol. Dis."},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Alexandru, H., Muthuraman, M., Chirumamilla, V.C., Koirala, N., Paktas, B., Deuschl, G., Zeuner, K.E., and Groppa, S. (2016). Grey Matter Microstructural Integrity Alterations in Blepharospasm Are Partially Reversed by Botulinum Neurotoxin Therapy. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0168652"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1016\/S0022-510X(97)00151-2","article-title":"The mechanism of action of Botulinum toxin type A in focal dystonia is most probably through its dual effect on efferent (motor) and afferent pathways at the injected site","volume":"152","author":"Giladi","year":"1997","journal-title":"J. Neurol. Sci."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"S60","DOI":"10.1002\/mds.20011","article-title":"Central Effects of Botulinum Toxin Type A: Evidence and Supposition","volume":"19","author":"Trompetto","year":"2004","journal-title":"Mov. Disord."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1016\/j.pbb.2009.08.012","article-title":"Central origin of the antinociceptive action of botulinum toxin type A","volume":"94","year":"2009","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_87","doi-asserted-by":"crossref","unstructured":"Filipovi\u0107, B., Matak, I., Bach-Rojecky, L., and Lackovi\u0107, 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.","DOI":"10.1371\/journal.pone.0029803"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1516","DOI":"10.1016\/j.pain.2014.04.027","article-title":"Botulinum toxin type A selectivity for certain types of pain is associated with capsaicin-sensitive neurons","volume":"155","author":"Matak","year":"2014","journal-title":"Pain"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"2627","DOI":"10.1007\/s00221-018-5322-3","article-title":"Changes in sensorimotor network activation after botulinum toxin type A injections in patients with cervical dystonia: A functional MRI study","volume":"236","author":"Hok","year":"2018","journal-title":"Exp. Brain Res."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1496","DOI":"10.1002\/mds.23497","article-title":"Botulinum toxin modulates basl ganglia but not deficient somatosensory activation in orofacial dystonia","volume":"26","author":"Dresel","year":"2011","journal-title":"Mov. Disord."},{"key":"ref_91","doi-asserted-by":"crossref","unstructured":"Delnooz, C.C.S., Pasman, J.W., Beckmann, C.F., and van de Warrenburg, B.P.C. (2013). Task-Free Functional MRI in Cervical Dystonia Reveals Multi-Network Changes That Partially Normalize with Botulinum Toxin. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0062877"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1007\/s00429-013-0671-y","article-title":"Altered striatal and pallidal connectivity in cervical dystonia","volume":"220","author":"Delnooz","year":"2015","journal-title":"Brain Struct. Funct."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"101792","DOI":"10.1016\/j.nicl.2019.101792","article-title":"Cause or effect: Altered brain network activity in cervical dystonia is partially normalized by botulinum toxin treatment","volume":"22","author":"Brodoehl","year":"2019","journal-title":"Neuroimage Clin."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"2856","DOI":"10.1007\/s11064-020-03133-9","article-title":"Intramuscular injection of BOTOX\u2000 boosts learning and memory in adult mice in association with enriched circulation of platelets and enhanced density of pyramidal neurons in the Hippocampus","volume":"45","author":"Yesudhas","year":"2020","journal-title":"Neurochem. Res."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1111\/bju.13163","article-title":"Retrograde transport of radiolabelled botulinum neurotoxin type A to the CNS after intradetrusor inejection in rats","volume":"117","author":"Papagiannopoulou","year":"2016","journal-title":"BJU Int."},{"key":"ref_96","doi-asserted-by":"crossref","unstructured":"Luvisetto, S. (2021). Botulinum Neurotoxins in Central Nervous System: An Overview from Animal Models to Human Therapy. Toxins, 13.","DOI":"10.3390\/toxins13110751"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"98","DOI":"10.3389\/fneur.2014.00098","article-title":"Spinal Central Effects of Peripherally Applied BotulinumNeurotoxin A in Comparison between Its Subtypes A1 and A2","volume":"5","author":"Koizumi","year":"2014","journal-title":"Front. Neurol"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1213\/ANE.0b013e3181ffa1d7","article-title":"Intrathecal administration of botulinum neurotoxin type A attenuates formalin-induced nociceptive responses in mice","volume":"112","author":"Lee","year":"2011","journal-title":"Anesth. Analg."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1480","DOI":"10.1002\/ejp.513","article-title":"Intrathecal administration of botulinum toxin type A improves urinary bladder function and reduces pain in rats with cystitis","volume":"18","author":"Coelho","year":"2014","journal-title":"Eur. J. Pain"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"1403","DOI":"10.1007\/s00702-016-1605-7","article-title":"Antinociceptive action of botulinum toxin type A in carrageenan-induced mirror pain","volume":"123","author":"Vlah","year":"2016","journal-title":"J. Neural Transm."},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"Huang, P.P., Khan, I., Suhail, M.S.A., Malkmus, S., and Yaksh, T.L. (2011). Spinal botulinum neurotoxin B: Effects on afferent transmitter release and nociceptive processing. PLoS ONE, 6.","DOI":"10.1371\/annotation\/1fe31fa2-e930-4a72-a208-64eb42d99f02"},{"key":"ref_102","doi-asserted-by":"crossref","unstructured":"Antipova, V., Wree, A., Holzmann, C., Mann, T., Palomero-Gallagher, N., Zilles, K., Schmitt, O., and Hawlitschka, A. (2018). UnilateralBotulinum Neurotoxin-A Injection into the Striatum of C57BL\/6 Mice Leads to a Different Motor Behavior Compared with Rats. Toxins, 10.","DOI":"10.3390\/toxins10070295"},{"key":"ref_103","doi-asserted-by":"crossref","unstructured":"Antipova, V., Holzmann, C., Hawlitschka, A., and Wree, A. (2019). Botulinum Neurotoxin-A Injected Intrastriatally into Hemiparkinsonian Rats Improves the Initiation Time for Left and Right Forelimbs in Both Forehand and Backhand Directions. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20040992"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"368","DOI":"10.3390\/toxins10090368","article-title":"Repeated Intrastriatal Botulinum Neurotoxin-A Injection in Hemiparkinsonian Rats Increased the Beneficial Effect on Rotational Behavior","volume":"10","author":"Hawlitschka","year":"2018","journal-title":"Toxins"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1002\/jnr.10443","article-title":"Animal model of dementia induced by entorhinal synaptic damage and partial restoration of cognitive deficits by BDNF and carnitine","volume":"70","author":"Ando","year":"2002","journal-title":"J. Neurosci. 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