Botulinum neurotoxins: Biology, pharmacology, and toxicology

Pharmacological Reviews

Volumn 69, Issue 2, 2017, Pages 200-235

  Pirazzini, Marco ^a   Rossetto, Ornella ^a   Eleopra, Roberto ^b   Montecucco, Cesare ^a  

^a UNIVERSITY OF PADOVA   (Italy)

^b SANTA MARIA DELLA MISERICORDIA UNIVERSITY HOSPITAL   (Italy)

Author keywords

[No Author keywords available]

Indexed keywords

BOTULINUM TOXIN; DISULFIDE; SNARE PROTEIN; NEUROTOXIN;

AUTONOMIC DYSFUNCTION; CHEMICAL STRUCTURE; DEPRESSION; DYSTONIC DISORDER; HUMAN; IMMUNOGENICITY; INTERNALIZATION; NERVE ENDING; NERVE PARALYSIS; NEUROPATHIC PAIN; NONHUMAN; PAIN; PARALYSIS; PREGNANCY; PRIMARY HEADACHE; PRIORITY JOURNAL; PROTEIN CLEAVAGE; PROTEIN DEGRADATION; PROTEIN PROTEIN INTERACTION; REDUCTION (CHEMISTRY); REVIEW; SPASTICITY; TOXIN STRUCTURE; URINARY TRACT DISEASE; ANIMAL;

ANIMALS; BOTULINUM TOXINS; HUMANS; NEUROTOXINS;

EID: 85016629565     PISSN: 00316997     EISSN: 15210081     Source Type: Journal    
DOI: 10.1124/pr.116.012658     Document Type: Review

References (425)

1. Adler M, Keller JE, Sheridan RE, and Deshpande SS (2001) Persistence of botulinum neurotoxin A demonstrated by sequential administration of serotypes A and E in rat EDL muscle. Toxicon 39:233–243.
2. Agarwal R, Schmidt JJ, Stafford RG, and Swaminathan S (2009) Mode of VAMP substrate recognition and inhibition of Clostridium botulinum neurotoxin F. Nat Struct Mol Biol 16:789–794.
3. Ahmed SA, Byrne MP, Jensen M, Hines HB, Brueggemann E, and Smith LA (2001) Enzymatic autocatalysis of botulinum A neurotoxin light chain. J Protein Chem 20: 221–231.
4. Albanese A (2011) Terminology for preparations of botulinum neurotoxins: what a difference a name makes. JAMA 305:89–90.
5. Albanese A and Lalli S (2009) Is this dystonia? Mov Disord 24:1725–1731.
6. Albanese A and Lalli S (2012) Update on dystonia. Curr Opin Neurol 25:483–490.
7. Amatsu S, Sugawara Y, Matsumura T, Kitadokoro K, and Fujinaga Y (2013) Crystal structure of Clostridium botulinum whole hemagglutinin reveals a huge triskelion-shaped molecular complex. J Biol Chem 288:35617–35625.
8. Antonucci F, Rossi C, Gianfranceschi L, Rossetto O, and Caleo M (2008) Longdistance retrograde effects of botulinum neurotoxin A. J Neurosci 28:3689–3696.
9. Aoki KR (2001) A comparison of the safety margins of botulinum neurotoxin serotypes A, B, and F in mice. Toxicon 39:1815–1820.
10. Apostolidis A, Popat R, Yiangou Y, Cockayne D, Ford AP, Davis JB, Dasgupta P, Fowler CJ, and Anand P (2005) Decreased sensory receptors P2X3 and TRPV1 in suburothelial nerve fibers following intradetrusor injections of botulinum toxin for human detrusor overactivity. J Urol 174:977–982, discussion 982–983.
11. Argoff CE (2002) A focused review on the use of botulinum toxins for neuropathic pain. Clin J Pain 18(Suppl 6)S177–S181.
12. Arnér ES and Holmgren A (2000) Physiological functions of thioredoxin and thioredoxin reductase. Eur J Biochem 267:6102–6109.
13. Arnon SS, Schechter R, Inglesby TV, Henderson DA, Bartlett JG, Ascher MS, Eitzen E, Fine AD, Hauer J, Layton M, et al.; Working Group on Civilian Biodefense (2001) Botulinum toxin as a biological weapon: medical and public health management. JAMA 285:1059–1070.
14. Arsenault J, Cuijpers SAG, Ferrari E, Niranjan D, Rust A, Leese C, O’Brien JA, Binz T, and Davletov B (2014) Botulinum protease-cleaved SNARE fragments induce cytotoxicity in neuroblastoma cells. J Neurochem 129:781–791.
15. Atassi MZ (2004) Basic immunological aspects of botulinum toxin therapy. Mov Disord 19 (Suppl 8):S68–S84.
16. Atassi MZ, Jankovic J, Steward LE, Aoki KR, and Dolimbek BZ (2012) Molecular immune recognition of botulinum neurotoxin B. The light chain regions that bind human blocking antibodies from toxin-treated cervical dystonia patients. Antigenic structure of the entire BoNT/B molecule. Immunobiology 217:17–27.
17. Attal N, de Andrade DC, Adam F, Ranoux D, Teixeira MJ, Galhardoni R, Raicher I, Üçeyler N, Sommer C, and Bouhassira D (2016) Safety and efficacy of repeated injections of botulinum toxin A in peripheral neuropathic pain (BOTNEP): a randomised, double-blind, placebo-controlled trial. Lancet Neurol 15:555–565.
18. Azarnia Tehran D, Pirazzini M, Leka O, Mattarei A, Lista F, Binz T, Rossetto O, and Montecucco C (2017) Hsp90 is involved in the entry of clostridial neurotoxins into the cytosol of nerve terminals. Cell Microbiol 19:e12647.
19. Azarnia Tehran D, Zanetti G, Leka O, Lista F, Fillo S, Binz T, Shone CC, Rossetto O, Montecucco C, Paradisi C, et al. (2015) A novel inhibitor prevents the peripheral neuroparalysis of botulinum neurotoxins. Sci Rep 5:17513.
20. Bade S, Rummel A, Reisinger C, Karnath T, Ahnert-Hilger G, Bigalke H, and Binz T (2004) Botulinum neurotoxin type D enables cytosolic delivery of enzymatically active cargo proteins to neurones via unfolded translocation intermediates. J Neurochem 91:1461–1472.
21. Band PA, Blais S, Neubert TA, Cardozo TJ, and Ichtchenko K (2010) Recombinant derivatives of botulinum neurotoxin A engineered for trafficking studies and neuronal delivery. Protein Expr Purif 71:62–73.
22. Benefield DA, Dessain SK, Shine N, Ohi MD, and Lacy DB (2013) Molecular assembly of botulinum neurotoxin progenitor complexes. Proc Natl Acad Sci USA 110:5630–5635.
23. Bennett MK, Calakos N, and Scheller RH (1992) Syntaxin: a synaptic protein implicated in docking of synaptic vesicles at presynaptic active zones. Science 257:255–259.
24. Benoit RM, Frey D, Hilbert M, Kevenaar JT, Wieser MM, Stirnimann CU, McMillan D, Ceska T, Lebon F, Jaussi R, et al. (2014) Structural basis for recognition of synaptic vesicle protein 2C by botulinum neurotoxin A. Nature 505:108–111.
25. Bentivoglio AR, Del Grande A, Petracca M, Ialongo T, and Ricciardi L (2015) Clinical differences between botulinum neurotoxin type A and B. Toxicon 107 (Pt A):77–84.
26. Bentivoglio AR, Fasano A, Ialongo T, Soleti F, Lo Fermo S, and Albanese A (2009) Outcome predictors, efficacy and safety of Botox and Dysport in the long-term treatment of hemifacial spasm. Eur J Neurol 16:392–398.
27. Bercsenyi K, Schmieg N, Bryson JB, Wallace M, Caccin P, Golding M, Zanotti G, Greensmith L, Nischt R, and Schiavo G (2014) Tetanus toxin entry. Nidogens are therapeutic targets for the prevention of tetanus. Science 346:1118–1123.
28. Berliocchi L, Fava E, Leist M, Horvat V, Dinsdale D, Read D, and Nicotera P (2005) Botulinum neurotoxin C initiates two different programs for neurite degeneration and neuronal apoptosis. J Cell Biol 168:607–618.
29. Berntsson RP, Peng L, Dong M, and Stenmark P (2013a) Structure of dual receptor binding to botulinum neurotoxin B. Nat Commun 4:2058.
30. Berntsson RP, Peng L, Svensson LM, Dong M, and Stenmark P (2013b) Crystal structures of botulinum neurotoxin DC in complex with its protein receptors synaptotagmin I and II. Structure 21:1602–1611.
31. Beske PH, Scheeler SM, Adler M, and McNutt PM (2015) Accelerated intoxication of GABAergic synapses by botulinum neurotoxin A disinhibits stem cell-derived neuron networks prior to network silencing. Front Cell Neurosci 9:159.
32. Binz T (2013) Clostridial neurotoxin light chains: devices for SNARE cleavage mediated blockade of neurotransmission. Curr Top Microbiol Immunol 364:139–157.
33. Binz T and Rummel A (2009) Cell entry strategy of clostridial neurotoxins. J Neurochem 109:1584–1595.
34. Bird SW, Maynard ND, Covert MW, and Kirkegaard K (2014) Nonlytic viral spread enhanced by autophagy components. Proc Natl Acad Sci USA 111:13081–13086.
35. Black JD and Dolly JO (1986) Interaction of 125I-labeled botulinum neurotoxins with nerve terminals. II. Autoradiographic evidence for its uptake into motor nerves by acceptor-mediated endocytosis. J Cell Biol 103:535–544.
36. Blasi J, Chapman ER, Link E, Binz T, Yamasaki S, De Camilli P, Südhof TC, Niemann H, and Jahn R (1993a) Botulinum neurotoxin A selectively cleaves the synaptic protein SNAP-25. Nature 365:160–163.
37. Blasi J, Chapman ER, Yamasaki S, Binz T, Niemann H, and Jahn R (1993b) Botulinum neurotoxin C1 blocks neurotransmitter release by means of cleaving HPC-1/ syntaxin. EMBO J 12:4821–4828.
38. Borodic G (2007) Botulinum toxin, immunologic considerations with long-term repeated use, with emphasis on cosmetic applications. Facial Plast Surg Clin North Am 15:11–16, v.
39. Boroff DA and Fleck U (1966) Statistical analysis of a rapid in vivo method for the titration of the toxin of Clostridium botulinum. J Bacteriol 92:1580–1581.
40. Boyken J, Grønborg M, Riedel D, Urlaub H, Jahn R, and Chua JJ (2013) Molecular profiling of synaptic vesicle docking sites reveals novel proteins but few differences between glutamatergic and GABAergic synapses. Neuron 78:285–297.
41. Breidenbach MA and Brunger AT (2004) Substrate recognition strategy for botulinum neurotoxin serotype A. Nature 432:925–929.
42. Brin MF, Lew MF, Adler CH, Comella CL, Factor SA, Jankovic J, O’Brien C, Murray JJ, Wallace JD, Willmer-Hulme A, et al. (1999) Safety and efficacy of NeuroBloc (botu-linum toxin type B) in type A-resistant cervical dystonia. Neurology 53:1431–1438.
43. Brisinda G, Sivestrini N, Bianco G, and Maria G (2015) Treatment of gastrointestinal sphincters spasms with botulinum toxin A. Toxins (Basel) 7:1882–1916.
44. Brunger AT, Breidenbach MA, Jin R, Fischer A, Santos JS, and Montal M (2007) Botulinum neurotoxin heavy chain belt as an intramolecular chaperone for the light chain. PLoS Pathog 3:1191–1194.
45. Brunger AT and Rummel A (2009) Receptor and substrate interactions of clostridial neurotoxins. Toxicon 54:550–560.
46. Bullens RW, O’Hanlon GM, Wagner E, Molenaar PC, Furukawa K, Furukawa K, Plomp JJ, and Willison HJ (2002) Complex gangliosides at the neuromuscular junction are membrane receptors for autoantibodies and botulinum neurotoxin but redundant for normal synaptic function. J Neurosci 22:6876–6884.
47. Buonocore M, Demartini L, Mandrini S, Dall’Angelo A, and Dalla Toffola E (2017) Effect of Botulinum toxin on disabling neuropathic pain: A case presentation suggesting a new therapeutic strategy. PM R 9:200–203.
48. Burgen AS, Dickens F, and Zatman LJ (1949) The action of botulinum toxin on the neuro-muscular junction. J Physiol 109:10–24.
49. Caleo M and Schiavo G (2009) Central effects of tetanus and botulinum neurotoxins. Toxicon 54:593–599.
50. Callaway JE (2004) Botulinum toxin type B (Myobloc): pharmacology and biochemistry. Clin Dermatol 22:23–28.
51. Carli L, Montecucco C, and Rossetto O (2009) Assay of diffusion of different botulinum neurotoxin type a formulations injected in the mouse leg. Muscle Nerve 40:374–380.
52. Carruthers JD and Carruthers JA (1992) Treatment of glabellar frown lines with C. botulinum-A exotoxin. J Dermatol Surg Oncol 18:17–21.
53. Carruthers J, Burgess C, Day D, Fabi SG, Goldie K, Kerscher M, Nikolis A, Pavicic T, Rho NK, Rzany B, et al. (2016) Consensus recommendations for combined aesthetic interventions in the face using botulinum toxin, fillers, and energy-based devices. Dermatol Surg 42:586–597.
54. Carter DW and Ben Renfroe J (2009) A novel approach to the treatment and prevention of laminitis: botulinum toxin type A for the treatment of laminitis. J Equine Vet Sci 29:595–600.
55. Chaddock JA, Purkiss JR, Alexander FC, Doward S, Fooks SJ, Friis LM, Hall YH, Kirby ER, Leeds N, Moulsdale HJ, et al. (2004) Retargeted clostridial endopepti-dases: inhibition of nociceptive neurotransmitter release in vitro, and antinociceptive activity in in vivo models of pain. Mov Disord 19 (Suppl 8):S42–S47.
56. Chai Q, Arndt JW, Dong M, Tepp WH, Johnson EA, Chapman ER, and Stevens RC (2006) Structural basis of cell surface receptor recognition by botulinum neurotoxin B. Nature 444:1096–1100.
57. Chancellor MB, Fowler CJ, Apostolidis A, de Groat WC, Smith CP, Somogyi GT, and Aoki KR (2008) Drug Insight: biological effects of botulinum toxin A in the lower urinary tract. Nat Clin Pract Urol 5:319–328.
58. Chatla K, Gaunt PS, Hanson L, Gao DX, and Wills R (2012) Determination of the median lethal dose of botulinum serotype E in channel catfish fingerlings. J Aquat Anim Health 24:105–109.
59. Chen S (2012) Clinical uses of botulinum neurotoxins: current indications, limitations and future developments. Toxins (Basel) 4:913–939.
60. Chen S and Barbieri JT (2009) Engineering botulinum neurotoxin to extend therapeutic intervention. Proc Natl Acad Sci USA 106:9180–9184.
61. Cheng Y (2015) Single-particle cryo-em at crystallographic resolution. Cell 161:450–457.
62. Cheng T, Shuang WB, Jia DD, Zhang M, Tong XN, Yang WD, Jia XM, and Li S (2016) Efficacy and safety of onabotulinumtoxina in patients with neurogenic detrusor overactivity: A systematic review and meta-analysis of randomized controlled trials. PLoS One 11:e0159307.
63. Cherington M (1998) Clinical spectrum of botulism. Muscle Nerve 21:701–710.
64. Chertow DS, Tan ET, Maslanka SE, Schulte J, Bresnitz EA, Weisman RS, Bernstein J, Marcus SM, Kumar S, Malecki J, et al. (2006) Botulism in 4 adults following cosmetic injections with an unlicensed, highly concentrated botulinum preparation. JAMA 296:2476–2479.
65. Chuang YC, Yoshimura N, Huang CC, Wu M, Chiang PH, and Chancellor MB (2008) Intraprostatic botulinum toxin a injection inhibits cyclooxygenase-2 expression and suppresses prostatic pain on capsaicin induced prostatitis model in rat. J Urol 180: 742–748.
66. Chuang YC, Tu CH, Huang CC, Lin HJ, Chiang PH, Yoshimura N, and Chancellor MB (2006) Intraprostatic injection of botulinum toxin type-A relieves bladder outlet obstruction in human and induces prostate apoptosis in dogs. BMC Urol 6:12.
67. Coelho A, Cruz F, Cruz CD, and Avelino A (2012) Spread of onabotulinumtoxinA after bladder injection. Experimental study using the distribution of cleaved SNAP-25 as the marker of the toxin action. Eur Urol 61:1178–1184.
68. Coelho A, Oliveira R, Rossetto O, Cruz CD, Cruz F, and Avelino A (2014) Intrathecal administration of botulinum toxin type A improves urinary bladder function and reduces pain in rats with cystitis. Eur J Pain 18:1480–1489.
69. Colasante C, Rossetto O, Morbiato L, Pirazzini M, Molgó J, and Montecucco C (2013) Botulinum neurotoxin type A is internalized and translocated from small synaptic vesicles at the neuromuscular junction. Mol Neurobiol 48:120–127.
70. Collier RJ (2009) Membrane translocation by anthrax toxin. Mol Aspects Med 30: 413–422.
71. Comella CL and Pullman SL (2004) Botulinum toxins in neurological disease. Muscle Nerve 29:628–644.
72. Couesnon A, Molgó J, Connan C, and Popoff MR (2012) Preferential entry of botulinum neurotoxin A Hc domain through intestinal crypt cells and targeting to cholinergic neurons of the mouse intestine. PLoS Pathog 8:e1002583.
73. Couesnon A, Shimizu T, and Popoff MR (2009) Differential entry of botulinum neurotoxin A into neuronal and intestinal cells. Cell Microbiol 11:289–308.
74. Cousin MA (2015) Synaptic vesicle endocytosis and endosomal recycling in central nerve terminals: discrete trafficking routes? Neuroscientist 21:413–423.
75. Criado M, Gil A, Viniegra S, and Gutiérrez LM (1999) A single amino acid near the C terminus of the synaptosomeassociated protein of 25 kDa (SNAP-25) is essential for exocytosis in chromaffin cells. Proc Natl Acad Sci USA 96:7256–7261.
76. Dashtipour K and Pedouim F (2016) Botulinum toxin: Preparations for clinical use, immunogenicity, side effects, and safety profile. Semin Neurol 36:29–33.
77. de Almeida AT and De Boulle K (2007) Diffusion characteristics of botulinum neurotoxin products and their clinical significance in cosmetic applications. J Cosmet Laser Ther 9 (Suppl 1):17–22.
78. de Paiva A, Meunier FA, Molgó J, Aoki KR, and Dolly JO (1999) Functional repair of motor endplates after botulinum neurotoxin type A poisoning: biphasic switch of synaptic activity between nerve sprouts and their parent terminals. Proc Natl Acad Sci USA 96:3200–3205.
79. de Paiva A, Poulain B, Lawrence GW, Shone CC, Tauc L, and Dolly JO (1993) A role for the interchain disulfide or its participating thiols in the internalization of botulinum neurotoxin A revealed by a toxin derivative that binds to ecto-acceptors and inhibits transmitter release intracellularly. J Biol Chem 268:20838–20844.
80. Deinhardt K, Salinas S, Verastegui C, Watson R, Worth D, Hanrahan S, Bucci C, and Schiavo G (2006) Rab5 and Rab7 control endocytic sorting along the axonal retrograde transport pathway. Neuron 52:293–305.
81. Del Sorbo F and Albanese A (2015) Botulinum neurotoxins for the treatment of focal dystonias: Review of rating tools used in clinical trials. Toxicon 107 (Pt A):89–97.
82. Dolimbek BZ, Aoki KR, Steward LE, Jankovic J, and Atassi MZ (2007) Mapping of the regions on the heavy chain of botulinum neurotoxin A (BoNT/A) recognized by antibodies of cervical dystonia patients with immunoresistance to BoNT/A. Mol Immunol 44:1029–1041.
83. Dolly JO, Black J, Williams RS, and Melling J (1984) Acceptors for botulinum neurotoxin reside on motor nerve terminals and mediate its internalization. Nature 307:457–460.
84. Dolman CE and Murakami L (1961) Clostridium botulinum type F with recent observation on other types. J Infect Dis 109:107.
85. Dong M, Liu H, Tepp WH, Johnson EA, Janz R, and Chapman ER (2008) Glycosy-lated SV2A and SV2B mediate the entry of botulinum neurotoxin E into neurons. Mol Biol Cell 19:5226–5237.
86. Dong M, Richards DA, Goodnough MC, Tepp WH, Johnson EA, and Chapman ER (2003) Synaptotagmins I and II mediate entry of botulinum neurotoxin B into cells. J Cell Biol 162:1293–1303.
87. Dong M, Yeh F, Tepp WH, Dean C, Johnson EA, Janz R, and Chapman ER (2006) SV2 is the protein receptor for botulinum neurotoxin A. Science 312:592–596.
88. Dressler D (2012) Clinical applications of botulinum toxin. Curr Opin Microbiol 15: 325–336.
89. Dressler D, Adib Saberi F, and Bigalke H (2016) Botulinum toxin therapy: reduction of injection site pain by pH normalisation. J Neural Transm (Vienna) 123:527–531.
90. Dressler D and Benecke R (2004) Autonomic side effects of botulinum toxin type B therapy. Adv Neurol 94:315–320.
91. Dressler D and Bigalke H (2005) Botulinum toxin type B de novo therapy of cervical dystonia: frequency of antibody induced therapy failure. J Neurol 252:904–907.
92. Dressler D, Paus S, Seitzinger A, Gebhardt B, and Kupsch A (2013) Long-term efficacy and safety of incobotulinumtoxinA injections in patients with cervical dystonia. J Neurol Neurosurg Psychiatry 84:1014–1019.
93. Dressler D and Rothwell JC (2000) Electromyographic quantification of the paralysing effect of botulinum toxin in the sternocleidomastoid muscle. Eur Neurol 43: 13–16.
94. Dressler D, Saberi FA, Kollewe K, and Schrader C (2015) Safety aspects of incobotulinumtoxinA high-dose therapy. J Neural Transm (Vienna) 122:327–333.
95. Duchen LW (1971) An electron microscopic study of the changes induced by botulinum toxin in the motor end-plates of slow and fast skeletal muscle fibres of the mouse. J Neurol Sci 14:47–60.
96. Duff JT, Wright GG, Klerer J, Moore DE, and Bibler RH (1957a) Studies on immunity to toxins of Clostridium botulinum. I. A simplified procedure for isolation of type A toxin. J Bacteriol 73:42–47.
97. Duff JT, Klerer J, Bibler RH, Moore DE, Gottfried C, and Wright GG (1957b) Studies on immunity to toxins of Clostridium botulinum. II. Production and purification of type B toxin for toxoid. J Bacteriol 73:597–601.
98. Duggan MJ, Quinn CP, Chaddock JA, Purkiss JR, Alexander FC, Doward S, Fooks SJ, Friis LM, Hall YH, Kirby ER, et al. (2002) Inhibition of release of neurotransmitters from rat dorsal root ganglia by a novel conjugate of a Clostridium botulinum toxin A endopeptidase fragment and Erythrina cristagalli lectin. J Biol Chem 277:34846–34852.
99. Eisele KH, Fink K, Vey M, and Taylor HV (2011) Studies on the dissociation of botulinum neurotoxin type A complexes. Toxicon 57:555–565.
100. Eklund MW and Dowell VR (1987) Avian Botulism, Charles C Thomas, Springfield, IL.
101. Eklund MW and Poysky FT (1974) Interconversion of type C and D strains of Clostridium botulinum by specific bacteriophages. Appl Microbiol 27:251–258.
102. Eleopra R, Montecucco C, Devigili G, Lettieri C, Rinaldo S, Verriello L, Pirazzini M, Caccin P, and Rossetto O (2013) Botulinum neurotoxin serotype D is poorly effective in humans: an in vivo electrophysiological study. Clin Neurophysiol 124:999–1004.
103. Eleopra R, Tugnoli V, Quatrale R, Gastaldo E, Rossetto O, De Grandis D, and Montecucco C (2002) Botulinum neurotoxin serotypes A and C do not affect motor units survival in humans: an electrophysiological study by motor units counting. Clin Neurophysiol 113:1258–1264.
104. Eleopra R, Tugnoli V, Quatrale R, Rossetto O, and Montecucco C (2004) Different types of botulinum toxin in humans. Mov Disord 19 (Suppl 8):S53–S59.
105. Eleopra R, Tugnoli V, Quatrale R, Rossetto O, Montecucco C, and Dressler D (2006) Clinical use of non-A botulinum toxins: botulinum toxin type C and botulinum toxin type F. Neurotox Res 9:127–131.
106. Eleopra R, Tugnoli V, Rossetto O, De Grandis D, and Montecucco C (1998) Different time courses of recovery after poisoning with botulinum neurotoxin serotypes A and E in humans. Neurosci Lett 256:135–138.
107. Eleopra R, Tugnoli V, Rossetto O, Montecucco C, and De Grandis D (1997) Botulinum neurotoxin serotype C: a novel effective botulinum toxin therapy in human. Neurosci Lett 224:91–94.
108. Elferink LA, Trimble WS, and Scheller RH (1989) Two vesicle-associated membrane protein genes are differentially expressed in the rat central nervous system. J Biol Chem 264:11061–11064.
109. Esquenazi A, Albanese A, Chancellor MB, Elovic E, Segal KR, Simpson DM, Smith CP, and Ward AB (2013) Evidence-based review and assessment of botulinum neurotoxin for the treatment of adult spasticity in the upper motor neuron syndrome. Toxicon 67:115–128.
110. Eswaramoorthy S, Sun J, Li H, Singh BR, and Swaminathan S (2015) Molecular Assembly of Clostridium botulinum progenitor M complex of type E. Sci Rep 5:17795.
111. Fan Y, Barash JR, Lou J, Conrad F, Marks JD, and Arnon SS (2016) Immunological Characterization and Neutralizing Ability of Monoclonal Antibodies Directed Against Botulinum Neurotoxin Type H. J Infect Dis 213:1606–1614.
112. Fernández-Salas E, Ho H, Garay P, Steward LE, and Aoki KR (2004a) Is the light chain subcellular localization an important factor in botulinum toxin duration of action? Mov Disord 19 (Suppl 8):S23–S34.
113. Fernández-Salas E, Steward LE, Ho H, Garay PE, Sun SW, Gilmore MA, Ordas JV, Wang J, Francis J, and Aoki KR (2004b) Plasma membrane localization signals in the light chain of botulinum neurotoxin. Proc Natl Acad Sci USA 101:3208–3213.
114. Ferrari E, Maywood ES, Restani L, Caleo M, Pirazzini M, Rossetto O, Hastings MH, Niranjan D, Schiavo G, and Davletov B (2011) Re-assembled botulinum neurotoxin inhibits CNS functions without systemic toxicity. Toxins (Basel) 3:345–355.
115. Finkelstein A, Oh KJ, Senzel L, Gordon M, Blaustein RO, and Collier RJ (2000) The diphtheria toxin channel-forming T-domain translocates its own NH2-terminal region and the catalytic domain across planar phospholipid bilayers. Int J Med Microbiol 290:435–440.
116. Finzi E and Rosenthal NE (2014) Treatment of depression with onabotulinumtoxinA: a randomized, double-blind, placebo controlled trial. J Psychiatr Res 52:1–6.
117. Finzi E and Wasserman E (2006) Treatment of depression with botulinum toxin A: a case series. Dermatol Surg 32:645–649, discussion 649–650.
118. Fischer A (2013) Synchronized chaperone function of botulinum neurotoxin domains mediates light chain translocation into neurons. Curr Top Microbiol Immunol 364: 115–137.
119. Fischer A, Garcia-Rodriguez C, Geren I, Lou J, Marks JD, Nakagawa T, and Montal M (2008) Molecular architecture of botulinum neurotoxin E revealed by single particle electron microscopy. J Biol Chem 283:3997–4003.
120. Fischer A and Montal M (2007) Crucial role of the disulfide bridge between botulinum neurotoxin light and heavy chains in protease translocation across membranes. J Biol Chem 282:29604–29611.
121. Fischer A and Montal M (2013) Molecular dissection of botulinum neurotoxin reveals interdomain chaperone function. Toxicon 75:101–107.
122. Fischer A, Nakai Y, Eubanks LM, Clancy CM, Tepp WH, Pellett S, Dickerson TJ, Johnson EA, Janda KD, and Montal M (2009) Bimodal modulation of the botulinum neurotoxin protein-conducting channel. Proc Natl Acad Sci USA 106: 1330–1335.
123. Fogolari F, Tosatto SC, Muraro L, and Montecucco C (2009) Electric dipole reor-ientation in the interaction of botulinum neurotoxins with neuronal membranes. FEBS Lett 583:2321–2325.
124. Foran PG, Mohammed N, Lisk GO, Nagwaney S, Lawrence GW, Johnson E, Smith L, Aoki KR, and Dolly JO (2003) Evaluation of the therapeutic usefulness of botulinum neurotoxin B, C1, E, and F compared with the long lasting type A. Basis for distinct durations of inhibition of exocytosis in central neurons. J Biol Chem 278: 1363–1371.
125. Fowler CJ, Griffiths D, and de Groat WC (2008) The neural control of micturition. Nat Rev Neurosci 9:453–466.
126. Frevert J (2009) Xeomin: an innovative new botulinum toxin type A. Eur J Neurol 16 (Suppl 2):11–13.
127. Frevert J (2010) Content of botulinum neurotoxin in Botox®/Vistabel®, Dysport®/Azzalure®, and Xeomin®/Bocouture®. Drugs R D 10:67–73.
128. Frevert J (2015) Pharmaceutical, biological, and clinical properties of botulinum neurotoxin type A products. Drugs R D 15:1–9.
129. Fujinaga Y, Inoue K, Nomura T, Sasaki J, Marvaud JC, Popoff MR, Kozaki S, and Oguma K (2000) Identification and characterization of functional subunits of Clostridium botulinum type A progenitor toxin involved in binding to intestinal microvilli and erythrocytes. FEBS Lett 467:179–183.
130. Fujinaga Y, Inoue K, Watanabe S, Yokota K, Hirai Y, Nagamachi E, and Oguma K (1997) The haemagglutinin of Clostridium botulinum type C progenitor toxin plays an essential role in binding of toxin to the epithelial cells of guinea pig small intestine, leading to the efficient absorption of the toxin. Microbiology 143:3841–3847.
131. Fujinaga Y, Inoue K, Watarai S, Sakaguchi Y, Arimitsu H, Lee J-C, Jin Y, Matsumura T, Kabumoto Y, Watanabe T, et al. (2004) Molecular characterization of binding subcomponents of Clostridium botulinum type C progenitor toxin for intestinal epithelial cells and erythrocytes. Microbiology 150:1529–1538.
132. Fujinaga Y, Sugawara Y, and Matsumura T (2013) Uptake of botulinum neurotoxin in the intestine. Curr Top Microbiol Immunol 364:45–59.
133. Garner CG, Straube A, Witt TN, Gasser T, and Oertel WH (1993) Time course of distant effects of local injections of botulinum toxin. Mov Disord 8:33–37.
134. Gart MS and Gutowski KA (2016) Overview of botulinum toxins for aesthetic uses. Clin Plast Surg 43:459–471.
135. Gendler E and Nagler A (2015) Aesthetic use of BoNT: Options and outcomes. Toxicon 107 (Pt A):120–128.
136. Giladi N (1997) 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. J Neurol Sci 152:132–135.
137. Gill DM (1982) Bacterial toxins: a table of lethal amounts. Microbiol Rev 46:86–94.
138. Gillespie EJ, Ho C-LC, Balaji K, Clemens DL, Deng G, Wang YE, Elsaesser HJ, Tamilselvam B, Gargi A, Dixon SD, et al. (2013) Selective inhibitor of endosomal trafficking pathways exploited by multiple toxins and viruses. Proc Natl Acad Sci USA 110:E4904–E4912.
139. Gilio F, Currà A, Lorenzano C, Modugno N, Manfredi M, and Berardelli A (2000) Effects of botulinum toxin type A on intracortical inhibition in patients with dystonia. Ann Neurol 48:20–26.
140. Gilmer WS, Trivedi MH, Rush AJ, Wisniewski SR, Luther J, Howland RH, Yohanna D, Khan A, and Alpert J (2005) Factors associated with chronic depressive episodes: a preliminary report from the STAR-D project. Acta Psychiatr Scand 112: 425–433.
141. Gimber N, Tadeus G, Maritzen T, Schmoranzer J, and Haucke V (2015) Diffusional spread and confinement of newly exocytosed synaptic vesicle proteins. Nat Commun 6:8392.
142. Gomelsky A and Dmochowski RR (2014) Clinical Use of Botulinum Neurotoxin: Urogenital Disorders Including Overactive Bladder, in Clinical Applications of Botulinum Neurotoxin (Foster AK, ed) pp 123–152, Springer, NY.
143. Gordon M and Finkelstein A (2001) The number of subunits comprising the channel formed by the T domain of diphtheria toxin. J Gen Physiol 118:471–480.
144. Gracies JM (2004) Physiological effects of botulinum toxin in spasticity. Mov Disord 19 (Suppl 8):S120–S128.
145. Gracies JM, Lugassy M, Weisz DJ, Vecchio M, Flanagan S, and Simpson DM (2009) Botulinum toxin dilution and endplate targeting in spasticity: a double-blind controlled study. Arch Phys Med Rehabil 90:9–16.e2.
146. Gu S and Jin R (2013) Assembly and function of the botulinum neurotoxin progenitor complex. Curr Top Microbiol Immunol 364:21–44.
147. Gu S, Rumpel S, Zhou J, Strotmeier J, Bigalke H, Perry K, Shoemaker CB, Rummel A, and Jin R (2012) Botulinum neurotoxin is shielded by NTNHA in an interlocked complex. Science 335:977–981.
148. Gui D, Cassetta E, Anastasio G, Bentivoglio AR, Maria G, and Albanese A (1994) Botulinum toxin for chronic anal fissure. Lancet 344:1127–1128.
149. Guidubaldi A, Bentivoglio RA, and Albanese A (2014) Clinical Use of Botulinum Neurotoxin: Neuromuscular Disorders, in Clinical Applications of Botulinum Neurotoxin (Foster AK, ed) pp 51–93, Springer, NY.
150. Guo Y, Lu Y, Liu T, Zhou Y, Yang P, Zhu J, Chen L, and Yang Q (2015) Efficacy and safety of botulinum toxin type a in the treatment of glabellar lines: A meta-analysis of randomized, placebo-controlled, double-blind trials. Plast Reconstr Surg 136: 310e–318e.
151. Habermann E (1974) 125I-labeled neurotoxin from Clostridium botulinum A: preparation, binding to synaptosomes and ascent to the spinal cord. Naunyn Schmie-debergs Arch Pharmacol 281:47–56.
152. Hallett M (2000) How does botulinum toxin work? Ann Neurol 48:7–8.
153. Hallett M, Albanese A, Dressler D, Segal KR, Simpson DM, Truong D, and Jankovic J (2013) Evidence-based review and assessment of botulinum neurotoxin for the treatment of movement disorders. Toxicon 67:94–114.
154. Hambleton P and Pickett AM (1994) Potency equivalence of botulinum toxin preparations. J R Soc Med 87:719.
155. Hanig JP and Lamanna C (1979) Toxicity of botulinum toxin: a stoichiometric model for the locus of its extraordinary potency and persistence at the neuromuscular junction. J Theor Biol 77:107–113.
156. Hanschmann EM, Godoy JR, Berndt C, Hudemann C, and Lillig CH (2013) Thioredoxins, glutaredoxins, and peroxiredoxins–molecular mechanisms and health significance: from cofactors to antioxidants to redox signaling. Antioxid Redox Signal 19:1539–1605.
157. Hardeman LC, van der Meij BR, Oosterlinck M, Veraa S, van der Kolk JH, Wijnberg ID, and Back W (2013) Effect of Clostridium botulinum toxin type A injections into the deep digital flexor muscle on the range of motion of the metacarpus and carpus, and the force distribution underneath the hooves, of sound horses at the walk. Vet J 198 (Suppl 1):e152–e156.
158. Harper CB, Martin S, Nguyen TH, Daniels SJ, Lavidis NA, Popoff MR, Hadzic G, Mariana A, Chau N, McCluskey A, et al. (2011) Dynamin inhibition blocks botulinum neurotoxin type A endocytosis in neurons and delays botulism. J Biol Chem 286:35966–35976.
159. Hasegawa K, Watanabe T, Suzuki T, Yamano A, Oikawa T, Sato Y, Kouguchi H, Yoneyama T, Niwa K, Ikeda T, et al. (2007) A novel subunit structure of Clostridium botulinum serotype D toxin complex with three extended arms. J Biol Chem 282:24777–24783.
160. Hayashi T, McMahon H, Yamasaki S, Binz T, Hata Y, Südhof TC, and Niemann H (1994) Synaptic vesicle membrane fusion complex: action of clostridial neurotoxins on assembly. EMBO J 13:5051–5061.
161. Helton SG and Lohoff FW (2015) Serotonin pathway polymorphisms and the treatment of major depressive disorder and anxiety disorders. Pharmacogenomics 16: 541–553.
162. Hennenlotter A, Dresel C, Castrop F, Ceballos-Baumann AO, Wohlschläger AM, and Haslinger B (2009) The link between facial feedback and neural activity within central circuitries of emotion–new insights from botulinum toxin-induced denervation of frown muscles. Cereb Cortex 19:537–542.
163. Herrero BA, Ecklung AE, Streett CS, Ford DF, and King JK (1967) Experimental botulism in monkeys–a clinical pathological study. Exp Mol Pathol 6:84–95.
164. Holzer E (1962) Botulism caused by inhalation [in German]. Med Klin 57:1735–1738.
165. Huang X, Wheeler MB, Kang YH, Sheu L, Lukacs GL, Trimble WS, and Gaisano HY (1998) Truncated SNAP-25 (1-197), like botulinum neurotoxin A, can inhibit insulin secretion from HIT-T15 insulinoma cells. Mol Endocrinol 12:1060–1070.
166. Hughes R and Whaler BC (1962) Influence of nerve-ending activity and of drugs on the rate of paralysis of rat diaphragm preparations by Cl. botulinum type A toxin. J Physiol 160:221–233.
167. Jabbari B and Machado D (2011) Treatment of refractory pain with botulinum toxins —an evidence-based review. Pain Med 12:1594–1606.
168. Jackson JL, Kuriyama A, and Hayashino Y (2012) Botulinum toxin A for prophylactic treatment of migraine and tension headaches in adults: a meta-analysis. JAMA 307:1736–1745.
169. Jacky BPS, Garay PE, Dupuy J, Nelson JB, Cai B, Molina Y, Wang J, Steward LE, Broide RS, Francis J, et al. (2013) Identification of fibroblast growth factor receptor 3 (FGFR3) as a protein receptor for botulinum neurotoxin serotype A (BoNT/A). PLoS Pathog 9:e1003369.
170. Jahn R and Scheller RH (2006) SNAREs—engines for membrane fusion. Nat Rev Mol Cell Biol 7:631–643.
171. Jin R, Rummel A, Binz T, and Brunger AT (2006) Botulinum neurotoxin B recognizes its protein receptor with high affinity and specificity. Nature 444:1092–1095.
172. Jin R, Sikorra S, Stegmann CM, Pich A, Binz T, and Brunger AT (2007) Structural and biochemical studies of botulinum neurotoxin serotype C1 light chain protease: implications for dual substrate specificity. Biochemistry 46:10685–10693.
173. Johnson EA and Montecucco C (2008) Botulism. Handb Clin Neurol 91:333–368.
174. Jost WH (2006) Other indications of botulinum toxin therapy. Eur J Neurol 13 (Suppl 1):65–69.
175. Jost WH, Benecke R, Hauschke D, Jankovic J, Kaṋnovský P, Roggenkämper P, Simpson DM, and Comella CL (2015) Clinical and pharmacological properties of incobotulinumtoxinA and its use in neurological disorders. Drug Des Devel Ther 9: 1913–1926.
176. Juzans P, Comella JX, Molgo J, Faille L, and Angaut-Petit D (1996) Nerve terminal sprouting in botulinum type-A treated mouse levator auris longus muscle. Neu-romuscul Disord 6:177–185.
177. Jähne S, Rizzoli SO, and Helm MS (2015) The structure and function of presynaptic endosomes. Exp Cell Res 335:172–179.
178. Kaji R, Miyashiro A, Sato N, Takeuchi T, Kaji S, and Furumoto T (2015) Randomised double-blind clinical trial of botulinum toxin subtype A2 (A2NTX) in comparison with subtype A1 (onabotulinumtoxinA). Neurology 84:14 (Suppl P4.333) (Clin-icalTrials.gov Identifier: NCT01910363)
179. Kammerer RA and Benoit RM (2014) Botulinum neurotoxins: new questions arising from structural biology. Trends Biochem Sci 39:517–526.
180. Karp BI (2004) Botulinum toxin treatment of occupational and focal hand dystonia. Mov Disord 19 (Suppl 8):S116–S119.
181. Katz B (1996) Neural transmitter release: from quantal secretion to exocytosis and beyond. The Fenn Lecture. J Neurocytol 25:677–686.
182. Kavalali ET (2015) The mechanisms and functions of spontaneous neurotransmitter release. Nat Rev Neurosci 16:5–16.
183. Keller JE (2006) Recovery from botulinum neurotoxin poisoning in vivo. Neuroscience 139:629–637.
184. Keller JE, Cai F, and Neale EA (2004) Uptake of botulinum neurotoxin into cultured neurons. Biochemistry 43:526–532.
185. Keller JE and Neale EA (2001) The role of the synaptic protein snap-25 in the potency of botulinum neurotoxin type A. J Biol Chem 276:13476–13482.
186. Keller JE, Neale EA, Oyler G, and Adler M (1999) Persistence of botulinum neurotoxin action in cultured spinal cord cells. FEBS Lett 456:137–142.
187. Khera M, Somogyi GT, Kiss S, Boone TB, and Smith CP (2004) Botulinum toxin A inhibits ATP release from bladder urothelium after chronic spinal cord injury. Neurochem Int 45:987–993.
188. Kim MJ, Neta M, Davis FC, Ruberry EJ, Dinescu D, Heatherton TF, Stotland MA, and Whalen PJ (2014) Botulinum toxin-induced facial muscle paralysis affects amygdala responses to the perception of emotional expressions: preliminary findings from an A-B-A design. Biol Mood Anxiety Disord 4:11.
189. Kitamura M, Takamiya K, Aizawa S, Furukawa K, and Furukawa K (1999) Gangliosides are the binding substances in neural cells for tetanus and botulinum toxins in mice. Biochim Biophys Acta 1441:1–3.
190. Knezeviṋc A, Polasek O, Gornik O, Rudan I, Campbell H, Hayward C, Wright A, Kolcic I, O’Donoghue N, Bones J, et al. (2009) Variability, heritability and environmental determinants of human plasma N-glycome. J Proteome Res 8:694–701.
191. Kononenko NL and Haucke V (2015) Molecular mechanisms of presynaptic membrane retrieval and synaptic vesicle reformation. Neuron 85:484–496.
192. Koriazova LK and Montal M (2003) Translocation of botulinum neurotoxin light chain protease through the heavy chain channel. Nat Struct Biol 10:13–18.
193. Kroken AR, Karalewitz AP, Fu Z, Kim JJ, and Barbieri JT (2011) Novel ganglioside-mediated entry of botulinum neurotoxin serotype D into neurons. J Biol Chem 286: 26828–26837.
194. Kull S, Schulz KM, Weisemann J, Kirchner S, Schreiber T, Bollenbach A, Dabrowski PW, Nitsche A, Kalb SR, Dorner MB, et al. (2015) Isolation and functional characterization of the novel Clostridium botulinum neurotoxin A8 subtype. PLoS One 10:e0116381.
195. Kumaran D, Eswaramoorthy S, Furey W, Navaza J, Sax M, and Swaminathan S (2009) Domain organization in Clostridium botulinum neurotoxin type E is unique: its implication in faster translocation. J Mol Biol 386:233–245.
196. Kutschenko A, Manig A, Reinert MC, Mönnich A, and Liebetanz D (2016) In-vivo comparison of the neurotoxic potencies of incobotulinumtoxinA, onabotulinumtoxinA, and abobotulinumtoxinA. Neurosci Lett 627:216–221.
197. Lacy DB, Tepp W, Cohen AC, DasGupta BR, and Stevens RC (1998) Crystal structure of botulinum neurotoxin type A and implications for toxicity. Nat Struct Biol 5: 898–902.
198. Lake, JM, and Wong RK (2006) Review article: the management of achalasia - a comparison of different treatment modalities. Aliment Pharmacol Ther 24:909–918.
199. Lam KH and Jin R (2015) Architecture of the botulinum neurotoxin complex: a molecular machine for protection and delivery. Curr Opin Struct Biol 31:89–95.
200. Lamanna C and Glassman HN (1947) The isolation of type B botulinum toxin. J Bacteriol 54:575–584.
201. Lamanna C, el-Hage AN, and Vick JA (1988) Cardiac effects of botulinal toxin. Arch Int Pharmacodyn Ther 293:69–83.
202. Lauc G, Pezer M, Rudan I, and Campbell H (2016) Mechanisms of disease: The human N-glycome. Biochim Biophys Acta 1860:1574–1582.
203. Lawrence GW, Ovsepian SV, Wang, J, Aoki KR, and Dolly JO (2012) Extravesicular intraneuronal migration of internalized botulinum neurotoxins without detectable inhibition of distal neurotransmission. Biochem J 441:443–452.
204. Lee K, Gu S, Jin L, Le TT, Cheng LW, Strotmeier J, Kruel AM, Yao G, Perry K, Rummel A, et al. (2013) Structure of a bimodular botulinum neurotoxin complex provides insights into its oral toxicity. PLoS Pathog 9:e1003690.
205. Lee K, Lam KH, Kruel AM, Mahrhold S, Perry K, Cheng LW, Rummel A, and Jin R (2015) Inhibiting oral intoxication of botulinum neurotoxin A complex by carbohydrate receptor mimics. Toxicon 107 (Pt A):43–49.
206. Leka O, Vallese F, Pirazzini M, Berto P, Montecucco C, and Zanotti G (2014) Diphtheria toxin conformational switching at acidic pH. FEBS J 281:2115–2122.
207. Lew MF, Adornato BT, Duane DD, Dykstra DD, Factor SA, Massey JM, Brin MF, Jankovic J, Rodnitzky RL, Singer C, et al. (1997) Botulinum toxin type B: a double-blind, placebo-controlled, safety and efficacy study in cervical dystonia. Neurology 49:701–707.
208. Li JY, Jahn R, and Dahlström A (1994) Synaptotagmin I is present mainly in autonomic and sensory neurons of the rat peripheral nervous system. Neuroscience 63: 837–850.
209. Li X and Coffield JA (2016) Structural and functional interactions between transient receptor potential vanilloid subfamily 1 and botulinum neurotoxin serotype A. PLoS One 11:e0143024.
210. Lin AT, Yang AH, and Chen KK (2007) Effects of botulinum toxin A on the contractile function of dog prostate. Eur Urol 52:582–589.
211. Liu BL, Yang F, Zhan HL, Feng ZY, Zhang ZG, Li WB, and Zhou XF (2014) Increased severity of inflammation correlates with elevated expression of TRPV1 nerve fibers and nerve growth factor on interstitial cystitis/bladder pain syndrome. Urol Int 92: 202–208.
212. Lotia M and Jankovic J (2016) Botulinum toxin for the treatment of tremor and tics. Semin Neurol 36:54–63.
213. Luvisetto S, Gazerani P, Cianchetti C, and Pavone F (2015) Botulinum toxin type a as a therapeutic agent against headache and related disorders. Toxins (Basel) 7: 3818–3844.
214. Magid M, Finzi E, Kruger TH, Robertson HT, Keeling BH, Jung S, Reichenberg JS, Rosenthal NE, and Wollmer MA (2015) Treating depression with botulinum toxin: a pooled analysis of randomized controlled trials. Pharmacopsychiatry 48:205–210.
215. Magid M, Reichenberg JS, Poth PE, Robertson HT, LaViolette AK, Kruger TH, and Wollmer MA (2014) Treatment of major depressive disorder using botulinum toxin A: a 24-week randomized, double-blind, placebo-controlled study. J Clin Psychiatry 75:837–844.
216. Mahrhold S, Rummel A, Bigalke H, Davletov B, and Binz T (2006) The synaptic vesicle protein 2C mediates the uptake of botulinum neurotoxin A into phrenic nerves. FEBS Lett 580:2011–2014.
217. Mahrhold S, Bergström T, Stern D, Dorner BG, Åstot C, and Rummel A (2016) Only the complex N559-glycan in the synaptic vesicle glycoprotein 2C mediates high affinity binding to botulinum neurotoxin serotype A1. Biochem J 473:2645–2654.
218. Mansfield MJ, Adams JB, and Doxey AC (2015) Botulinum neurotoxin homologs in non-Clostridium species. FEBS Lett 589:342–348.
219. Marchand-Pauvert V, Aymard C, Giboin L-S, Dominici F, Rossi A, and Mazzocchio R (2013) Beyond muscular effects: depression of spinal recurrent inhibition after botulinum neurotoxin A. J Physiol 591:1017–1029.
220. Maria G, Brisinda G, Bentivoglio AR, Cassetta E, Gui D, and Albanese A (1998) Botulinum toxin injections in the internal anal sphincter for the treatment of chronic anal fissure: long-term results after two different dosage regimens. Ann Surg 228:664–669.
221. Marinelli S, Vacca V, Ricordy R, Uggenti C, Tata AM, Luvisetto S, and Pavone F (2012) The analgesic effect on neuropathic pain of retrogradely transported botulinum neurotoxin A involves Schwann cells and astrocytes. PLoS One 7:e47977.
222. Maslanka SE, Lúquez C, Dykes JK, Tepp WH, Pier CL, Pellett S, Raphael BH, Kalb SR, Barr JR, Rao A, et al. (2016) A novel botulinum neurotoxin, previously reported as serotype H, has a hybrid-like structure with regions of similarity to the structures of serotypes a and f and is neutralized with serotype a antitoxin. J Infect Dis 213:379–385.
223. Masuyer G, Chaddock JA, Foster KA, and Acharya KR (2014) Engineered botulinum neurotoxins as new therapeutics. Annu Rev Pharmacol Toxicol 54:27–51.
224. Masuyer G, Davies JR, Moore K, Chaddock JA, and Ravi Acharya K (2015) Structural analysis of Clostridium botulinum neurotoxin type D as a platform for the development of targeted secretion inhibitors. Sci Rep 5:13397.
225. Matak I, Bach-Rojecky L, Filipoviṋc B, and Lackoviṋc Z (2011) Behavioral and immu-nohistochemical evidence for central antinociceptive activity of botulinum toxin A. Neuroscience 186:201–207.
226. Matak I and Lackoviṋc Z (2014) Botulinum toxin A, brain and pain. Prog Neurobiol 119-120:39–59.
227. Matak I, Lackoviṋc Z, and Relja M (2016) Botulinum toxin type A in motor nervous system: unexplained observations and new challenges. J Neural Transm (Vienna) 123:1415–1421.
228. Matak I, Riederer P, and Lackoviṋc Z (2012) Botulinum toxin’s axonal transport from periphery to the spinal cord. Neurochem Int 61:236–239.
229. Matak I, Rossetto O, and Lackoviṋc Z (2014) Botulinum toxin type A selectivity for certain types of pain is associated with capsaicin-sensitive neurons. Pain 155: 1516–1526.
230. Matsuda M, Ozutsumi K, Du PY, and Sugimoto N (1986) Rapid method for purification of Clostridium botulinum type C neurotoxin by high performance liquid chromatography (HPLC). Eur J Epidemiol 2:265–271.
231. Mazzocchio R and Caleo M (2015) More than at the neuromuscular synapse: actions of botulinum neurotoxin A in the central nervous system. Neuroscientist 21:44–61.
232. Mclellan K, Das RE, Ekong TA, and Sesardic D (1996) Therapeutic botulinum type A toxin: factors affecting potency. Toxicon 34:975–985.
233. McNutt P, Celver J, Hamilton T, and Mesngon M (2011) Embryonic stem cell-derived neurons are a novel, highly sensitive tissue culture platform for botulinum research. Biochem Biophys Res Commun 405:85–90.
234. Megighian A, Zordan M, Pantano S, Scorzeto M, Rigoni M, Zanini D, Rossetto O, and Montecucco C (2013) Evidence for a radial SNARE super-complex mediating neurotransmitter release at the Drosophila neuromuscular junction. J Cell Sci 126: 3134–3140.
235. Meng J, Dolly JO, and Wang J (2014) Selective cleavage of SNAREs in sensory neurons unveils protein complexes mediating peptide exocytosis triggered by different stimuli. Mol Neurobiol 50:574–588.
236. Meng J, Wang J, Steinhoff M, and Dolly JO (2016) TNFa induces co-trafficking of TRPV1/TRPA1 in VAMP1-containing vesicles to the plasmalemma via Munc18-1/ syntaxin1/SNAP-25 mediated fusion. Sci Rep 6:21226.
237. Meunier FA, Schiavo G, and Molgó J (2002) Botulinum neurotoxins: from paralysis to recovery of functional neuromuscular transmission. J Physiol Paris 96:105–113.
238. Meunier FA, Lisk G, Sesardic D, and Dolly JO (2003) Dynamics of motor nerve terminal remodeling unveiled using SNARE-cleaving botulinum toxins: the extent and duration are dictated by the sites of SNAP-25 truncation. Mol Cell Neurosci 22:454–466.
239. Meyer Y, Buchanan BB, Vignols F, and Reichheld JP (2009) Thioredoxins and glutaredoxins: unifying elements in redox biology. Annu Rev Genet 43:335–367.
240. Middlebrook JL and Dorland RB (1984) Bacterial toxins: cellular mechanisms of action. Microbiol Rev 48:199–221.
241. Miesenböck G, De Angelis DA, and Rothman JE (1998) Visualizing secretion and synaptic transmission with pH-sensitive green fluorescent proteins. Nature 394: 192–195.
242. Miyata K, Yoneyama T, Suzuki T, Kouguchi H, Inui K, Niwa K, Watanabe T, and Ohyama T (2009) Expression and stability of the nontoxic component of the botulinum toxin complex. Biochem Biophys Res Commun 384:126–130.
243. Montal M (2010) Botulinum neurotoxin: a marvel of protein design. Annu Rev Biochem 79:591–617.
244. Montecucco C (1986) How do tetanus and botulinum toxins bind to neuronal membranes? Trends Biochem Sci 11:314–317.
245. Montecucco C and Rasotto MB (2015) On botulinum neurotoxin variability. MBio 6: e02131–14.
246. Montecucco C, Rossetto O, and Schiavo G (2004) Presynaptic receptor arrays for clostridial neurotoxins. Trends Microbiol 12:442–446.
247. Montecucco C and Schiavo G (1995) Structure and function of tetanus and botulinum neurotoxins. Q Rev Biophys 28:423–472.
248. Montecucco C, Schiavo G, and Dasgupta BR (1989) Effect of pH on the interaction of botulinum neurotoxins A, B and E with liposomes. Biochem J 259:47–53.
249. Montecucco C, Schiavo G, and Pantano S (2005) SNARE complexes and neuro-exocytosis: how many, how close? Trends Biochem Sci 30:367–372.
250. Morbiato L, Carli L, Johnson EA, Montecucco C, Molgó J, and Rossetto O (2007) Neuromuscular paralysis and recovery in mice injected with botulinum neurotoxins A and C. Eur J Neurosci 25:2697–2704.
251. Moremen KW, Tiemeyer M, and Nairn AV (2012) Vertebrate protein glycosylation: diversity, synthesis and function. Nat Rev Mol Cell Biol 13:448–462.
252. Morra ME, Elgebaly A, Elmaraezy A, Khalil AM, Altibi AM, Vu TL, Mostafa MR, Huy NT, and Hirayama K (2016) Therapeutic efficacy and safety of Botulinum Toxin A Therapy in Trigeminal Neuralgia: a systematic review and meta-analysis of randomized controlled trials. J Headache Pain 17:63 10.1186/s10194-016-0651-8.
253. Mukai Y, Shimatani Y, Sako W, Asanuma K, Nodera H, Sakamoto T, Izumi Y, Kohda T, Kozaki S, and Kaji R (2014) Comparison between botulinum neurotoxin type A2 and type A1 by electrophysiological study in healthy individuals. Toxicon 81:32–36.
254. Muraro L, Tosatto S, Motterlini L, Rossetto O, and Montecucco C (2009) The N-terminal half of the receptor domain of botulinum neurotoxin A binds to microdomains of the plasma membrane. Biochem Biophys Res Commun 380:76–80.
255. Nakamura K, Kohda T, Umeda K, Yamamoto H, Mukamoto M, and Kozaki S (2010) Characterization of the D/C mosaic neurotoxin produced by Clostridium botulinum associated with bovine botulism in Japan. Vet Microbiol 140:147–154.
256. Nakamura T, Tonozuka T, Ide A, Yuzawa T, Oguma K, and Nishikawa A (2008) Sugar-binding sites of the HA1 subcomponent of Clostridium botulinum type C progenitor toxin. J Mol Biol 376:854–867.
257. Nakamura T, Tonozuka T, Ito S, Takeda Y, Sato R, Matsuo I, Ito Y, Oguma K, and Nishikawa A (2011) Molecular diversity of the two sugar-binding sites of the b-trefoil lectin HA33/C (HA1) from Clostridium botulinum type C neurotoxin. Arch Biochem Biophys 512:69–77.
258. Naumann M, Albanese A, Heinen F, Molenaers G, and Relja M (2006) Safety and efficacy of botulinum toxin type A following long-term use. Eur J Neurol 13 (Suppl 4):35–40.
259. Naumann M, Boo LM, Ackerman AH, and Gallagher CJ (2013a) Immunogenicity of botulinum toxins. J Neural Transm (Vienna) 120:275–290.
260. Naumann M, Dressler D, Hallett M, Jankovic J, Schiavo G, Segal KR, and Truong D (2013b) Evidence-based review and assessment of botulinum neurotoxin for the treatment of secretory disorders. Toxicon 67:141–152.
261. Naumann M and Jankovic J (2004) Safety of botulinum toxin type A: a systematic review and meta-analysis. Curr Med Res Opin 20:981–990.
262. Neale EA, Bowers LM, Jia M, Bateman KE, and Williamson LC (1999) Botulinum neurotoxin A blocks synaptic vesicle exocytosis but not endocytosis at the nerve terminal. J Cell Biol 147:1249–1260.
263. Nishiki T, Kamata Y, Nemoto Y, Omori A, Ito T, Takahashi M, and Kozaki S (1994) Identification of protein receptor for Clostridium botulinum type B neurotoxin in rat brain synaptosomes. J Biol Chem 269:10498–10503.
264. Nordera P, Serra MD, and Menestrina G (1997) The adsorption of Pseudomonas aeruginosa exotoxin A to phospholipid monolayers is controlled by pH and surface potential. Biophys J 73:1468–1478.
265. Notermans S, Dufrenne J, and Kozaki S (1982) The relation between toxicity and toxin-related-antigen contents of Clostridium botulinum types C and D cultures as determined by mouse bioassay and ELISA. Jpn J Med Sci Biol 35:203–211.
266. Nuemket N, Tanaka Y, Tsukamoto K, Tsuji T, Nakamura K, Kozaki S, Yao M, and Tanaka I (2011) Structural and mutational analyses of the receptor binding domain of botulinum D/C mosaic neurotoxin: insight into the ganglioside binding mechanism. Biochem Biophys Res Commun 411:433–439.
267. Ozcan C and Ismi O (2016) Botulinum toxin for rhinitis. Curr Allergy Asthma Rep 16:58.
268. Oguma K, Yokota K, Hayashi S, Takeshi K, Kumagai M, Itoh N, Tachi N, and Chiba S (1990) Infant botulism due to Clostridium botulinum type C toxin. Lancet 336: 1449–1450.
269. Ohishi I and Sakaguchi G (1980) Oral toxicities of Clostridium botulinum type C and D toxins of different molecular sizes. Infect Immun 28:303–309.
270. Ohishi I, Sugii S, and Sakaguchi G (1977) Oral toxicities of Clostridium botulinum toxins in response to molecular size. Infect Immun 16:107–109.
271. Oishi I and Sakaguchi G (1974) Purification of Clostridium botuliunum type F progenitor toxin. Appl Microbiol 28:923–928.
272. Olesen J, Burstein R, Ashina M, and Tfelt-Hansen P (2009) Origin of pain in migraine: evidence for peripheral sensitisation. Lancet Neurol 8:679–690.
273. Omote H, Miyaji T, Juge N, and Moriyama Y (2011) Vesicular neurotransmitter transporter: bioenergetics and regulation of glutamate transport. Biochemistry 50: 5558–5565.
274. Otto H, Hanson PI, Chapman ER, Blasi J, and Jahn R (1995) Poisoning by botulinum neurotoxin A does not inhibit formation or disassembly of the synaptosomal fusion complex. Biochem Biophys Res Commun 212:945–952.
275. Oyler GA, Higgins GA, Hart RA, Battenberg E, Billingsley M, Bloom FE, and Wilson MC (1989) The identification of a novel synaptosomal-associated protein, SNAP-25, differentially expressed by neuronal subpopulations. J Cell Biol 109:3039–3052.
276. Pandolfino JE and Gawron AJ (2015) Achalasia: a systematic review. JAMA 313: 1841–1852.
277. Pantano S and Montecucco C (2014) The blockade of the neurotransmitter release apparatus by botulinum neurotoxins. Cell Mol Life Sci 71:793–811.
278. Papagiannopoulou D, Vardouli L, Dimitriadis F, and Apostolidis A (2016) Retrograde transport of radiolabelled botulinum neurotoxin type A to the CNS after intradetrusor injection in rats. BJU Int 117:697–704.
279. Park E and Rapoport TA (2012) Bacterial protein translocation requires only one copy of the SecY complex in vivo. J Cell Biol 198:881–893.
280. Park JB and Simpson LL (2003) Inhalational poisoning by botulinum toxin and inhalation vaccination with its heavy-chain component. Infect Immun 71: 1147–1154.
281. Parsons SM (2000) Transport mechanisms in acetylcholine and monoamine storage. FASEB J 14:2423–2434.
282. Pasricha PJ, Ravich WJ, Hendrix TR, Sostre S, Jones B, and Kalloo AN (1995) Intrasphincteric botulinum toxin for the treatment of achalasia. N Engl J Med 332: 774–778.
283. Patarnello T, Bargelloni L, Rossetto O, Schiavo G, and Montecucco C (1993) Neurotransmission and secretion. Nature 364:581–582.
284. Pearce CS (2014) Can I treat this pregnant patient with botulinum toxin? Pract Neurol 14:32–33.
285. Peck MW (2006) Clostridium botulinum and the safety of minimally heated, chilled foods: an emerging issue? J Appl Microbiol 101:556–570.
286. Peck MW, Stringer SC, and Carter AT (2011) Clostridium botulinum in the post-genomic era. Food Microbiol 28:183–191.
287. Pellett S, Tepp WH, Clancy CM, Borodic GE, and Johnson EA (2007) A neuronal cell-based botulinum neurotoxin assay for highly sensitive and specific detection of neutralizing serum antibodies. FEBS Lett 581:4803–4808.
288. Pellett S, Tepp WH, Scherf JM, and Johnson EA (2015a) Botulinum neurotoxins can enter cultured neurons independent of synaptic vesicle recycling. PLoS One 10: e0133737.
289. Pellett S, Tepp WH, Scherf JM, Pier CL, and Johnson EA (2015b) Activity of botulinum neurotoxin type D (strain 1873) in human neurons. Toxicon 101:63–69.
290. Pellett S, Tepp WH, Whitemarsh RC, Bradshaw M, and Johnson EA (2015c) In vivo onset and duration of action varies for botulinum neurotoxin A subtypes 1-5. Toxicon 107 (Pt A):37–42.
291. Pellett S, Yaksh TL, and Ramachandran R (2015d) Current status and future directions of botulinum neurotoxins for targeting pain processing. Toxins (Basel) 7: 4519–4563.
292. Pellizzari R, Rossetto O, Lozzi L, Giovedi’ S, Johnson E, Shone CC, and Montecucco C (1996) Structural determinants of the specificity for synaptic vesicle-associated membrane protein/synaptobrevin of tetanus and botulinum type B and G neurotoxins. J Biol Chem 271:20353–20358.
293. Peng L, Adler M, Demogines A, Borrell A, Liu H, Tao L, Tepp WH, Zhang S-C, Johnson EA, Sawyer SL, et al. (2014) Widespread sequence variations in VAMP1 across vertebrates suggest a potential selective pressure from botulinum neurotoxins. PLoS Pathog 10:e1004177.
294. Peng L, Berntsson RP, Tepp WH, Pitkin RM, Johnson EA, Stenmark P, and Dong M (2012) Botulinum neurotoxin D-C uses synaptotagmin I and II as receptors, and human synaptotagmin II is not an effective receptor for type B, D-C and G toxins. J Cell Sci 125:3233–3242.
295. Peng L, Liu H, Ruan H, Tepp WH, Stoothoff WH, Brown RH, Johnson EA, Yao WD, Zhang SC, and Dong M (2013) Cytotoxicity of botulinum neurotoxins reveals a direct role of syntaxin 1 and SNAP-25 in neuron survival. Nat Commun 4:1472.
296. Peng L, Tepp WH, Johnson EA, and Dong M (2011) Botulinum neurotoxin D uses synaptic vesicle protein SV2 and gangliosides as receptors. PLoS Pathog 7: e1002008.
297. Pickett A (2010) Re-engineering clostridial neurotoxins for the treatment of chronic pain: current status and future prospects. BioDrugs 24:173–182.
298. Pickett A (2014) Botulinum toxin as a clinical product: manufacture and pharmacology, in Clinical Applications of Botulinum Neurotoxin (Foster AK, ed) pp 7–49, Springer, NY.
299. Pier CL, Chen C, Tepp WH, Lin G, Janda KD, Barbieri JT, Pellett S, and Johnson EA (2011) Botulinum neurotoxin subtype A2 enters neuronal cells faster than subtype A1. FEBS Lett 585:199–206.
300. Pietrobon D and Moskowitz MA (2013) Pathophysiology of migraine. Annu Rev Physiol 75:365–391.
301. Pirazzini M, Azarnia Tehran D, Zanetti G, Megighian A, Scorzeto M, Fillo S, Shone CC, Binz T, Rossetto O, Lista F, et al. (2014) Thioredoxin and its reductase are present on synaptic vesicles, and their inhibition prevents the paralysis induced by botulinum neurotoxins. Cell Reports 8:1870–1878.
302. Pirazzini M, Bordin F, Rossetto O, Shone CC, Binz T, and Montecucco C (2013a) The thioredoxin reductase-thioredoxin system is involved in the entry of tetanus and botulinum neurotoxins in the cytosol of nerve terminals. FEBS Lett 587:150–155.
303. Pirazzini M, Henke T, Rossetto O, Mahrhold S, Krez N, Rummel A, Montecucco C, and Binz T (2013b) Neutralisation of specific surface carboxylates speeds up translocation of botulinum neurotoxin type B enzymatic domain. FEBS Lett 587: 3831–3836.
304. Pirazzini M and Rossetto O (2017) Challenges in searching for therapeutics against Botulinum Neurotoxins, Exp Op Drug Discov DOI: 10.1080/17460441.2017.1303476 [published ahead of print].
305. Pirazzini M, Rossetto O, Bertasio C, Bordin F, Shone CC, Binz T, and Montecucco C (2013c) Time course and temperature dependence of the membrane translocation of tetanus and botulinum neurotoxins C and D in neurons. Biochem Biophys Res Commun 430:38–42.
306. Pirazzini M, Rossetto O, Bolognese P, Shone CC, and Montecucco C (2011) Double anchorage to the membrane and intact inter-chain disulfide bond are required for the low pH induced entry of tetanus and botulinum neurotoxins into neurons. Cell Microbiol 13:1731–1743.
307. Pirazzini M, Azarnia Tehran D, Leka O, Zanetti G, Rossetto O, and Montecucco C (2016) On the translocation of botulinum and tetanus neurotoxins across the membrane of acidic intracellular compartments. Biochim Biophys Acta 1858:467–474.
308. Polley EH, Vick JA, Ciuchta HP, Fischetti DA, MacChitelli FJ, and Montanarelli N (1965) Botulinum toxin, type A: effects on central nervous system. Science 147: 1036–1037.
309. Poulain B, Molgó J, and Thesleff S (1995) Quantal neurotransmitter release and the clostridial neurotoxins’ targets. Curr Top Microbiol Immunol 195:243–255.
310. Prinetti A, Loberto N, Chigorno V, and Sonnino S (2009) Glycosphingolipid behaviour in complex membranes. Biochim Biophys Acta 1788:184–193.
311. Priori A, Berardelli A, Mercuri B, and Manfredi M (1995) Physiological effects produced by botulinum toxin treatment of upper limb dystonia. Changes in reciprocal inhibition between forearm muscles. Brain 118:801–807.
312. Ptitsyn OB, Pain RH, Semisotnov GV, Zerovnik E, and Razgulyaev OI (1990) Evidence for a molten globule state as a general intermediate in protein folding. FEBS Lett 262:20–24.
313. Pucic M, Pinto S, Novokmet M, Knezevic A, Gornik O, Polasek O, Vlahovicek K, Wang W, Rudd PM, Wright AF, et al. (2010) Common aberrations from the normal human plasma N-glycan profile. Glycobiology 20:970–975.
314. Raciborska DA, Trimble WS, and Charlton MP (1998) Presynaptic protein interactions in vivo: evidence from botulinum A, C, D and E action at frog neuromuscular junction. Eur J Neurosci 10:2617–2628.
315. Ramirez-Castaneda J and Jankovic J (2014) Long-term efficacy, safety, and side effect profile of botulinum toxin in dystonia: a 20-year follow-up. Toxicon 90:344–348.
316. Ramzan Z and Nassri AB (2013) The role of Botulinum toxin injection in the management of achalasia. Curr Opin Gastroenterol 29:468–473.
317. Rapp DE, Turk KW, Bales GT, and Cook SP (2006) Botulinum toxin type a inhibits calcitonin gene-related peptide release from isolated rat bladder. J Urol 175: 1138–1142.
318. Rawlings ND and Barrett AJ (1991) Homologues of insulinase, a new superfamily of metalloendopeptidases. Biochem J 275:389–391.
319. Restani L, Antonucci F, Gianfranceschi L, Rossi C, Rossetto O, and Caleo M (2011) Evidence for anterograde transport and transcytosis of botulinum neurotoxin A (BoNT/A). J Neurosci 31:15650–15659.
320. Restani L, Giribaldi F, Manich M, Bercsenyi K, Menendez G, Rossetto O, Caleo M, and Schiavo G (2012a) Botulinum neurotoxins A and E undergo retrograde axonal transport in primary motor neurons. PLoS Pathog 8:e1003087.
321. Restani L, Novelli E, Bottari D, Leone P, Barone I, Galli-Resta L, Strettoi E, and Caleo M (2012b) Botulinum neurotoxin A impairs neurotransmission following retrograde transynaptic transport. Traffic 13:1083–1089.
322. Rickman C, Hu K, Carroll J, and Davletov B (2005) Self-assembly of SNARE fusion proteins into star-shaped oligomers. Biochem J 388:75–79.
323. Rogozhin AA, Pang KK, Bukharaeva E, Young C, and Slater CR (2008) Recovery of mouse neuromuscular junctions from single and repeated injections of botulinum neurotoxin A. J Physiol 586:3163–3182.
324. Rosales RL, Bigalke H, and Dressler D (2006) Pharmacology of botulinum toxin: differences between type A preparations. Eur J Neurol 13 (Suppl 1):2–10.
325. Rosales RL and Dressler D (2010) On muscle spindles, dystonia and botulinum toxin. Eur J Neurol 17 (Suppl 1):71–80.
326. Rossetto O, Pirazzini M, and Montecucco C (2014) Botulinum neurotoxins: genetic, structural and mechanistic insights. Nat Rev Microbiol 12:535–549.
327. Rossetto O, Schiavo G, Montecucco C, Poulain B, Deloye F, Lozzi L, and Shone CC (1994) SNARE motif and neurotoxins. Nature 372:415–416.
328. Rossetto O, Scorzeto M, Megighian A, and Montecucco C (2013) Tetanus neurotoxin. Toxicon 66:59–63.
329. Rossi V, Banfield DK, Vacca M, Dietrich LE, Ungermann C, D’Esposito M, Galli T, and Filippini F (2004) Longins and their longin domains: regulated SNAREs and multifunctional SNARE regulators. Trends Biochem Sci 29:682–688.
330. Rummel A (2013) Double receptor anchorage of botulinum neurotoxins accounts for their exquisite neurospecificity. Curr Top Microbiol Immunol 364:61–90.
331. Rummel A (2015) The long journey of botulinum neurotoxins into the synapse. Toxicon 107 (Pt A):9–24.
332. Rummel A, Eichner T, Weil T, Karnath T, Gutcaits A, Mahrhold S, Sandhoff K, Proia RL, Acharya KR, Bigalke H, et al. (2007) Identification of the protein receptor binding site of botulinum neurotoxins B and G proves the double-receptor concept. Proc Natl Acad Sci USA 104:359–364.
333. Rummel A, Häfner K, Mahrhold S, Darashchonak N, Holt M, Jahn R, Beermann S, Karnath T, Bigalke H, and Binz T (2009) Botulinum neurotoxins C, E and F bind gangliosides via a conserved binding site prior to stimulation-dependent uptake with botulinum neurotoxin F utilising the three isoforms of SV2 as second receptor. J Neurochem 110:1942–1954.
334. Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D, Niederehe G, Thase ME, Lavori PW, Lebowitz BD, et al. (2006) Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry 163:1905–1917.
335. Saheki Y and De Camilli P (2012) Synaptic vesicle endocytosis. Cold Spring Harb Perspect Biol 4:a005645.
336. Sanes JR and Lichtman JW (1999) Development of the vertebrate neuromuscular junction. Annu Rev Neurosci 22:389–442.
337. Sanford DC, Barnewall RE, Vassar ML, Niemuth N, Metcalfe K, House RV, Henderson I, and Shearer JD (2010) Inhalational botulism in rhesus macaques exposed to botulinum neurotoxin complex serotypes A1 and B1. Clin Vaccine Immunol 17: 1293–1304.
338. Santamato A, Micello MF, Ranieri M, Valeno G, Albano A, Baricich A, Cisari C, Intiso D, Pilotto A, Logroscino G, et al. (2015) Employment of higher doses of botulinum toxin type A to reduce spasticity after stroke. J Neurol Sci 350:1–6.
339. Santini M, Fabri S, Sagnelli P, Manfredi M, and Francia A (1999) Botulism: a case associated with pyramidal signs. Eur J Neurol 6:91–93.
340. Scaglione F (2016) Conversion Ratio between Botox®, Dysport®, and Xeomin® in Clinical Practice. Toxins (Basel) 8:E65.
341. Schantz EJ and Johnson EA (1990) Dose standardisation of botulinum toxin. Lancet 335:421.
342. Schiavo G, Benfenati F, Poulain B, Rossetto O, Polverino de Laureto P, DasGupta BR, and Montecucco C (1992a) Tetanus and botulinum-B neurotoxins block neurotransmitter release by proteolytic cleavage of synaptobrevin. Nature 359:832–835.
343. Schiavo G, Malizio C, Trimble WS, Polverino de Laureto P, Milan G, Sugiyama H, Johnson EA, and Montecucco C (1994) Botulinum G neurotoxin cleaves VAMP/ synaptobrevin at a single Ala-Ala peptide bond. J Biol Chem 269:20213–20216.
344. Schiavo G, Papini E, Genna G, and Montecucco C (1990) An intact interchain disulfide bond is required for the neurotoxicity of tetanus toxin. Infect Immun 58: 4136–4141.
345. Schiavo G, Poulain B, Rossetto O, Benfenati F, Tauc L, and Montecucco C (1992b) Tetanus toxin is a zinc protein and its inhibition of neurotransmitter release and protease activity depend on zinc. EMBO J 11:3577–3583.
346. Schiavo G, Rossetto O, Catsicas S, Polverino de Laureto P, DasGupta BR, Benfenati F, and Montecucco C (1993a) Identification of the nerve terminal targets of botulinum neurotoxin serotypes A, D, and E. J Biol Chem 268:23784–23787.
347. Schiavo G, Rossetto O, Santucci A, DasGupta BR, and Montecucco C (1992c) Botulinum neurotoxins are zinc proteins. J Biol Chem 267:23479–23483.
348. Schiavo G, Santucci A, Dasgupta BR, Mehta PP, Jontes J, Benfenati F, Wilson MC, and Montecucco C (1993b) Botulinum neurotoxins serotypes A and E cleave SNAP-25 at distinct COOH-terminal peptide bonds. FEBS Lett 335:99–103.
349. Schiavo G, Shone CC, Rossetto O, Alexander FC, and Montecucco C (1993c) Botulinum neurotoxin serotype F is a zinc endopeptidase specific for VAMP/synapto-brevin. J Biol Chem 268:11516–11519.
350. Schmieg N, Menendez G, Schiavo G, and Terenzio M (2014) Signalling endosomes in axonal transport: travel updates on the molecular highway. Semin Cell Dev Biol 27:32–43.
351. Schneider SA, Edwards MJ, Cordivari C, Macleod WN, and Bhatia KP (2006) Botulinum toxin A may be efficacious as treatment for jaw tremor in Parkinson’s disease. Mov Disord 21:1722–1724.
352. Schulte-Mattler WJ, Opatz O, Blersch W, May A, Bigalke H, and Wohlfahrt K (2007) Botulinum toxin A does not alter capsaicin-induced pain perception in human skin. J Neurol Sci 260:38–42.
353. Schurch B, Stöhrer M, Kramer G, Schmid DM, Gaul G, and Hauri D (2000) Botulinum-A toxin for treating detrusor hyperreflexia in spinal cord injured patients: a new alternative to anticholinergic drugs? Preliminary results. J Urol 164:692–697.
354. Schwab ME, Suda K, and Thoenen H (1979) Selective retrograde transsynaptic transfer of a protein, tetanus toxin, subsequent to its retrograde axonal transport. J Cell Biol 82:798–810.
355. Scott AB (1980) Botulinum toxin injection into extraocular muscles as an alternative to strabismus surgery. Ophthalmology 87:1044–1049.
356. Scott AB, Rosenbaum A, and Collins CC (1973) Pharmacologic weakening of extraocular muscles. Invest Ophthalmol 12:924–927.
357. Scott AB and Suzuki D (1988) Systemic toxicity of botulinum toxin by intramuscular injection in the monkey. Mov Disord 3:333–335.
358. Sesardic T (2012) Bioassays for evaluation of medical products derived from bacterial toxins. Curr Opin Microbiol 15:310–316.
359. Shevel E (2011) The extracranial vascular theory of migraine–a great story confirmed by the facts. Headache 51:409–417.
360. Shi X, Curran JE, Liao Z, and Gordon RK (2009) The biological activity of ubiquiti-nated BoNT/B light chain in vitro and in human SHSY-5Y neuronal cells. J Cell Biochem 108:660–667.
361. Shoemaker CB and Oyler GA (2013) Persistence of Botulinum neurotoxin in-activation of nerve function. Curr Top Microbiol Immunol 364:179–196.
362. Sikorra S, Litschko C, Müller C, Thiel N, Galli T, Eichner T, and Binz T (2016) Identification and Characterization of Botulinum Neurotoxin A Substrate Binding Pockets and Their Re-Engineering for Human SNAP-23. J Mol Biol 428 (2 Pt A):372–384.
363. Simoens S and Laekeman G (2009) Pharmacotherapy of allergic rhinitis: a pharmacoeconomic approach. Allergy 64:85–95.
364. Simons K and Toomre D (2000) Lipid rafts and signal transduction. Nat Rev Mol Cell Biol 1:31–39.
365. Simpson DM, Blitzer A, Brashear A, Comella C, Dubinsky R, Hallett M, Jankovic J, Karp B, Ludlow CL, Miyasaki JM, et al.; Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology (2008) Assessment: Botulinum neurotoxin for the treatment of movement disorders (an evidence-based re-view): report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 70:1699–1706.
366. Simpson DM, Hallett M, Ashman EJ, Comella CL, Green MW, Gronseth GS, Armstrong MJ, Gloss D, Potrebic S, Jankovic J, et al. (2016) Practice guideline update summary: Botulinum neurotoxin for the treatment of blepharospasm, cervical dystonia, adult spasticity, and headache: Report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology 86:1818–1826.
367. Simpson L (2013) The life history of a botulinum toxin molecule. Toxicon 68:40–59.
368. Simpson LL (1980) Kinetic studies on the interaction between botulinum toxin type A and the cholinergic neuromuscular junction. J Pharmacol Exp Ther 212:16–21.
369. Simpson LL (1983) Ammonium chloride and methylamine hydrochloride antagonize clostridial neurotoxins. J Pharmacol Exp Ther 225:546–552.
370. Simpson LL (1985) Pharmacological experiments on the binding and internalization of the 50,000 dalton carboxyterminus of tetanus toxin at the cholinergic neuromuscular junction. J Pharmacol Exp Ther 234:100–105.
371. Simpson LL, Maksymowych AB, Park JB, and Bora RS (2004) The role of the interchain disulfide bond in governing the pharmacological actions of botulinum toxin. J Pharmacol Exp Ther 308:857–864.
372. Smith CD, Stival A, Howell DL, and Swafford V (2006) Endoscopic therapy for achalasia before Heller myotomy results in worse outcomes than heller myotomy alone. Ann Surg 243:579–584, discussion 584–586.
373. Smith CP, Radziszewski P, Borkowski A, Somogyi GT, Boone TB, and Chancellor MB (2004) Botulinum toxin a has antinociceptive effects in treating interstitial cystitis. Urology 64:871–875, discussion 875.
374. Smith LDS and Sugiyama H (1988) Botulism: the organism, its toxins, the disease, 2nd ed. Charles C Thomas, Springfield, IL.
375. Smith TJ, Hill KK, and Raphael BH (2015) Historical and current perspectives on Clostridium botulinum diversity. Res Microbiol 166:290–302.
376. Sonnino S, Chigorno V, Valsecchi M, Pitto M, and Tettamanti G (1992) Specific ganglioside-cell protein interactions: a study performed with GM1 ganglioside derivative containing photoactivable azide and rat cerebellar granule cells in culture. Neurochem Int 20:315–321.
377. Sonnino S, Mauri L, Chigorno V, and Prinetti A (2007) Gangliosides as components of lipid membrane domains. Glycobiology 17:1R–13R.
378. Soykan T, Maritzen T, and Haucke V (2016) Modes and mechanisms of synaptic vesicle recycling. Curr Opin Neurobiol 39:17–23.
379. Strotmeier J, Gu S, Jutzi S, Mahrhold S, Zhou J, Pich A, Eichner T, Bigalke H, Rummel A, Jin R, et al. (2011) The biological activity of botulinum neurotoxin type C is dependent upon novel types of ganglioside binding sites. Mol Microbiol 81:143–156.
380. Strotmeier J, Lee K, Völker AK, Mahrhold S, Zong Y, Zeiser J, Zhou J, Pich A, Bigalke H, Binz T, et al. (2010) Botulinum neurotoxin serotype D attacks neurons via two carbohydrate-binding sites in a ganglioside-dependent manner. Biochem J 431:207–216.
381. Strotmeier J, Willjes G, Binz T, and Rummel A (2012) Human synaptotagmin-II is not a high affinity receptor for botulinum neurotoxin B and G: increased therapeutic dosage and immunogenicity. FEBS Lett 586:310–313.
382. Sugawara Y, Matsumura T, Takegahara Y, Jin Y, Tsukasaki Y, Takeichi M, and Fujinaga Y (2010) Botulinum hemagglutinin disrupts the intercellular epithelial barrier by directly binding E-cadherin. J Cell Biol 189:691–700.
383. Sun S, Suresh S, Liu H, Tepp WH, Johnson EA, Edwardson JM, and Chapman ER (2011) Receptor binding enables botulinum neurotoxin B to sense low pH for translocation channel assembly. Cell Host Microbe 10:237–247.
384. Sun S, Tepp WH, Johnson EA, and Chapman ER (2012) Botulinum neurotoxins B and E translocate at different rates and exhibit divergent responses to GT1b and low pH. Biochemistry 51:5655–5662.
385. Sutton RB, Fasshauer D, Jahn R, and Brunger AT (1998) Crystal structure of a SNARE complex involved in synaptic exocytosis at 2.4 A resolution. Nature 395: 347–353.
386. Swaminathan S and Eswaramoorthy S (2000) Structural analysis of the catalytic and binding sites of Clostridium botulinum neurotoxin B. Nat Struct Biol 7:693–699.
387. Takamori S, Holt M, Stenius K, Lemke EA, Grønborg M, Riedel D, Urlaub H, Schenck S, Brügger B, Ringler P, et al. (2006) Molecular anatomy of a trafficking organelle. Cell 127:831–846.
388. Tsai YC, Maditz R, Kuo CL, Fishman PS, Shoemaker CB, Oyler GA, and Weissman AM (2010) Targeting botulinum neurotoxin persistence by the ubiquitin-proteasome system. Proc Natl Acad Sci USA 107:16554–16559.
389. Tsui JK, Eisen A, Mak E, Carruthers J, Scott A, and Calne DB (1985) A pilot study on the use of botulinum toxin in spasmodic torticollis. Can J Neurol Sci 12:314–316.
390. Tsukamoto K, Kohda T, Mukamoto M, Takeuchi K, Ihara H, Saito M, and Kozaki S (2005) Binding of Clostridium botulinum type C and D neurotoxins to ganglioside and phospholipid. Novel insights into the receptor for clostridial neurotoxins. J Biol Chem 280:35164–35171.
391. Tyler HR (1963) Botulinus toxin: effect on the central nervous system of man. Science 139:847–848.
392. Vagin O, Tokhtaeva E, Garay PE, Souda P, Bassilian S, Whitelegge JP, Lewis R, Sachs G, Wheeler L, Aoki R, et al. (2014) Recruitment of septin cytoskeletal proteins by botulinum toxin A protease determines its remarkable stability. J Cell Sci 127:3294–3308.
393. Vaidyanathan VV, Yoshino K, Jahnz M, Dörries C, Bade S, Nauenburg S, Niemann H, and Binz T (1999) Proteolysis of SNAP-25 isoforms by botulinum neurotoxin types A, C, and E: domains and amino acid residues controlling the formation of enzyme-substrate complexes and cleavage. J Neurochem 72:327–337.
394. van der Goot FG, González-Mañas JM, Lakey JH, and Pattus F (1991) A ‘molten-globule’ membrane-insertion intermediate of the pore-forming domain of colicin A. Nature 354:408–410.
395. Van der Kloot W and Molgó J (1994) Quantal acetylcholine release at the vertebrate neuromuscular junction. Physiol Rev 74:899–991.
396. Villar RG, Elliott SP, and Davenport KM (2006) Botulism: the many faces of botulinum toxin and its potential for bioterrorism. Infect Dis Clin North Am 20: 313–327, ix.
397. Wang D, Krilich J, Pellett S, Baudys J, Tepp WH, Barr JR, Johnson EA, and Kalb SR (2013) Comparison of the catalytic properties of the botulinum neurotoxin subtypes A1 and A5. Biochim Biophys Acta 1834:2722–2728.
398. Wang J, Zurawski TH, Meng J, Lawrence G, Olango WM, Finn DP, Wheeler L, and Dolly JO (2011) A dileucine in the protease of botulinum toxin A underlies its long-lived neuroparalysis: transfer of longevity to a novel potential therapeutic. J Biol Chem 286:6375–6385.
399. Wang T, Martin S, Papadopulos A, Harper CB, Mavlyutov TA, Niranjan D, Glass NR, Cooper-White JJ, Sibarita JB, Choquet D, et al. (2015) Control of autophagosome axonal retrograde flux by presynaptic activity unveiled using botulinum neurotoxin type a. J Neurosci 35:6179–6194.
400. Wang J, Wang Q, Wu Q, Chen Y, and Wu P (2016) Intravesical botulinum toxin a injections for bladder pain syndrome/interstitial cystitis: a systematic review and meta-analysis of controlled studies. Med Sci Monit 22:3257–3267.
401. Ward AB (2002) A summary of spasticity management–a treatment algorithm. Eur J Neurol 9 (Suppl 1):48–52, 53–61.
402. Wentzel LM, Sterne M, and Polson A (1950) High toxicity of pure botulinum type D toxin. Nature 166:739–740.
403. Wheeler A and Smith HS (2013) Botulinum toxins: mechanisms of action, antinociception and clinical applications. Toxicology 306:124–146.
404. Whitemarsh RC, Strathman MJ, Chase LG, Stankewicz C, Tepp WH, Johnson EA, and Pellett S (2012) Novel application of human neurons derived from induced pluripotent stem cells for highly sensitive botulinum neurotoxin detection. Toxicol Sci 126:426–435.
405. Whitemarsh RC, Tepp WH, Bradshaw M, Lin G, Pier CL, Scherf JM, Johnson EA, and Pellett S (2013) Characterization of botulinum neurotoxin A subtypes 1 through 5 by investigation of activities in mice, in neuronal cell cultures, and in vitro. Infect Immun 81:3894–3902.
406. Whitemarsh RC, Tepp WH, Johnson EA, and Pellett S (2014) Persistence of botulinum neurotoxin a subtypes 1-5 in primary rat spinal cord cells. PLoS One 9: e90252.
407. 125 I-labelled botulinum A neurotoxin: pharmacokinetics in cats after intramuscular injection. Naunyn Schmie-debergs Arch Pharmacol 292:161–165.
408. Wienisch M and Klingauf J (2006) Vesicular proteins exocytosed and subsequently retrieved by compensatory endocytosis are nonidentical. Nat Neurosci 9: 1019–1027.
409. Williamson LC and Neale EA (1994) Bafilomycin A1 inhibits the action of tetanus toxin in spinal cord neurons in cell culture. J Neurochem 63:2342–2345.
410. Williamson LC and Neale EA (1998) Syntaxin and 25-kDa synaptosomal-associated protein: differential effects of botulinum neurotoxins C1 and A on neuronal survival. J Neurosci Res 52:569–583.
411. Willjes G, Mahrhold S, Strotmeier J, Eichner T, Rummel A, and Binz T (2013) Botulinum neurotoxin G binds synaptotagmin-II in a mode similar to that of serotype B: tyrosine 1186 and lysine 1191 cause its lower affinity. Biochemistry 52: 3930–3938.
412. Wise JB and Greco T (2006) Injectable treatments for the aging face. Facial Plast Surg 22:140–146.
413. Wohlfarth K, Schubert M, Rothe B, Elek J, and Dengler R (2001) Remote F-wave changes after local botulinum toxin application. Clin Neurophysiol 112:636–640.
414. Wollmer MA, de Boer C, Kalak N, Beck J, Götz T, Schmidt T, Hodzic M, Bayer U, Kollmann T, Kollewe K, et al. (2012) Facing depression with botulinum toxin: a randomized controlled trial. J Psychiatr Res 46:574–581.
415. Wright GP (1955) The neurotoxins of Clostridium botulinum and Clostridium tetani. Pharmacol Rev 7:413–465.
416. Yao G, Zhang S, Mahrhold S, Lam KH, Stern D, Bagramyan K, Perry K, Kalkum M, Rummel A, Dong M, et al. (2016) N-linked glycosylation of SV2 is required for binding and uptake of botulinum neurotoxin A. Nat Struct Mol Biol 23:656–662.
417. Zanetti G, Azarnia Tehran D, Pirazzini M, Binz T, Shone CC, Fillo S, Lista F, Rossetto O, and Montecucco C (2015) Inhibition of botulinum neurotoxins interchain disulfide bond reduction prevents the peripheral neuroparalysis of botulism. Biochem Pharmacol 98:522–530.
418. Zaninotto G, Annese V, Costantini M, Del Genio A, Costantino M, Epifani M, Gatto G, D’onofrio V, Benini L, Contini S, et al. (2004) Randomized controlled trial of botulinum toxin versus laparoscopic heller myotomy for esophageal achalasia. Ann Surg 239:364–370.
419. Zhang Y, Gardberg AS, Edwards TE, Sankaran B, Robinson H, Varnum SM, and Buchko GW (2013) Structural insights into the functional role of the Hcn subdomain of the receptor-binding domain of the botulinum neurotoxin mosaic serotype C/D. Biochimie 95:1379–1385.
420. Zhang Y and Varnum SM (2012) The receptor binding domain of botulinum neurotoxin serotype C binds phosphoinositides. Biochimie 94:920–923.
421. Zhao LC, Yang B, Wang R, Lipton SA, and Zhang D (2010) Type C botulinum toxin causes degeneration of motoneurons in vivo. Neuroreport 21:14–18.
422. Zychowska M, Rojewska E, Makuch W, Luvisetto S, Pavone F, Marinelli S, Przewlocka B, and Mika J (2016) Participation of pro- and anti-nociceptive interleukins in botulinum toxin A-induced analgesia in a rat model of neuropathic pain. Eur J Pharmacol 791:377–388.
423. Zornetta I, Azarnia Tehran D, Arrigoni G, Anniballi F, Bano L, Leka O, Zanotti G, Binz T, and Montecucco C (2016) The first non Clostridial botulinum-like toxin cleaves VAMP within the juxtamembrane domain. Sci Rep 6:30257.
424. Zuverink M, Chen C, Przedpelski A, Blum FC, and Barbieri JT (2015) A heterologous reporter defines the role of the tetanus toxin interchain disulfide in light-chain translocation. Infect Immun 83:2714–2724.
425. Zweifel LS, Kuruvilla R, and Ginty DD (2005) Functions and mechanisms of retrograde neurotrophin signalling. Nat Rev Neurosci 6:615–625.