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Review Articles

Critical analysis in the advancement of cell-based assays for botulinum neurotoxin

, & ORCID Icon
Pages 1-17 | Received 08 Sep 2021, Accepted 11 Jan 2022, Published online: 25 Feb 2022

References

  • Adler S, Bicker G, Bigalke H, Bishop C, Blümel J, Dressler D, Fitzgerald J, Gessler F, Heuschen H, Kegel B, et al. 2010. The current scientific and legal status of alternative methods to the LD50 test for botulinum neurotoxin potency testing. The report and recommendations of a ZEBET Expert Meeting. Altern Lab Anim. 38(4):315–330.
  • Ahsan CR, Hajnóczky G, Maksymowych AB, Simpson LL. 2005. Visualization of binding and transcytosis of botulinum toxin by human intestinal epithelial cells. J Pharmacol Exp Ther. 315(3):1028–1035.
  • Akaike N, Ito Y, Shin M-C, Nonaka K, Torii Y, Harakawa T, Ginnaga A, Kozaki S, Kaji R. 2010. Effects of A2 type botulinum toxin on spontaneous miniature and evoked transmitter release from the rat spinal excitatory and inhibitory synapses. Toxicon. 56(8):1315–1326.
  • Arango MT, Quintero-Ronderos P, Castiblanco J, Montoya-Ortíz G, et al. 2013. Cell culture and cell analysis. In: Anaya JM, Shoenfeld Y, Rojas-Villarraga A, editors. Autoimmunity: from bench to bedside [Internet]. Bogota (Colombia): El Rosario University Press. Chapter 45. https://www.ncbi.nlm.nih.gov/books/NBK459464.
  • Arnon SS, Schechter R, Inglesby TV, Henderson DA, Bartlett JG, Ascher MS, Eitzen E, Fine AD, Hauer J, Layton M, Working Group on Civilian Biodefense, et al. 2001. Botulinum toxin as a biological weapon: medical and public health management. JAMA. 285(8):1059–1070.
  • Auguet M, Favre-Guilmard C, Cornet S, Carre D, Rocher MN, Pignol B, Pham B, Chabrier PE. 2013. Effects of botulinum toxin type A on digit abduction score and running wheel assays and assessment of diffusion using calcium-activated potassium channel expression. Toxicon. 68:82.
  • Babrak L, Lin A, Stanker L, McGarvey J, Hnasko R. 2016. Rapid microfluidic assay for the detection of botulinum neurotoxin in animal sera. Toxins. 8(1):13.
  • Bagramyan K, Barash JR, Arnon SS, Kalkum M. 2008. Attomolar detection of botulinum toxin type A in complex biological matrices. PLOS One. 3(4):e2041.
  • Bang S, Lee B-J, Lee S-R, Na S, Jang JM, Kang M, Kim S-Y, Min D-H, Song JM, Ho W-K, et al. 2018. Reliable autapse formation using the single-cell patterning method. Biofabrication. 11(1):015008.
  • Barash JR, Arnon SS. 2014. A novel strain of Clostridium botulinum that produces type B and type H botulinum toxins. J Infect Dis. 209(2):183–191
  • Benatar MG, Willison HJ, Vincent A. 1997. Lack of effect of Miller Fisher sera/plasmas on transmitter release from PC12 cells. J Neuroimmunol. 80(1–2):1–5.
  • Bercsenyi K, Giribaldi F, Schiavo G. 2013. The elusive compass of clostridial neurotoxins: deciding when and where to go? Curr Top Microbiol Immunol. 364:91–113.
  • Beske PH, Scheeler SM, Adler M, 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.
  • Bigalke H, Rummel A. 2015. Botulinum neurotoxins: qualitative and quantitative analysis using the mouse phrenic nerve hemidiaphragm assay (MPN). Toxins. 7(12):4895–4905.
  • Bigalke H, Dreyer F, Bergey G. 1985. Botulinum A neurotoxin inhibits non-cholinergic synaptic transmission in mouse spinal cord neurons in culture. Brain Res. 360(1–2):318–324.
  • Bigalke H, Dimpfel W, Habermann E. 1978. Suppression of 3H-acetylcholine release from primary nerve cell cultures by tetanus and botulinum-A toxin. Naunyn Schmiedebergs Arch Pharmacol. 303(2):133–138.
  • Bitz S. 2010. The botulinum neurotoxin LD50 test – problems and solutions. ALTEX. 27(2):114–116.
  • Blasi J, Chapman ER, Link E, Binz T, Yamasaki S, De Camilli P, Südhof TC, Niemann H, Jahn R. 1993. Botulinum neurotoxin A selectively cleaves the synaptic protein SNAP-25. Nature. 365(6442):160–163.
  • Blum FC, Przedpelski A, Tepp WH, Johnson EA, Barbieri JT. 2014. Entry of a recombinant, full-length, atoxic tetanus neurotoxin into Neuro-2a cells. Infect Immun. 82(2):873–881.
  • Bonventre PF. 1979. Absorption of botulinal toxin from the gastrointestinal tract. Rev Infect Dis. 1(4):663–667.
  • CDC 1998. Botulism in the United States, 1899--1996: handbook for epidemiologists, clinicians, and laboratory workers. Atlanta: US Department of Health and Human Services, CDC. http://www.cdc.gov/ncidod/dbmd/diseaseinfo.
  • Chen S. 2012. Clinical uses of botulinum neurotoxins: current indications, limitations and future developments. Toxins. 4(10):913–939.
  • Cherington M. 1998. Clinical spectrum of botulism. Muscle Nerve. 21(6):701–710.
  • Chipman PH, Zhang Y, Rafuse VF. 2014. A stem-cell based bioassay to critically assess the pathology of dysfunctional neuromuscular junctions. PLOS One. 9(3):e91643.
  • Couesnon A, Shimizu T, Popoff MR. 2009. Differential entry of botulinum neurotoxin A into neuronal and intestinal cells. Cell Microbiol. 11(2):289–308.
  • Couesnon A, Pereira Y, Popoff MR. 2008. Receptor-mediated transcytosis of botulinum neurotoxin A through intestinal cell monolayers. Cell Microbiol. 10(2):375–387.
  • Dong M, Tepp WH, Liu H, Johnson EA, Chapman ER. 2007. Mechanism of botulinum neurotoxin B and G entry into hippocampal neurons. J Cell Biol. 179(7):1511–1522.
  • Dong M, Yeh F, Tepp WH, Dean C, Johnson EA, Janz R, Chapman ER. 2006. SV2 is the protein receptor for botulinum neurotoxin A. Science. 312(5773):592–596.
  • Dong M, Richards DA, Goodnough MC, Tepp WH, Johnson EA, Chapman ER. 2003. Synaptotagmins I and II mediate entry of botulinum neurotoxin B into cells. J Cell Biol. 162(7):1293–1303.
  • Dong M, Tepp WH, Johnson EA, Chapman ER. 2004. Using fluorescent sensors to detect botulinum neurotoxin activity in vitro and in living cells. Proc Natl Acad Sci USA. 101(41):14701–14706.
  • Elias M, Al-Saleem F, Ancharski DM, Singh A, Nasser Z, Olson RM, Simpson LL. 2011. Evidence that botulinum toxin receptors on epithelial cells and neuronal cells are not identical: implications for development of a non-neurotropic vaccine. J Pharmacol Exp Ther. 336(3):605–612.
  • Evidente VG, Adler CH. 2010. An update on the neurologic applications of botulinum toxins. Curr Neurol Neurosci Rep. 10(5):338–344.
  • Fernandez-Salas E. 2012. Botulinum neurotoxin serotype A specific cell-based potency assay to replace the mouse bioassay. PLOS One. 7(11):e49516.
  • Foran PG, Mohammed N, Lisk GO, Nagwaney S, Lawrence GW, Johnson E, Smith L, Aoki KR, 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(2):1363–1371.
  • Foster KA. 2016. Molecular aspects of botulinum neurotoxin. New York, NY: Springer.
  • Frisk ML, Tepp WH, Johnson EA, Beebe DJ. 2009. Self-assembled peptide monolayers as a toxin sensing mechanism within arrayed microchannels. Anal Chem. 81(7):2760–2767.
  • Fujinaga Y, Inoue K, Nomura T, Sasaki J, Marvaud JC, Popoff MR, Kozaki S, 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(2–3):179–183.
  • 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(Pt 5):1529–1538.
  • Fujinaga Y, Inoue K, Watanabe S, Yokota K, Hirai Y, Nagamachi E, 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(12):3841–3847.
  • Fujinaga Y. 2010. Interaction of botulinum toxin with the epithelial barrier. J Biomed Biotechnol. 2010:974943.
  • Ghosal KJ, Patel K, Singh BR, Hale ML. 2018. Role of critical elements in botulinum neurotoxin complex in toxin routing across intestinal and bronchial barriers. PLOS One. 13(7):e0199524.
  • Guo J, Xu C, Li X, Chen S. 2014. A simple, rapid and sensitive FRET assay for botulinum neurotoxin serotype B detection. PLOS One. 9(12):e114124.
  • Habermann E, Dreyer F, Bigalke H. 1980. Tetanus toxin blocks the neuromuscular transmission in vitro like botulinum A toxin. Naunyn Schmiedebergs Arch Pharmacol. 311(1):33–40.
  • Hamark C, Berntsson RP, Masuyer G, Henriksson LM, Gustafsson R, Stenmark P, Widmalm G. 2017. Glycans confer specificity to the recognition of ganglioside receptors by botulinum neurotoxin A. J Am Chem Soc. 139(1):218–230.
  • Han SW, Jang E, Koh W-G. 2015. Microfluidic-based multiplex immunoassay system integrated with an array of QD-encoded microbeads. Sens Actuators, B. 209:242–251.
  • Hatheway CL. 1995. Botulism: the present status of the disease. Curr Top Microbiol Immunol. 195:55–75.
  • Haubner F, Ohmann E, Müller-Vogt U, Kummer P, Strutz J, Gassner HG. 2012. Effects of botulinum toxin a on cytokine synthesis in a cell culture model of cutaneous scarring. Arch Facial Plast Surg. 14(2):122–126.
  • Homann U, Thiel G. 1994. Cl- and K + channel currents during the action potential in Chara. Simultaneous recording of membrane voltage and patch currents. J Membr Biol. 141(3):297–309.
  • Hong WS, Young EWK, Tepp WH, Johnson EA, Beebe DJ. 2013. A microscale neuron and Schwann cell coculture model for increasing detection sensitivity of botulinum neurotoxin type A. Toxicol Sci. 134(1):64–72.
  • Hubbard K, Beske P, Lyman M, McNutt P. 2015. Functional evaluation of biological neurotoxins in networked cultures  of stem cell-derived central nervous system neurons. J Vis Exp. (96).DOI:10.3791/52361
  • Hubbard KS, Gut IM, Lyman ME, Tuznik KM, Mesngon MT, McNutt PM. 2012. High yield derivation of enriched glutamatergic neurons from suspension-cultured mouse ESCs for neurotoxicology research. BMC Neurosci. 13:127.
  • Inoue K, Fujinaga Y, Watanabe T, Ohyama T, Takeshi K, Moriishi K, Nakajima H, Inoue K, Oguma K. 1996. Molecular composition of Clostridium botulinum type A progenitor toxins. Infect Immun. 64(5):1589–1594.
  • Jin Y, Takegahara Y, Sugawara Y, Matsumura T, Fujinaga Y. 2009. Disruption of the epithelial barrier by botulinum haemagglutinin (HA) proteins – differences in cell tropism and the mechanism of action between HA proteins of types A or B, and HA proteins of type C. Microbiology. 155(Pt 1):35–45.
  • Johnson EA, Montecucco C. 2008. Botulism. Handb Clin Neurol. 91:333–368.
  • Jones RGA, Alsop T-A, Hull R, Tierney R, Rigsby P, Holley J, Sesardic D. 2006. Botulinum type A toxin neutralisation by specific IgG and its fragments: a comparison of mouse systemic toxicity and local flaccid paralysis assays. Toxicon. 48(3):246–254.
  • Kegel B, Behrensdorf-Nicol HA, Bonifas U, Silberbach K, Klimek J, Krämer B, Weißer K. 2007. An in vitro assay for detection of tetanus neurotoxin activity: using antibodies for recognizing the proteolytically generated cleavage product. Toxicol in Vitro. 21(8):1641–1649.
  • Keller JE, Cai F, Neale EA. 2004. Uptake of botulinum neurotoxin into cultured neurons. Biochemistry. 43(2):526–532.
  • Kiris E, Nuss JE, Burnett JC, Kota KP, Koh DC, Wanner LM, Torres-Melendez E, Gussio R, Tessarollo L, Bavari S. 2011. Embryonic stem cell-derived motoneurons provide a highly sensitive cell culture model for botulinum neurotoxin studies, with implications for high-throughput drug discovery. Stem Cell Res. 6(3):195–205.
  • Koga T, Kozaki S, Takahashi M. 2002. Exocytotic release of alanine from cultured cerebellar neurons. Brain Res. 952(2):282–289.
  • 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(2):e0116381.
  • Kumar R, Baisvar VS, Kushwaha B, Waikhom G, Singh M. 2019. Evolutionary analysis of genus Channa based on karyological and 16S rRNA sequence data. J Genet. 98(5):112
  • Kutschenko A, Weisemann J, Kollewe K, Fiedler T, Alvermann S, Böselt S, Escher C, Garde N, Gingele S, Kaehler S-B, et al. 2019. Botulinum neurotoxin serotype D – A potential treatment alternative for BoNT/A and B non-responding patients. Clin Neurophysiol. 130(6):1066–1073.
  • Lam K-H, Guo Z, Krez N, Matsui T, Perry K, Weisemann J, Rummel A, Bowen ME, Jin R. 2018. A viral-fusion-peptide-like molecular switch drives membrane insertion of botulinum neurotoxin A1. Nat Commun. 9(1):5367.
  • Lam KH, Jin R. 2015. Architecture of the botulinum neurotoxin complex: a molecular machine for protection and delivery. Curr Opin Struct Biol. 31:89–95.
  • Lamanna C, Spero L, Schantz EJ. 1970. Dependence of time to death on molecular size of botulinum toxin. Infect Immun. 1(4):423–424.
  • Lamanna C, Hillowalla RA, Alling CC. 1967. Buccal exposure to botulinal toxin. J Infect Dis. 117(4):327–331.
  • Lamotte JDD, Roqueviere S, Gautier H, Raban E, Bouré C, Fonfria E, Krupp J, Nicoleau C. 2021. hiPSC-derived neurons provide a robust and physiologically relevant in vitro platform to test botulinum neurotoxins. Front Pharmacol. 11:617867.
  • Lin L, Olson ME, Eubanks LM, Janda KD. 2019. Strategies to counteract botulinum neurotoxin A: nature's deadliest biomolecule. Acc Chem Res. 52(8):2322–2331.
  • Maksymowych AB, Simpson LL. 1998. Binding and transcytosis of botulinum neurotoxin by polarized human colon carcinoma cells. J Biol Chem. 273(34):21950–21957.
  • Maksymowych AB, Simpson LL. 2004. Structural features of the botulinum neurotoxin molecule that govern binding and transcytosis across polarized human intestinal epithelial cells. J Pharmacol Exp Ther. 310(2):633–641.
  • Maksymowych AB, Reinhard M, Malizio CJ, Goodnough MC, Johnson EA, Simpson LL. 1999. Pure botulinum neurotoxin is absorbed from the stomach and small intestine and produces peripheral neuromuscular blockade. Infect Immun. 67(9):4708–4712.
  • Matsumura T. 2008. The HA proteins of botulinum toxin disrupt intestinal epithelial intercellular junctions to increase toxin absorption. Cell Microbiol. 10(2):355–364.
  • McInnes C, Dolly JO. 1990. Ca2(+)-dependent noradrenaline release from permeabilised PC12 cells is blocked by botulinum neurotoxin A or its light chain. FEBS Lett. 261(2):323–326.
  • McNutt P, Beske P, Thirunavukkarsu N. 2015. Cell-based assays for neurotoxins. In: Gopalakrishnakone P, Balali-Mood M, Llewellyn L, Singh BR, editors. Biological toxins and bioterrorism toxinology. Dordrecht: Springer.
  • McNutt P, Celver J, Hamilton T, Mesngon M. 2011. Embryonic stem cell-derived neurons are a novel, highly sensitive tissue culture platform for botulinum research. Biochem Biophys Res Commun. 405(1):85–90.
  • Montal M. 2010. Botulinum neurotoxin: a marvel of protein design. Annu Rev Biochem. 79:591–617.
  • Montecucco C. 1986. How do tetanus and botulinum toxins bind to neuronal membranes? Trends Biochem Sci. 11(8):314–317.
  • Montecucco C, Schiavo G. 1995. Structure and function of tetanus and botulinum neurotoxins. Q Rev Biophys. 28(4):423–472.
  • Montecucco C, Rasotto MB. 2015. On botulinum neurotoxin variability. mBio. 6(1). DOI:10.1128/mBio.02131-14
  • Munchau A, Bhatia KP. 2000. Uses of botulinum toxin injection in medicine today. BMJ. 320(7228):161–165.
  • Nakamura T, Tonozuka T, Ide A, Yuzawa T, Oguma K, Nishikawa A. 2008. Sugar-binding sites of the HA1 subcomponent of Clostridium botulinum type C progenitor toxin. J Mol Biol. 376(3):854–867.
  • Nishiki T, Kamata Y, Nemoto Y, Omori A, Ito T, Takahashi M, Kozaki S. 1994. Identification of protein receptor for Clostridium botulinum type B neurotoxin in rat brain synaptosomes. J Biol Chem. 269(14):10498–10503.
  • Nuss JE, Ruthel G, Tressler LE, Wanner LM, Torres-Melendez E, Hale ML, Bavari S. 2010. Development of cell-based assays to measure botulinum neurotoxin serotype A activity using cleavage-sensitive antibodies. J Biomol Screen. 15(1):42–51.
  • O'Grady NP, Alexander M, Dellinger EP, Gerberding JL, Heard SO, Maki DG, Masur H, McCormick RD, Mermel LA, Pearson ML, et al. 2002. Guidelines for the prevention of intravascular catheter-related infections. Clin Infect Dis. 35(11):1281–1307.
  • Pan C, Kumar C, Bohl S, Klingmueller U, Mann M. 2009. Comparative proteomic phenotyping of cell lines and primary cells to assess preservation of cell type-specific functions. Mol Cell Proteomics. 8(3):443–450.
  • Park JB, Simpson LL. 2003. Inhalational poisoning by botulinum toxin and inhalation vaccination with its heavy-chain component. Infect Immun. 71(3):1147–1154.
  • Patel KB, Cai S, Adler M, Singh BK, Parmar VS, Singh BR. 2018. Natural compounds and their analogues as potent antidotes against the most poisonous bacterial toxin. Appl Environ Microbiol. 84(24):1–15. DOI:10.1128/aem.01280-18
  • Peck MW. 2009. Biology and genomic analysis of Clostridium botulinum. Adv Microb Physiol. 55:183–265.
  • Pellett S, Tepp WH, Clancy CM, Borodic GE, Johnson EA. 2007. A neuronal cell-based botulinum neurotoxin assay for highly sensitive and specific detection of neutralizing serum antibodies. FEBS Lett. 581(25):4803–4808.
  • Pellett S, Tepp WH, Toth SI, Johnson EA. 2010. Comparison of the primary rat spinal cord cell (RSC) assay and the mouse bioassay for botulinum neurotoxin type A potency determination. J Pharmacol Toxicol Methods. 61(3):304–310.
  • Pellett S, Tepp WH, Bradshaw M, Kalb SR, Dykes JK, Lin G, Nawrocki EM, Pier CL, Barr JR, Maslanka SE, et al. 2016. Purification and characterization of botulinum neurotoxin FA from a genetically modified Clostridium botulinum strain. mSphere. 1(1).DOI:10.1128/msphere.00100-15
  • Pellett S. 2013. Progress in cell based assays for botulinum neurotoxin detection. Curr Top Microbiol Immunol. 364:257–285.
  • Pellett S, Du ZW, Pier CL, Tepp WH, Zhang SC, Johnson EA. 2011. Sensitive and quantitative detection of botulinum neurotoxin in neurons derived from mouse embryonic stem cells. Biochem Biophys Res Commun. 404(1):388–392.
  • Pellett S, Tepp WH, Johnson EA. 2019. Botulinum neurotoxins A, B, C, E, and F preferentially enter cultured human motor neurons compared to other cultured human neuronal populations. FEBS Lett. 593(18):2675–2685.
  • Peng L, Tepp WH, Johnson EA, Dong M. 2011. Botulinum neurotoxin D uses synaptic vesicle protein SV2 and gangliosides as receptors. PLOS Pathog. 7(3):e1002008.
  • Peng L, Liu H, Ruan H, Tepp WH, Stoothoff WH, Brown RH, Johnson EA, Yao W-D, Zhang S-C, Dong M, et al. 2013. Cytotoxicity of botulinum neurotoxins reveals a direct role of syntaxin 1 and SNAP-25 in neuron survival. Nat Commun. 4:1472.
  • Phillips RW, Abbott D. 2008. High-throughput enzyme-linked immunoabsorbant assay (ELISA) electrochemiluminescent detection of botulinum toxins in foods for food safety and defence purposes. Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 25(9):1084–1088.
  • Pirazzini M, Azarnia Tehran D, Zanetti G, Lista F, Binz T, Shone CC, Rossetto O, Montecucco C. 2015. The thioredoxin reductase–thioredoxin redox system cleaves the interchain disulphide bond of botulinum neurotoxins on the cytosolic surface of synaptic vesicles. Toxicon. 107(Pt A):32–36.
  • Pirazzini M, Azarnia Tehran D, Leka O, Zanetti G, Rossetto O, Montecucco C. 2016. On the translocation of botulinum and tetanus neurotoxins across the membrane of acidic intracellular compartments. Biochim Biophys Acta. 1858(3):467–474.
  • 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 Rep. 8(6):1870–1878.
  • Pirazzini M, Bordin F, Rossetto O, Shone CC, Binz T, Montecucco C. 2013. The thioredoxin reductase-thioredoxin system is involved in the entry of tetanus and botulinum neurotoxins in the cytosol of nerve terminals. FEBS Lett. 587(2):150–155.
  • Purkiss JR, Friis LM, Doward S, Quinn CP. 2001. Clostridium botulinum neurotoxins act with a wide range of potencies on SH-SY5Y human neuroblastoma cells. Neurotoxicology. 22(4):447–453.
  • Rao AK, Sobel J, Chatham-Stephens K, Luquez C. 2021. Clinical guidelines for diagnosis and treatment of botulism, 2021. MMWR Recomm Rep. 70(2):1–30.
  • Rasetti-Escargueil C, Liu Y, Rigsby P, Jones RGA, Sesardic D. 2011. Phrenic nerve-hemidiaphragm as a highly sensitive replacement assay for determination of functional botulinum toxin antibodies. Toxicon. 57(7–8):1008–1016.
  • Ravichandran E, Gong Y, Al Saleem FH, Ancharski DM, Joshi SG, Simpson LL. 2006. An initial assessment of the systemic pharmacokinetics of botulinum toxin. J Pharmacol Exp Ther. 318(3):1343–1351.
  • Ravichandran E, Janardhanan P, Patel K, Riding S, Cai S, Singh BR. 2016. In vivo toxicity and immunological characterization of detoxified recombinant botulinum neurotoxin type A. Pharm Res. 33(3):639–652.
  • Rossetto O, Schiavo G, Montecucco C, Poulain B, Deloye F, Lozzi L, Shone CC. 1994. SNARE motif and neurotoxins. Nature. 372(6505):415–416.
  • Rossetto O, Pirazzini M, Montecucco C. 2014. Botulinum neurotoxins: genetic, structural and mechanistic insights. Nat Rev Microbiol. 12(8):535–549.
  • Rummel A. 2013. Double receptor anchorage of botulinum neurotoxins accounts for their exquisite neurospecificity. Curr Top Microbiol Immunol. 364:61–90.
  • Rummel A, Karnath T, Henke T, Bigalke H, Binz T. 2004. Synaptotagmins I and II act as nerve cell receptors for botulinum neurotoxin G. J Biol Chem. 279(29):30865–30870.
  • Rummel A. 2017. Two feet on the membrane: uptake of Clostridial neurotoxins. Curr Top Microbiol Immunol. 406:1–37.
  • Rummel A, Häfner K, Mahrhold S, Darashchonak N, Holt M, Jahn R, Beermann S, Karnath T, Bigalke H, Binz T, et al. 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(6):1942–1954.
  • Rust A, Doran C, Hart R, Binz T, Stickings P, Sesardic D, Peden AA, Davletov B. 2017. A cell line for detection of botulinum neurotoxin type B. Front Pharmacol. 8:796.
  • Saini J, Faroni A, Abd Al Samid M, Reid AJ, Lightfoot AP, Mamchaoui K, Mouly V, Butler-Browne G, McPhee JS, Degens H, et al. 2019. Simplified in vitro engineering of neuromuscular junctions between rat embryonic motoneurons and immortalized human skeletal muscle cells. Stem Cells Cloning. 12:1–9.
  • Sakaguchi G. 1982. Clostridium botulinum toxins. Pharmacol Ther. 19(2):165–194.
  • Sakaguchi K, Okuda M, Tanigaito Y, Ohnishi M. 1983. Nasal polyps and appearance of basophilic cells on the mucosal surface of nose. Nihon Jibiinkoka Gakkai Kaiho. 86(1):30–35.
  • Santhanam N, Kumanchik L, Guo X, Sommerhage F, Cai Y, Jackson M, Martin C, Saad G, McAleer CW, Wang Y, et al. 2018. Stem cell derived phenotypic human neuromuscular junction model for dose response evaluation of therapeutics. Biomaterials. 166:64–78.
  • Scarlatos A, Cadotte AJ, DeMarse TB, Welt BA. 2008. Cortical networks grown on microelectrode arrays as a biosensor for botulinum toxin. J Food Science. 73(3):E129–36.
  • Schantz EJ, Kautter DA. 1978. Standardized Assay for Clostridium botulinum Toxins. J Assoc of Off Anal Chem. 61(1):96–99.
  • Schenke M, Schjeide BM, Puschel GP, Seeger B. 2020. Analysis of motor neurons differentiated from human induced pluripotent stem cells for the use in cell-based botulinum neurotoxin activity assays. Toxins (Basel). 12(5):276.
  • Schenke M, Prause HC, Bergforth W, Przykopanski A, Rummel A, Klawonn F, Seeger B. 2021. Human-relevant sensitivity of iPSC-derived human motor neurons to BoNT/A1 and B1. Toxins. 13(8):585.
  • Schiavo G, Benfenati F, Poulain B, Rossetto O, Polverino de Laureto P, DasGupta BR, Montecucco C. 1992. Tetanus and botulinum-B neurotoxins block neurotransmitter release by proteolytic cleavage of synaptobrevin. Nature. 359(6398):832–835.
  • Schiavo G, Shone CC, Rossetto O, Alexander FC, Montecucco C. 1993. Botulinum neurotoxin serotype F is a zinc endopeptidase specific for VAMP/synaptobrevin. J Biol Chem. 268(16):11516–11519.
  • Schiavo G, Malizio C, Trimble WS, Polverino de Laureto P, Milan G, Sugiyama H, Johnson EA, Montecucco C. 1994. Botulinum G neurotoxin cleaves VAMP/synaptobrevin at a single Ala-Ala peptide bond. J Biol Chem. 269(32):20213–20216.
  • Schiavo G, Rossetto O, Catsicas S, Polverino de Laureto P, DasGupta BR, Benfenati F, Montecucco C. 1993. Identification of the nerve terminal targets of botulinum neurotoxin serotypes A, D, and E. J Biol Chem. 268(32):23784–23787.
  • Schiavo G, Santucci A, Dasgupta BR, Mehta PP, Jontes J, Benfenati F, Wilson MC, Montecucco C. 1993. Botulinum neurotoxins serotypes A and E cleave SNAP-25 at distinct COOH-terminal peptide bonds. FEBS Lett. 335(1):99–103.
  • Scott AB. 1980. Botulinum toxin injection into extraocular muscles as an alternative to strabismus surgery. Ophthalmology. 87(10):1044–1049.
  • Scott AB. 1981. Botulinum toxin injection of eye muscles to correct strabismus. Trans Am Ophthalmol Soc. 79:734–770.
  • Scott AB, Rosenbaum A, Collins CC. 1973. Pharmacologic weakening of extraocular muscles. Invest Ophthalmol. 12(12):924–927.
  • Sheridan RE. 1998. Gating and permeability of ion channels produced by botulinum toxin types A and E in PC12 cell membranes. Toxicon. 36(5):703–717.
  • Sheridan RE, Smith TJ, Adler M. 2005. Primary cell culture for evaluation of botulinum neurotoxin antagonists. Toxicon. 45(3):377–382.
  • Shone CC, Melling J. 1992. Inhibition of calcium-dependent release of noradrenaline from PC12 cells by botulinum type-A neurotoxin. Long-term effects of the neurotoxin on intact cells. Eur J Biochem. 207(3):1009–1016.
  • Simpson LL. 2004. Identification of the major steps in botulinum toxin action. Annu Rev Pharmacol Toxicol. 44:167–193.
  • Simpson LL, Rapport MM. 1971. The binding of botulinum toxin to membrane lipids: phospholipids and proteolipid. J Neurochem. 18(9):1761–1767.
  • Singh BR. 2006. Botulinum neurotoxin structure, engineering, and novel cellular trafficking and targeting. Neurotox Res. 9(2–3):73–92.
  • Singh BR, Thirunavukkarasu N, Ghosal K, Ravichandran E, Kukreja R, Cai S, Zhang P, Ray R, Ray P. 2010. Clostridial neurotoxins as a drug delivery vehicle targeting nervous system. Biochimie. 92(9):1252–1259.
  • Smith LDS, Sugiyama H. 1988. Botulism: the organism, its toxins, the disease. Springfield, Ill., USA: Thomas.
  • Smith TJ, Hill KK, Raphael BH. 2015. Historical and current perspectives on Clostridium botulinum diversity. Res Microbiol. 166(4):290–302.
  • Solomon HM, Lilly T. Jr. 2001. Clostridium botulinum. Bacteriological analytical manual, 8th ed, Revision A, 1998. Chapter 17.
  • Stahl AM, Ruthel G, Torres-Melendez E, Kenny TA, Panchal RG, Bavari S. 2007. Primary cultures of embryonic chicken neurons for sensitive cell-based assay of botulinum neurotoxin: implications for therapeutic discovery. J Biomol Screen. 12(3):370–377.
  • 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(1):143–156.
  • Thirunavukkarasusx N, Ghosal KJ, Kukreja R, Zhou Y, Dombkowski A, Cai S, Singh BR. 2011. Microarray analysis of differentially regulated genes in human neuronal and epithelial cell lines upon exposure to type A botulinum neurotoxin. Biochem Biophys Res Commun. 405(4):684–690.
  • Thyagarajan B. 2015. Antidotes to Botulinum Neurotoxin. In: Gopalakrishnakone P, Balali-Mood M, Llewellyn L, Singh BR, editors. Biological toxins and bioterrorism toxinology. Dordrecht: Springer.
  • Truong DD, Stenner A, Reichel G. 2009. Current clinical applications of botulinum toxin. Curr Pharm Des. 15(31):3671–3680.
  • Tsaioun K, Blaauboer BJ, Hartung T. 2016. Evidence-based absorption, distribution, metabolism, excretion (ADME) and its interplay with alternative toxicity methods. ALTEX. 33(4):343–358.
  • Tulin EKC, Nakazawa C, Nakamura T, Saito S, Ohzono N, Hiemori K, Nakakita S-I, Tateno H, Tonozuka T, Nishikawa A. 2021. Glycan detecting tools developed from the Clostridium botulinum whole hemagglutinin complex. Sci Rep. 11(1):21973.
  • Vazquez-Cintron EJ, Beske PH, Tenezaca L, Tran BQ, Oyler JM, Glotfelty EJ, Angeles CA, Syngkon A, Mukherjee J, Kalb SR, et al. 2017. Engineering botulinum neurotoxin C1 as a molecular vehicle for intra-neuronal drug delivery. Sci Rep. 7:42923
  • Verderio C, Pozzi D, Pravettoni E, Inverardi F, Schenk U, Coco S, Proux-Gillardeaux V, Galli T, Rossetto O, Frassoni C, et al. 2004. SNAP-25 modulation of calcium dynamics underlies differences in GABAergic and glutamatergic responsiveness to depolarization. Neuron. 41(4):599–610.
  • Wainwright RB, Heyward WL, Middaugh JP, Hatheway CL, Harpster AP, Bender TR. 1988. Food-borne botulism in Alaska, 1947-1985: epidemiology and clinical findings. J Infect Dis. 157(6):1158–1162.
  • Wang D, Krilich J, Pellett S, Baudys J, Tepp WH, Barr JR, Johnson EA, Kalb SR. 2013. Comparison of the catalytic properties of the botulinum neurotoxin subtypes A1 and A5. Biochim Biophys Acta. 1834(12):2722–2728.
  • Wang L, Ringelberg CS, Singh BR. 2020. Dramatic neurological and biological effects by botulinum neurotoxin type A on SH-SY5Y neuroblastoma cells, beyond the blockade of neurotransmitter release. BMC Pharmacol Toxicol. 21(1):66.
  • Wang L, Sun Y, Yang W, Lindo P, Singh BR. 2014. Type A botulinum neurotoxin complex proteins differentially modulate host response of neuronal cells. Toxicon. 82:52–60.
  • Welch MJ, Purkiss JR, Foster KA. 2000. Sensitivity of embryonic rat dorsal root ganglia neurons to Clostridium botulinum neurotoxins. Toxicon. 38(2):245–258.
  • Whitemarsh RCM, Tepp WH, Bradshaw M, Lin G, Pier CL, Scherf JM, Johnson EA, 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(10):3894–3902.
  • Whitemarsh RCM, Strathman MJ, Chase LG, Stankewicz C, Tepp WH, Johnson EA, Pellett S. 2012. Novel application of human neurons derived from induced pluripotent stem cells for highly sensitive botulinum neurotoxin detection. Toxicol Sci. 126(2):426–435.
  • Wilder-Kofie TD, Lúquez C, Adler M, Dykes JK, Coleman JD, Maslanka SE. 2011. An alternative in vivo method to refine the mouse bioassay for botulinum toxin detection. Comp Med. 61(3):235–242.
  • Williamson LC, Halpern JL, Montecucco C, Brown JE, Neale EA. 1996. Clostridial neurotoxins and substrate proteolysis in intact neurons: botulinum neurotoxin C acts on synaptosomal-associated protein of 25 kDa. J Biol Chem. 271(13):7694–7699.
  • Xia Y, Whitesides GM. 1998. Soft lithography. Angew Chem Int Ed Engl. 37(5):550–575.
  • Xiao L, Cheng J, Dai J, Zhang D. 2011. Botulinum toxin decreases hyperalgesia and inhibits P2X3 receptor over-expression in sensory neurons induced by ventral root transection in rats. Pain Med. 12(9):1385–1394.
  • Xiao Z, Zhang F, Lin W, Zhang M, Liu Y. 2010. Effect of botulinum toxin type A on transforming growth factor beta1 in fibroblasts derived from hypertrophic scar: a preliminary report. Aesth Plast Surg. 34(4):424–427.
  • Yaguchi T, Nishizaki T. 2010. Extracellular high K + stimulates vesicular glutamate release from astrocytes by activating voltage‐dependent calcium channels. J Cell Physiol. 225(2):512–518.
  • Yiangou Y, Anand U, Otto WR, Sinisi M, Fox M, Birch R, … Anand P. 2011. Increased levels of SV2A botulinum neurotoxin receptor in clinical sensory disorders and functional effects of botulinum toxins A and E in cultured human sensory neurons. J Pain Res. 4:347–355.
  • Yowler BC, Kensinger RD, Schengrund CL. 2002. Botulinum neurotoxin A activity is dependent upon the presence of specific gangliosides in neuroblastoma cells expressing synaptotagmin I. J Biol Chem. 277(36):32815–32819.
  • Zhang P, Ray R, Singh BR, Li D, Adler M, Ray P. 2009. An efficient drug delivery vehicle for botulism countermeasure. BMC Pharmacol. 9(1):12.
  • Zhang S, Masuyer G, Zhang J, Shen Y, Lundin D, Henriksson L, Miyashita S-I, Martínez-Carranza M, Dong M, Stenmark P. 2017. Identification and characterization of a novel botulinum neurotoxin. Nat Commun. 8:14130.
  • Zhu H, Wang J, Jacky BPS, Hodges DD, Fernandez-Salas E, inventors; Allergan Inc, assignee. 2010. Cells useful for immuno-based botulinum toxin serotype a activity assays. US-Patent 12/722801.

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