Application of Purified Botulinum Type A Neurotoxin to Treat Experimental Trigeminal Neuropathy in Rats and Patients with Urinary Incontinence and Prostatic Hyperplasia
Type A neurotoxin (NTX) of Clostridium botulinum was purified by a simple procedure using a lactose gel column. The toxicity of this purified toxin preparation was retained for at least 1 year at ？30°C by supplementation with either 0.1% albumin or 0.05% albumin plus 1% trehalose. When purified NTX was used to treat 49 patients with urinary incontinence caused by either refractory idiopathic or neurogenic detrusor overactivity, 36 patients showed significant improvement in symptoms. These beneficial effects were also observed in cases of prostatic hyperplasia. The results obtained with NTX were similar to that of Botox. The effects of NTX on trigeminal neuralgia induced by infraorbital nerve constriction (IoNC) in rats were also studied. Trigeminal ganglion neurons from ipsilateral to IoNC exhibited significantly faster onset of FM4-64 release than sham-operated contralateral neurons. Intradermal injection of NTX in the area of IoNC alleviated IoNC-induced pain behavior and reduced the exaggerated FM4-64 release in trigeminal ganglion neurons. 1. Introduction In this manuscript, three main topics are described: (1) the structure of type A progenitor toxin and purification of type A neurotoxin by a lactose gel column based on progenitor toxin characteristics; (2) treatment of patients with urinary incontinence and prostate hyperplasia with this purified neurotoxin; (3) application of the purified neurotoxin for treating trigeminal neuralgia in a rat model. Introduction including the purpose of these three topics is described at the beginning of each paragraph. 2. Structure of Type A Progenitor Toxin and Purification of Type A Neurotoxin Clostridium botulinum strains produce immunologically distinct neurotoxins (NTX; types A to G) with molecular masses (Mr) of approximately 150？kDa. In an activated form, the NTXs have a cleavage site at the one third position of their N terminus conjugated with an S–S bond, which can be cleaved by cellular proteases or exogenously added trypsin. In culture fluid and in acidic foods, the NTXs associate with nontoxic components and form large complexes designated progenitor toxins (PTXs). PTXs are found in three forms with Mr of 900？kDa (19S, LL), 500？kDa (16S, L), and 300？kDa (12S, M); later, it became clear that the actual Mr of the L and LL toxins is much larger than 500 and 900？kDa, respectively (see below). The M toxin is composed of an NTX and a nontoxic component having no hemagglutinin (HA) activity (designated nontoxic non-HA; NTNH), whereas the L and LL toxins are composed of an NTX(s), an NTNH(s), and HAs. The
References
[1]
G. Sakaguchi, S. Kozaki, and I. Ohishi, “Structure and function of botulinum toxins,” in Bacterial Protein Toxins, J. E. Alouf, F. J. Fehrenbach, J. H. Freer, and J. Jeljaszewicz, Eds., pp. 435–443, Academic Press, London, UK, 1984.
[2]
K. Oguma, K. Inoue, Y. Fujinaga et al., “Structure and function of Clostridium botulinum progenitor toxin,” Journal of Toxicology, vol. 18, no. 1, pp. 17–34, 1999.
[3]
K. Inoue, Y. Fujinaga, T. Watanabe et al., “Molecular composition of Clostridium botulinum type A progenitor toxins,” Infection and Immunity, vol. 64, no. 5, pp. 1589–1594, 1996.
[4]
K. Inoue, Y. Fujinaga, K. Honke et al., “Clostridium botulinum type A haemagglutinin-positive progenitor toxin (HA+-PTX) binds to oligosaccharides containing Galβ1-4GIcNAc through one subcomponent of haemagglutinin (HA1),” Microbiology, vol. 147, no. 4, pp. 811–819, 2001.
[5]
K. Inoue, M. Sobhany, T. R. Transue, K. Oguma, L. C. Pedersen, and M. Negishi, “Structural analysis by X-ray crystallography and calorimetry of a haemagglutinin component (HA1) of the progenitor toxin for Clostridium botulinum,” Microbiology, vol. 149, no. 12, pp. 3361–3370, 2003.
[6]
T. Nakamura, T. Tonozuka, A. Ide, T. Yuzawa, K. Oguma, and A. Nishikawa, “Sugar-binding sites of the HA1 subcomponent of Clostridium botulinum type C progenitor toxin,” Journal of Molecular Biology, vol. 376, no. 3, pp. 854–867, 2008.
[7]
T. Nakamura, M. Kotani, T. Tonozuka, A. Ide, K. Oguma, and A. Nishikawa, “Crystal structure of the HA3 subcomponent of Clostridium botulinum type C progenitor toxin,” Journal of Molecular Biology, vol. 385, no. 4, pp. 1193–1206, 2009.
[8]
K. Hasegawa, T. Watanabe, T. Suzuki et al., “A novel subunit structure of Clostridium botulinum serotype D toxin complex with three extended arms,” The Journal of Biological Chemistry, vol. 282, no. 34, pp. 24777–24783, 2007.
[9]
A. B. Scott, “Botulinum toxin injection into extraocular muscles as an alternative to strabismus surgery,” Ophthalmology, vol. 87, no. 10, pp. 1044–1049, 1980.
[10]
J. Jankovic and M. F. Brin, “Therapeutic uses of botulinum toxin,” The New England Journal of Medicine, vol. 324, no. 17, pp. 1186–1194, 1991.
[11]
H. C. Kuo, “Prostate botulinum a toxin injection—an alternative treatment for benign prostatic obstruction in poor surgical candidates,” Urology, vol. 65, no. 4, pp. 670–674, 2005.
[12]
Y. C. Chuang, P. H. Chiang, N. Yoshimura, F. De Miguel, and M. B. Chancellor, “Sustained beneficial effects of intraprostatic botulinum toxin type A on lower urinary tract symptoms and quality of life in men with benign prostatic hyperplasia,” BJU International, vol. 98, no. 5, pp. 1033–1037, 2006.
[13]
J. Silva, R. Pinto, T. Carvalho et al., “Intraprostatic Botulinum toxin type A injection in patients with benign prostatic enlargement: duration of the effect of a single treatment,” BMC Urology, vol. 9, no. 1, article 9, 2009.
[14]
B. Schurch, M. St？hrer, G. Kramer, D. M. Schmid, G. Gaul, and D. Hauri, “Botulinum-A toxin for treating detrusor hyperreflexia in spinal cord injured patients: a new alternative to anticholinergic drugs? Preliminary results,” The Journal of Urology, vol. 164, no. 3, pp. 692–697, 2000.
[15]
A. Sahai, M. S. Khan, and P. Dasgupta, “Efficacy of botulinum toxin-a for treating idiopathic detrusor overactivity: results from a single center, randomized, double-blind, placebo controlled trial,” The Journal of Urology, vol. 177, no. 6, pp. 2231–2236, 2007.
[16]
R. Dmochowski, C. Chapple, V. W. Nitti et al., “Efficacy and safety of onabotulinumtoxina for idiopathic overactive bladder: a double-blind, placebo controlled, randomized, dose ranging trial,” The Journal of Urology, vol. 184, no. 6, pp. 2416–2422, 2010.
[17]
J. C. Lee, K. Yokota, H. Arimitsu et al., “Production of anti-neurotoxin antibody is enhanced by two subcomponents, HA1 and HA3b, of Clostridium botulinum type B 16S toxin-haemagglutinin,” Microbiology, vol. 151, no. 11, pp. 3739–3747, 2005.
[18]
J. C. Lee, T. Yokoyama, H. J. Hwang et al., “Clinical application of Clostridium botulinum type A neurotoxin purified by a simple procedure for patients with urinary incontinence caused by refractory destrusor overactivity,” FEMS Immunology and Medical Microbiology, vol. 51, no. 3, p. 587, 2007.
[19]
T. Yahagi, M. Nagao, Y. Seino, et al., “Mutagenicities of N nitrosamines on Salmonella,” Mutation Research, vol. 48, no. 2, pp. 121–129, 1977.
[20]
F. Cruz, S. Herschorn, P. Aliotta et al., “Efficacy and safety of onabotulinumtoxina in patients with urinary incontinence due to neurogenic detrusor overactivity: a randomised, double-blind, placebo-controlled trial,” European Urology, vol. 60, no. 4, pp. 742–750, 2011.
[21]
G. Maria, G. Brisinda, I. M. Civello, A. R. Bentivoglio, G. Sganga, and A. Albanese, “Relief by botulinum toxin of voiding dysfunction due to benign prostatic hyperplasia: results of a randomized, placebo-controlled study,” Urology, vol. 62, no. 2, pp. 259–264, 2003.
[22]
G. H. Fromm, “Trigeminal neuralgia and related disorders,” Neurologic Clinics, vol. 7, no. 2, pp. 305–319, 1989.
[23]
The American Academy of Orofacial Pain, “Episodic and continuous neuropathic pain,” in Orofacial Pain Guidelines for Assessment, Diagnosis, and Management, R. de Leeuw, Ed., pp. 83–99, Quintessence, Chicago, Ill, USA, 4th edition, 2008.
[24]
J. M. Zakrzewska and P. N. Patsalos, “Drugs used in the management of trigeminal neuralgia,” Oral Surgery Oral Medicine and Oral Pathology, vol. 74, no. 4, pp. 439–450, 1992.
[25]
J. X. Li, W. L. Zhao, and J. H. Liang, “Effects of carbamazepine on morphine-induced behavioral sensitization in mice,” Brain Research, vol. 1019, no. 1-2, pp. 77–83, 2004.
[26]
E. J. Piovesan, H. G. Teive, P. A. Kowacs, M. V. Della Coletta, L. C. Werneck, and S. D. Silberstein, “An open study of botulinum-A toxin treatment of trigeminal neuralgia,” Neurology, vol. 65, no. 8, pp. 1306–1308, 2005.
[27]
B. Bohluli, M. H. K. Motamedi, S. C. Bagheri et al., “Use of botulinum toxin A for drug-refractory trigeminal neuralgia: preliminary report,” Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology and Endodontology, vol. 111, no. 1, pp. 47–50, 2011.
[28]
L. Bach-Rojecky, M. Relja, and Z. Lackovi？, “Botulinum toxin type A in experimental neuropathic pain,” Journal of Neural Transmission, vol. 112, no. 2, pp. 215–219, 2005.
[29]
H. J. Park, Y. Lee, J. Lee, C. Park, and D. E. Moon, “The effects of botulinum toxin A on mechanical and cold allodynia in a rat model of neuropathic pain,” Canadian Journal of Anesthesia, vol. 53, no. 5, pp. 470–477, 2006.
[30]
S. Luvisetto, S. Marinelli, S. Cobianchi, and F. Pavone, “Anti-allodynic efficacy of botulinum neurotoxin A in a model of neuropathic pain,” Neuroscience, vol. 145, no. 1, pp. 1–4, 2007.
[31]
M. Linde, K. Hagen, and L. J. Stovner, “Botulinum toxin treatment of secondary headaches and cranial neuralgias: a review of evidence,” Acta Neurologica Scandinavica, vol. 124, no. 191, pp. 50–55, 2011.
[32]
Y. Kitamura, Y. Matsuka, I. Spigelman et al., “Botulinum toxin type a (150？kDa) decreases exaggerated neurotransmitter release from trigeminal ganglion neurons and relieves neuropathy behaviors induced by infraorbital nerve constriction,” Neuroscience, vol. 159, no. 4, pp. 1422–1429, 2009.
[33]
B. Filipovi？, I. Matak, L. Bach-Rojecky, et al., “Central action of peripherally applied botulinum toxin type a on pain and dural protein extravasation in rat model of trigeminal neuropathy,” PLoS ONE, vol. 7, no. 1, Article ID e29803, 2012.
[34]
A. Kumada, Y. Matsuka, I. Spigelman et al., “Intradermal injection of Botulinum toxin type A alleviates infraorbital nerve constriction-induced thermal hyperalgesia in an operant assay,” Journal of Oral Rehabilitation, vol. 39, no. 1, pp. 63–72, 2011.
[35]
F. Antonucci, C. Rossi, L. Gianfranceschi, O. Rossetto, and M. Caleo, “Long-distance retrograde effects of botulinum neurotoxin A,” Journal of Neuroscience, vol. 28, no. 14, pp. 3689–3696, 2008.
[36]
I. Matak, L. Bach-Rojecky, B. Filipovi？, and Z. Lackovi？, “Behavioral and immunohistochemical evidence for central antinociceptive activity of botulinum toxin A,” Neuroscience, vol. 186, pp. 201–207, 2011.
[37]
H. Arimitsu, K. Inoue, Y. Sakaguchi et al., “Purification of fully activated Clostridium botulinum serotype B toxin for treatment of patients with dystonia,” Infection and Immunity, vol. 71, no. 3, pp. 1599–1603, 2003.
