Botulinum Neurotoxin Type A Subtype 2 Confers Greater Safety than Subtype 1
in a Rat Parkinson’s Disease Model

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ABSTRACT

Botulinum neurotoxin type A (BoNT/A) cleaves SNAP-25 and interrupts the release of acetylcholine. We previously reported that BoNT/A subtype 2 (BoNT/A2) ameliorates pathologic behavior more effectively than subtype 1 (BoNT/A1) in a rat Parkinson’s disease model. Here, we further show BoNT/A2 has fewer adverse effects than BoNT/A1. We first confirmed that intrastriatal treatments of both BoNT/As had no-effect on dopaminergic terminals in the striatum. SNAP-25 cleaved by BoNT/A2 was strictly localized to the striatum on the injected side; however, SNAP-25 cleaved by BoNT/A1 diffused contralaterally. Furthermore, treatment with BoNT/A1 caused a significant reduction in body weight, while BoNT/A2 treatment did not. These results suggest that BoNT/A2 is more beneficial for clinical application against Parkinson’s disease than BoNT/A1.

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Most cited references 22

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Neurotoxins affecting neuroexocytosis.

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Nerve terminals are specific sites of action of a very large number of toxins produced by many different organisms. The mechanism of action of three groups of presynaptic neurotoxins that interfere directly with the process of neurotransmitter release is reviewed, whereas presynaptic neurotoxins acting on ion channels are not dealt with here. These neurotoxins can be grouped in three large families: 1) the clostridial neurotoxins that act inside nerves and block neurotransmitter release via their metalloproteolytic activity directed specifically on SNARE proteins; 2) the snake presynaptic neurotoxins with phospholipase A(2) activity, whose site of action is still undefined and which induce the release of acethylcholine followed by impairment of synaptic functions; and 3) the excitatory latrotoxin-like neurotoxins that induce a massive release of neurotransmitter at peripheral and central synapses. Their modes of binding, sites of action, and biochemical activities are discussed in relation to the symptoms of the diseases they cause. The use of these toxins in cell biology and neuroscience is considered as well as the therapeutic utilization of the botulinum neurotoxins in human diseases characterized by hyperfunction of cholinergic terminals.

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Bregma, lambda and the interaural midpoint in stereotaxic surgery with rats of different sex, strain and weight.

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Craniometric and stereotaxic data from rats of different sex, strain and weight were compared. It was found that stereotaxic atlases can be used with rats of different sex and strain provided that the weights of the rats conform to those used in the reference atlas. If rats of different weights are used, greater accuracy can be achieved if bregma is used as the reference point for work with rostral structures and the interaural line for work with caudal structures.

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Long-distance retrograde effects of botulinum neurotoxin A.

Flavia Antonucci, Chiara Rossi, Laura Gianfranceschi … (2008)

Botulinum neurotoxins (designated BoNT/A-BoNT/G) are bacterial enzymes that block neurotransmitter release by cleaving essential components of the vesicle fusion machinery. BoNT/A, which cleaves SNAP-25 (synaptosomal-associated protein of 25 kDa), is extensively exploited in clinical medicine to treat neuromuscular pathologies, facial wrinkles, and various types of pain. It is widely assumed that BoNT/A remains at the synaptic terminal and its effects are confined to the injection site. Here we demonstrate that catalytically active BoNT/A is retrogradely transported by central neurons and motoneurons and is then transcytosed to afferent synapses, in which it cleaves SNAP-25. SNAP-25 cleavage by BoNT/A was observed in the contralateral hemisphere after unilateral BoNT/A delivery to the hippocampus. Appearance of cleaved SNAP-25 resulted in blockade of hippocampal activity in the untreated hemisphere. Injections of BoNT/A into the optic tectum led to the appearance of BoNT/A-truncated SNAP-25 in synaptic terminals within the retina. Cleaved SNAP-25 also appeared in the facial nucleus after injection of the toxin into rat whisker muscles. Experiments excluded passive spread of the toxin and demonstrated axonal migration and neuronal transcytosis of BoNT/A. These findings reveal a novel pathway of BoNT/A trafficking in neurons and have important implications for the clinical uses of this neurotoxin.

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Author and article information

Journal

Journal ID (nlm-ta): J Vet Med Sci

Journal ID (iso-abbrev): J. Vet. Med. Sci

Journal ID (publisher-id): JVMS

Title: The Journal of Veterinary Medical Science

Publisher: The Japanese Society of Veterinary Science

ISSN (Print): 0916-7250

ISSN (Electronic): 1347-7439

Publication date (Electronic): 21 May 2014

Publication date (Print): August 2014

Volume: 76

Issue: 8

Pages: 1189-1193

Affiliations

[1) ]Laboratory of Veterinary Pharmacology, Graduate School of Life and Environmental Science, Osaka Prefecture University, 1–58 Rinku Ourai Kita, Izumisano-shi, Osaka 598–8531, Japan

[2) ]Laboratory of Veterinary Epidemiology, Graduate School of Life and Environmental Science, Osaka Prefecture University, 1–58 Rinku Ourai Kita, Izumisano-shi, Osaka 598–8531, Japan

Author notes

[* ]Correspondence to: Nakajima, H., Laboratory of Veterinary Pharmacology, Graduate School of Life and Environmental Science, Osaka Prefecture University, 1–58 Rinku Ourai Kita, Izumisano-shi, Osaka 598–8531, Japan. e-mail: hnakajima@ 123456vet.osakafu-u.ac.jp

Article

Publisher ID: 14-0184

DOI: 10.1292/jvms.14-0184

PMC ID: 4155206

PubMed ID: 24849052

SO-VID: 7eff48cc-95e4-4548-8226-4d136b98d1a2

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives (by-nc-nd) License.

History

Date received : 06 April 2014

Date accepted : 28 April 2014

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