Unilateral Botulinum Neurotoxin-A Injection into the Striatum of C57BL/6 Mice Leads to a Different Motor Behavior Compared with Rats

Different morphological changes in the caudate-putamen (CPu) of naïve rats and mice were observed after intrastriatal botulinum neurotoxin-A (BoNT-A) injection. For this purpose we here studied various motor behaviors in mice (n = 46) longitudinally up to 9 months after intrastriatal BoNT-A administration as previously reported for rats, and compared both outcomes. Apomorphine- and amphetamine-induced rotational behavior, spontaneous motor behavior, as well as lateralized neglect were studied in mice after the injection of single doses of BoNT-A into the right CPu, comparing them with sham-injected animals. Unilateral intrastriatal injection of BoNT-A in mice induced significantly increased contralateral apomorphine-induced rotations for 1 to 3 months, as well as significantly increased contralateral amphetamine-induced rotations 1 to 9 months after injection. In rats (n = 28), unilateral BoNT-A injection also induced significantly increased contralateral apomorphine-induced rotations 3 months after injection, but did not provoke amphetamine-induced rotations at all. Lateralized sensorimotor integration, forelimb preference, and forelimb stepping were significantly impaired on the left side. The differences in motor behaviors between rats and mice may be caused by different BoNT-A effects on cholinergic and catecholaminergic fibers in rat and mouse striata, interspecies differences in striatal receptor densities, and different connectomes of the basal ganglia.

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Repeated Intrastriatal Botulinum Neurotoxin-A Injection in Hemiparkinsonian Rats Increased the Beneficial Effect on Rotational Behavior

Toxins ◽

10.3390/toxins10090368 ◽

2018 ◽

Vol 10 (9) ◽

pp. 368 ◽

Cited By ~ 2

Author(s):

Alexander Hawlitschka ◽

Carsten Holzmann ◽

Andreas Wree ◽

Veronica Antipova

Keyword(s):

Beneficial Effect ◽

Rotation Rate ◽

Botulinum Neurotoxin ◽

Acetylcholinesterase Inhibitor ◽

Rotational Behavior ◽

Motor Symptoms ◽

Botulinum Neurotoxin A ◽

Motor Behaviors

Injection of botulinum neurotoxin-A (BoNT-A) into the striatum of hemiparkinsonian (hemi-PD) rats reduced apomorphine-induced rotation behavior significantly, for at least 3 months. Thereafter, rotation behavior increased again. We injected hemi-PD rats with 1 ng BoNT-A twice, the second injection following 6 months after the first one and tested the rats for apomorphine-induced rotations and spontaneous motor behaviors, i.e., corridor task and stepping test. To test the hypothesis that BoNT-A reduced striatal hypercholinism in hemi-PD rats, the acetylcholinesterase inhibitor donepezil was injected prior to separate apomorphine-induced rotation tests. In hemi-PD rats, the first BoNT-A injection led to a clear reduction of the apomorphine-induced rotations, and the second BoNT-A injection to a more massive and prolonged reaction. In hemi-PD rats whose apomorphine-induced rotation behavior was strongly reduced by an intrastriatal BoNT-A, subsequent donepezil injections led to significant increases of the rotation rate. Concerning corridor task and stepping test, neither first nor second BoNT-A injections changed hemi-PD rats’ behavior significantly. The data give evidence for the possibility of repeated intrastriatal administrations of BoNT-A, for treatment of motor symptoms in experimental hemi-PD over a longer time.

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Intrastriatal injection of botulinum neurotoxin-A is not cytotoxic in rat brain – A histological and stereological analysis

Brain Research ◽

10.1016/j.brainres.2015.10.056 ◽

2016 ◽

Vol 1630 ◽

pp. 18-24 ◽

Cited By ~ 14

Author(s):

Juliane Mehlan ◽

Hans Brosig ◽

Oliver Schmitt ◽

Eilhard Mix ◽

Andreas Wree ◽

...

Keyword(s):

Rat Brain ◽

Botulinum Neurotoxin ◽

Botulinum Neurotoxin A ◽

Stereological Analysis ◽

Intrastriatal Injection

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Hypothalamic dopamine neurons control sensorimotor behavior by modulating brainstem premotor nuclei

10.1101/2020.07.13.195982 ◽

2020 ◽

Author(s):

Joshua P. Barrios ◽

Wei-Chun Wang ◽

Roman England ◽

Erica Reifenberg ◽

Adam D. Douglass

Keyword(s):

Sensorimotor Integration ◽

Motor Behavior ◽

Third Ventricle ◽

Dopamine Neurons ◽

Preoptic Nucleus ◽

Anatomy And Physiology ◽

Motor Behaviors ◽

Hypothalamic Nuclei ◽

The Brain ◽

Hypothalamic Dopamine

SummaryDopamine (DA)-producing neurons are critically involved in the production of motor behaviors in multiple circuits that are conserved from basal vertebrates to mammals. While there is increasing evidence that DA neurons in the hypothalamus play a locomotor role, their precise contributions to behavior and the circuit mechanisms by which they are achieved remain unclear. Here we demonstrate that tyrosine hydroxylase 2-expressing (th2+) DA neurons in the zebrafish hypothalamus fire phasic bursts of activity to acutely promote swimming and modulate audiomotor behaviors on fast timescales. Their anatomy and physiology reveal two distinct functional DA modules within the hypothalamus. The first comprises an interconnected set of cerebrospinal fluid-contacting DA nuclei surrounding the third ventricle, which lack distal projections outside of the hypothalamus and influence locomotion through unknown means. The second includes neurons in the preoptic nucleus, which send long-range projections to targets throughout the brain, including the mid- and hindbrain, where they activate premotor circuits involved in swimming and sensorimotor integration. These data suggest a broad regulation of motor behavior by DA neurons within multiple hypothalamic nuclei and elucidate a novel functional mechanism for the preoptic DA neurons in the initiation of movement.

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Identification of novel inhibitors of botulinum neurotoxin A

Planta Medica ◽

10.1055/s-0035-1556290 ◽

2015 ◽

Vol 81 (11) ◽

Author(s):

C Yalamanchili ◽

VK Manda ◽

AG Chittiboyina ◽

WA Harrell Jr ◽

RP Webb ◽

...

Keyword(s):

Botulinum Neurotoxin ◽

Botulinum Neurotoxin A

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Botulinumtoxin zur Behandlung von neuropathischen Schmerzen

Nervenheilkunde ◽

10.1055/s-0038-1627027 ◽

2017 ◽

Vol 36 (05) ◽

pp. 315-323

Author(s):

N. Üçeyler ◽

C. Sommer

Keyword(s):

Botulinum Neurotoxin ◽

Neuropathische Schmerzen ◽

Botulinum Neurotoxin A ◽

Topische Therapien

ZusammenfassungDie Behandlung neuropathischer Schmerzen mit systemisch wirksamen oral verabreichten Pharmaka ist bei vielen Patienten wirksam, kann jedoch zu zentralnervösen unerwünschten Wirkungen wie Müdigkeit oder Schwindel führen. Daher sind in den letzten Jahren topische Therapien in das Zentrum der Aufmerksamkeit gerückt. Botulinumtoxin, etabliert in der Therapie von Dystonien und Spastik, wurde zunehmend bei Schmerzerkrankungen getestet, hierbei ist Botulinum-Neurotoxin A der am besten untersuchte Serotyp. Die häufigsten Indikationen waren Schmerzen im Trigeminusversorgungsbereich und periphere neuropathische Schmerzen. Bei den meisten Studien war Botulinum-Neurotoxin A Placebo deutlich überlegen. Präklinische Studien zum Wirkmechanismus erbrachten die Erkenntnis, dass neben dem erwarteten peripheren Effekt sehr wahrscheinlich auch eine zentrale Reduktion der Ausschüttung von exzitatorischen Neurotransmittern an der Wirkung beteiligt ist.

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Komplexproteinfreies Botulinum Neurotoxin A - Blepharospasmus und Torticollis

psychoneuro ◽

10.1055/s-2007-991580 ◽

2007 ◽

Vol 33 (9) ◽

pp. 376-376

Keyword(s):

Botulinum Neurotoxin ◽

Botulinum Neurotoxin A

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Primary Cultures of Embryonic Chicken Neurons for Sensitive Cell-Based Assay of Botulinum Neurotoxin: Implications for Therapeutic Discovery

CrossRef Listing of Deleted DOIs ◽

10.1177/1087057106299163 ◽

2007 ◽

Vol 12 (3) ◽

pp. 370-377 ◽

Cited By ~ 29

Author(s):

Andrea M. Stahl ◽

Gordon Ruthel ◽

Edna Torres-Melendez ◽

Tara A. Kenny ◽

Rekha G. Panchal ◽

...

Keyword(s):

Nervous System ◽

Botulinum Toxin ◽

Neutralizing Antibodies ◽

Botulinum Neurotoxin ◽

Potent Inhibitor ◽

Primary Cultures ◽

Embryonic Chick ◽

Sensitive Cell ◽

Botulinum Neurotoxin A ◽

Therapeutic Compounds

Botulinum toxin is an exceedingly potent inhibitor of neurotransmission across the neuromuscular junction, causing flaccid paralysis and death. The potential for misuse of this deadly poison as a bioweapon has added a greater urgency to the search for effective therapeutics. The development of sensitive and efficient cell-based assays for the evaluation of toxin antagonists is crucial to the rapid and successful identification of therapeutic compounds. The authors evaluated the sensitivity of primary cultures from 4 distinct regions of the embryonic chick nervous system to botulinum neurotoxin A (BoNT/A) cleavage of synaptosomal-associated protein of 25 kD (SNAP-25). Although differences in sensitivity were apparent, SNAP-25 cleavage was detectable in neuronal cells from each of the 4 regions within 3 h at BoNT/A concentrations of 1 nM or lower. Co-incubation of chick neurons with BoNT/A and toxin-neutralizing antibodies inhibited SNAP-25 cleavage, demonstrating the utility of these cultures for the assay of BoNT/A antagonists. ( Journal of Biomolecular Screening 2007:370-377)

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Intratracheal inoculation of AHc vaccine induces protection against aerosolized botulinum neurotoxin A challenge in mice

npj Vaccines ◽

10.1038/s41541-021-00349-w ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Changjiao Gan ◽

Wenbo Luo ◽

Yunzhou Yu ◽

Zhouguang Jiao ◽

Sha Li ◽

...

Keyword(s):

Bronchoalveolar Lavage ◽

Clostridium Botulinum ◽

Freeze Drying ◽

Botulinum Neurotoxin ◽

Secretory Iga ◽

Immune Protection ◽

Dry Powder ◽

Botulinum Neurotoxin A ◽

Spray Freeze Drying

AbstractBotulinum neurotoxin (BoNT), produced by Clostridium botulinum, is generally known to be the most poisonous of all biological toxins. In this study, we evaluate the protection conferred by intratracheal (i.t.) inoculation immunization with recombinant Hc subunit (AHc) vaccines against aerosolized BoNT/A intoxication. Three AHc vaccine formulations, i.e., conventional liquid, dry powder produced by spray freeze drying, and AHc dry powder reconstituted in water are prepared, and mice are immunized via i.t. inoculation or subcutaneous (s.c.) injection. Compared with s.c.-AHc-immunized mice, i.t.-AHc-immunized mice exhibit a slightly stronger protection against a challenge with 30,000× LD50 aerosolized BoNT/A. Of note, only i.t.-AHc induces a significantly higher level of toxin-neutralizing mucosal secretory IgA (SIgA) production in the bronchoalveolar lavage of mice. In conclusion, our study demonstrates that the immune protection conferred by the three formulations of AHc is comparable, while i.t. immunization of AHc is superior to s.c. immunization against aerosolized BoNT/A intoxication.

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