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Botulinum Neurotoxins Serotypes A and B induce paralysis of mouse striated and smooth muscles with different potencies

Maignel-Ludop, J;Huchet, M;Krupp, J;

To address the scarcity of direct comparison of botulinum neurotoxin serotypes activity on smooth versus striatal muscle, we have studied the action of BoNT/A1 and BoNT/B1 on ex vivo preparations of both muscle types. We have set up and characterized a model of neurogenic contractions in the isolated mouse bladder, and used this model to explore the effects of the two serotypes on contractions evoked by electrical field stimulation. Both toxins were also tested in the mouse phrenic nerve hemidiaphragm assay, to compare their potency in smooth versus striated muscle. The characterization of the model of neurogenic contractions in the isolated mouse bladder indicates that about half of the activity is driven by purinergic signaling, and about half by cholinergic signaling. Furthermore, we find that BoNT/B1 is more potent than BoNT/A1 in inhibiting activity in the mouse detrusor smooth muscle preparation, but that both toxins have comparable potency on the striated muscle activity of the phrenic nerve hemidiaphragm model. We also show that these findings are mouse strain independent. In conclusion, the established mouse bladder detrusor smooth muscle model is able to discriminate between different botulinum neurotoxin serotypes and could be a useful preclinical tool to explore the pathophysiology of bladder overactivity, as well as the effects of new therapeutic candidates. It is interesting to note that the high proportion of purinergic transmission driving detrusor contractions in this model is similar to that seen in neurodetrusor overactivity disease, making this model relevant with regard to pathophysiological interest.