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In vivo targeting of mouse sensory nerve fibers by C2C. Latissimus dorsi samples were obtained after subcutaneous administration of fluorescently derivatized C2C followed by treatment with antibody reporters. a Cryosections. Top row; DAPI DNA stain (white), sensory neuron marker anti-calcitonin gene related peptide (CGRP, green), general nerve fiber marker anti-neurofilament (NF, red), C2C (blue). Bottom row; as for top row but anti-choline acetyltransferase (ChAT) replaces NeuF (red). Scale bar is 20 µm, inset scale bar is 5 µm. b Whole mounts with 1.2 µm optical slices; anti-calcitonin gene related peptide (CGRP, blue), C2C (green). Scale bar is 30 µm.
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The engineered multifunctional protein C2C was tested for control of sensory neuron activity by targeted G-actin modification. C2C consists of the heptameric oligomer, C2II-CI, and the monomeric ribosylase, C2I. C2C treatment of sensory neurons and SH-SY5Y cells in vitro remodeled actin and reduced calcium influx in a reversible manner. C2C prepare...
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Citations
... Reducing sensory neuron F-actin content by shifting actin treadmilling could block pain signaling by limiting ion channel activity. We have previously demonstrated the design and use of a novel recombinant protein (N-001) as a candidate inflammatory pain analgesic in vitro and in vivo 24,25 . N-001 is a recombinant protein engineered from several Clostridium botulinum toxins. ...
... The result of N-001 restoring normal gait after paw incision provides supporting evidence for its effectiveness against nociception particularly when combined with www.nature.com/scientificreports/ stimulus-dependent efficacy results 24 . The increased duration of efficacy at 72 h was noticeably longer than current analgesics. ...
... The increased duration of efficacy at 72 h was noticeably longer than current analgesics. Additionally the antinociceptive behavior in mice was reversible presumably because N-001 entered the cell by receptor-mediated endocytosis, limiting its intracellular amount where it reversibly modified actin 24 . The hind paw incision model used here for simulating post-operative pain has been recognized as a useful tool for drug testing and studying mechanisms of postoperative pain 40 . ...
Inhibition of actin remodeling in nerves modulates action potential propagation and therefore could be used to treat acute pain. N-001 is a novel protein analgesic engineered from several C. Botulinum toxins. N-001 targets sensory neurons through ganglioside GT1b binding and ADP-ribosylates G-actin reducing actin remodeling. The activity and efficacy of N-001 was evaluated previously in vitro and in a mouse inflammatory pain model. To assess the relevance of N-001 for treatment of acute post-surgical pain, the current study evaluated the efficacy of N-001 in a mouse hind-paw incision model by peri-incisional and popliteal nerve block administration combined with mechanical testing. N-001 provided relief of pain-like behavior over 3 days and 2 days longer than the conventional long-acting anesthetic bupivacaine. Preclinical safety studies of N-001 indicated the drug produced no toxic or adverse immunological reactions over multiple doses in mice. These results combined with past targeting results encourage further investigation of N-001 as an analgesic for post-operative pain management with the potential to function as a differential nociceptor-specific nerve block.
... Interestingly, we found strong colocalisation of 5-HT and αSMA in mechanosensory cells of L. terrestris. Actin is involved in sensory impulse transmission (Allen et al., 2020). αSMA, an actin isoform that contributes to cell-generated mechanical tension, is normally restricted to cells of vascular smooth muscle, but it can also be expressed in certain nonmuscle cells, most notably in myofibroblasts. ...
Ciliated and non‐ciliated mechanosensory cells in invertebrates have intricate cytoskeletal structures that, combined with microtubules, act as a mechanical link between external stimulus and signal processing. As a result, they can perceive forces like touch, cuticle deformation, gravity and sound. Through the expression of antibodies against serotonin (5‐HT), calbindin, inducible nitric oxide synthase (iNOS) and α‐smooth muscle actin (αSMA), this research aims to investigate mechanosensory cells in the integument of Lumbricus terrestris (Linnaeus, 1758) in an evolutionary perspective. In the epidermis, we discovered isolated mechanosensory cells that were immunopositive to every antibody examined. Our findings improve the knowledge and the evolution of annelid sensory biology adding new insights on the sensory signal transduction and help to better understand the morpho‐structural adaptations of invertebrate skin on an evolutionary scale and to give more taxonomic data for species distinction.
The treatment of pain with botulinum neurotoxins is now entering a new era due to the discovery of new peripheral and central pain receptors and the emergence of newly engineered toxins (chimeras). These chimeras that selectively target peripheral and central sensory neurons potentially offer a more effective means of pain control. This chapter discusses the newly developed BoNT chimeras and what they can offer for relieving pain. Furthermore, newly published data indicating a role for botulinum toxin therapy in reducing tissue damage, promoting regeneration, and alleviating neuropathic pain after nervous system injury is presented.
