title: Therapeutic effects of Clostridium botulinum C3 exoenzyme.
abstract: C3 exoenzyme from Clostridium botulinum, specifically ADP-ribosylates small GTP-binding proteins RhoA, B, and C. ADP-ribosylation causes functional inactivation of Rho proteins resulting in cessation of the complete downstream signaling. Rho proteins are general regulators of a lot of essential cellular functions, among others, the neuronal growth cone. Rho activation, triggered by neuronal injury, inhibits neuronal repair mechanisms. To prevent the detrimental effect of active Rho in the recovery of injured neuronal systems, C3 has become a promising drug to inactivate RhoA in neurons. During the advancement of C3 to a drug candidate, it was found that ADP-ribosyltransferase activity of C3, in fact, is not essential for axonal and dendritic growth and branching. Rather, a peptide fragment of C3 covering the surface exposed ARTT loop from C3 (C3(154-182) peptide) is sufficient to induce growth and branching of neurons comparable to the effect of full-length C3. Whereas full-length C3 also acts on astrocytes and microglia to induce-at least in an in vitro model-inflammation and glial scar formation, C3(154-182) peptide is inert and seems only to act on neurons. In addition to its axono- and dendritotrophic effects on cultured primary hippocampal neurons, C3(154-182) peptide enhanced functional recovery and regeneration in a mouse model of spinal cord injury. Thus, in a proof-of-principle experiment, C3 peptide was shown to be efficacious in post-traumatic neuro-regeneration.
authors.affiliation: Institut für Toxikologie, Medizinische Hochschule Hannover, 30625 Hannover, Germany. just.ingo@mh-hannover.de
authors.forename: Ingo
authors.initials: I
authors.lastname: Just
authors.forename: Astrid
authors.initials: A
authors.lastname: Rohrbeck
authors.forename: Stefanie C
authors.initials: SC
authors.lastname: Huelsenbeck
authors.forename: Markus
authors.initials: M
authors.lastname: Hoeltje
mesh_terms: D036002:ADP Ribose Transferases / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001905:Botulinum Toxins / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D009416:Nerve Regeneration / Q000187:drug effects; D013119:Spinal Cord Injuries / Q000188:drug therapy*; D020741:rho GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D036002:ADP Ribose Transferases; C063007:exoenzyme C3, Clostridium botulinum; D001905:Botulinum Toxins; D020741:rho GTP-Binding Proteins