title: Peptide mimetic of the S100A4 protein modulates peripheral nerve regeneration and attenuates the progression of neuropathy in myelin protein P0 null mice.
abstract: We recently found that S100A4, a member of the multifunctional S100 protein family, protects neurons in the injured brain and identified two sequence motifs in S100A4 mediating its neurotrophic effect. Synthetic peptides encompassing these motifs stimulated neuritogenesis and survival in vitro and mimicked the S100A4-induced neuroprotection in brain trauma. Here, we investigated a possible function of S100A4 and its mimetics in the pathologies of the peripheral nervous system (PNS). We found that S100A4 was expressed in the injured PNS and that its peptide mimetic (H3) affected the regeneration and survival of myelinated axons. H3 accelerated electrophysiological, behavioral and morphological recovery after sciatic nerve crush while transiently delaying regeneration after sciatic nerve transection and repair. On the basis of the finding that both S100A4 and H3 increased neurite branching in vitro, these effects were attributed to the modulatory effect of H3 on initial axonal sprouting. In contrast to the modest effect of H3 on the time course of regeneration, H3 had a long-term neuroprotective effect in the myelin protein P0 null mice, a model of dysmyelinating neuropathy (Charcot-Marie-Tooth type 1 disease), where the peptide attenuated the deterioration of nerve conduction, demyelination and axonal loss. From these results, S100A4 mimetics emerge as a possible means to enhance axonal sprouting and survival, especially in the context of demyelinating neuropathies with secondary axonal loss, such as Charcot-Marie-Tooth type 1 disease. Moreover, our data suggest that S100A4 is a neuroprotectant in PNS and that other S100 proteins, sharing high homology in the H3 motif, may have important functions in PNS pathologies.
authors.affiliation: Nerve Laboratory, Department of Neuroscience and Pharmacology, Panum Institute, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Mihai
authors.initials: M
authors.lastname: Moldovan
authors.forename: Volodymyr
authors.initials: V
authors.lastname: Pinchenko
authors.forename: Oksana
authors.initials: O
authors.lastname: Dmytriyeva
authors.forename: Stanislava
authors.initials: S
authors.lastname: Pankratova
authors.forename: Kåre
authors.initials: K
authors.lastname: Fugleholm
authors.forename: Jorg
authors.initials: J
authors.lastname: Klingelhofer
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Bock
authors.forename: Vladimir
authors.initials: V
authors.lastname: Berezin
authors.forename: Christian
authors.initials: C
authors.lastname: Krarup
authors.forename: Darya
authors.initials: D
authors.lastname: Kiryushko
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002607:Charcot-Marie-Tooth Disease / Q000188:drug therapy / Q000503:physiopathology; D006624:Hippocampus / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018993:Myelin P0 Protein / Q000235:genetics; D009416:Nerve Regeneration / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D010455:Peptides / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D009418:S100 Proteins / Q000494:pharmacology* / Q000627:therapeutic use; D012584:Sciatic Nerve / Q000187:drug effects* / Q000293:injuries / Q000503:physiopathology; D013979:Tibial Nerve / Q000187:drug effects / Q000503:physiopathology
chemical_list: D018993:Myelin P0 Protein; D018696:Neuroprotective Agents; D010455:Peptides; D009418:S100 Proteins