Counteraction of axonal growth inhibitory properties of Semaphorin 3A and myelin-associated proteins by a synthetic neurotrophic compound.
One of the reasons for the lack of nerve regeneration in the CNS is the formation of a glial scar over-expressing multiple inhibitory factors including myelin-associated proteins and members of the Semaphorin family. Innovative therapeutic strategies must stimulate axon extension across the lesion site despite this inhibitory molecular barrier. We recently developed a synthetic neurotrophic compound combining an omega-alkanol with a retinol-like cycle (3-(15-hydroxy-pentadecyl)-2,4,4,-trimethyl-cyclohexen-2-one (tCFA15)). Here, we demonstrate that tCFA15 is able to promote cortical axon outgrowth in vitro even in the presence of the inhibitory Semaphorin 3A and myelin extracts. This growth-promoting effect is selectively observed in axons and requires multiple growth-associated intracellular pathways. Our results illustrate the potential use of synthetic neurotrophic compounds to promote nerve regeneration by counteracting the axonal growth inhibition triggered by glial scar-associated inhibitory factors.
Hanbali
Mazen
M
INSERM U575, Physiopathologie du Système Nerveux, Centre de Neurochimie, Strasbourg, France.
Bernard
Frédéric
F
Berton
Caroline
C
Gatineau
Gilles
G
Perraut
Martine
M
Aunis
Dominique
D
Luu
Bang
B
Bagnard
Dominique
D
D000818:Animals; D000831:Animals, Newborn; D001369:Axons / Q000187:drug effects* / Q000502:physiology; D015153:Blotting, Western / Q000379:methods; D002452:Cell Count / Q000379:methods; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D003512:Cyclohexanones / Q000737:chemistry / Q000494:pharmacology*; D003712:Dendrites / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005233:Fatty Alcohols; D007150:Immunohistochemistry / Q000379:methods; D051379:Mice; D018992:Myelin-Associated Glycoprotein / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D009414:Nerve Growth Factors / Q000494:pharmacology*; D016501:Neurites / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000166:cytology* / Q000187:drug effects; D040121:Semaphorin-3A / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects
C420963:3-(15-hydroxypentadecyl)-2,4,4-trimethyl-2-cyclohexen-1-one; D003512:Cyclohexanones; D004791:Enzyme Inhibitors; D005233:Fatty Alcohols; D018992:Myelin-Associated Glycoprotein; D009414:Nerve Growth Factors; D040121:Semaphorin-3A