Counteraction of axonal growth inhibitory properties of Semaphorin 3A and myelin‐associated proteins by a synthetic neurotrophic compound

• Published in: Journal of neurochemistry Vol. 90; no. 6; pp. 1423 - 1431
• Main Authors: Hanbali, Mazen, Bernard, Frédéric, Berton, Caroline, Gatineau, Gilles, Perraut, Martine, Aunis, Dominique, Luu, Bang, Bagnard, Dominique
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Science Ltd 01.09.2004; Blackwell
• Subjects: Animals; Animals, Newborn; axon; Axons - drug effects; Axons - physiology; Biological and medical sciences; Blotting, Western - methods; Cell Count - methods; Cells, Cultured; Cerebral Cortex - cytology; cortex; Cyclohexanones - chemistry; Cyclohexanones - pharmacology; Dendrites - drug effects; Development. Senescence. Regeneration. Transplantation; Dose-Response Relationship, Drug; Drug Interactions; Enzyme Inhibitors - pharmacology; Fatty Alcohols; Fundamental and applied biological sciences. Psychology; Immunohistochemistry - methods; Mice; myelin; Myelin-Associated Glycoprotein - antagonists & inhibitors; Myelin-Associated Glycoprotein - pharmacology; Nerve Growth Factors - pharmacology; Neurites - drug effects; Neurites - physiology; Neurons - cytology; Neurons - drug effects; neurotrophic factor; regeneration; Semaphorin; Semaphorin-3A - antagonists & inhibitors; Semaphorin-3A - pharmacology; Signal Transduction - drug effects; Vertebrates: nervous system and sense organs; cortex; Neurotrophic factor; Regeneration; Cerebral cortex; Growth; Myelin; Central nervous system; Axon; Semaphorin; Encephalon
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2004.02601.x

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 ω‐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.