title: Prevention of posttraumatic axon sprouting by blocking collapsin response mediator protein 2-mediated neurite outgrowth and tubulin polymerization.
abstract: Epileptogenesis following traumatic brain injury (TBI) is likely due to a combination of increased excitability, disinhibition, and increased excitatory connectivity via aberrant axon sprouting. Targeting these pathways could be beneficial in the prevention and treatment of posttraumatic epilepsy. Here, we tested this possibility using the novel anticonvulsant (R)-N-benzyl 2-acetamido-3-methoxypropionamide ((R)-lacosamide [LCM]), which acts on both voltage-gated sodium channels and collapsin response mediator protein 2 (CRMP2), an axonal growth/guidance protein. LCM inhibited CRMP2-mediated neurite outgrowth, an effect phenocopied by CRMP2 knockdown. Mutation of LCM-binding sites in CRMP2 reduced the neurite inhibitory effect of LCM by ∼8-fold. LCM also reduced CRMP2-mediated tubulin polymerization. Thus, LCM selectively impairs CRMP2-mediated microtubule polymerization, which underlies its neurite outgrowth and branching. To determine whether LCM inhibits axon sprouting in vivo, LCM was injected into rats subjected to partial cortical isolation, an animal model of posttraumatic epileptogenesis that exhibits axon sprouting in cortical pyramidal neurons. Two weeks following injury, excitatory synaptic connectivity of cortical layer V pyramidal neurons was mapped using patch clamp recordings and laser scanning photostimulation of caged glutamate. In comparison with injured control animals, there was a significant decrease in the map size of excitatory synaptic connectivity in LCM-treated rats, suggesting that LCM treatment prevented enhanced excitatory synaptic connectivity due to posttraumatic axon sprouting. These findings suggest, for the first time, that LCM's mode of action involves interactions with CRMP2 to inhibit posttraumatic axon sprouting.
authors.affiliation: Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: S M
authors.initials: SM
authors.lastname: Wilson
authors.forename: W
authors.initials: W
authors.lastname: Xiong
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.forename: X
authors.initials: X
authors.lastname: Ping
authors.forename: J D
authors.initials: JD
authors.lastname: Head
authors.forename: J M
authors.initials: JM
authors.lastname: Brittain
authors.forename: P D
authors.initials: PD
authors.lastname: Gagare
authors.forename: P V
authors.initials: PV
authors.lastname: Ramachandran
authors.forename: X
authors.initials: X
authors.lastname: Jin
authors.forename: R
authors.initials: R
authors.lastname: Khanna
mesh_terms: D000081:Acetamides / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001369:Axons / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004834:Epilepsy, Post-Traumatic / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D055785:Gene Knockdown Techniques; D036341:Intercellular Signaling Peptides and Proteins; D000078334:Lacosamide; D009416:Nerve Regeneration / Q000187:drug effects* / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D016501:Neurites / Q000187:drug effects* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D034741:RNA, Small Interfering; D051381:Rats; D017207:Rats, Sprague-Dawley; D014404:Tubulin / Q000378:metabolism*
chemical_list: D000081:Acetamides; D000927:Anticonvulsants; D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; D014404:Tubulin; C095114:collapsin response mediator protein-2; D000078334:Lacosamide