title: Chondroitinase ABC combined with neurotrophin NT-3 secretion and NR2D expression promotes axonal plasticity and functional recovery in rats with lateral hemisection of the spinal cord.
abstract: Elevating spinal levels of neurotrophin NT-3 (NT3) while increasing expression of the NR2D subunit of the NMDA receptor using a HSV viral construct promotes formation of novel multisynaptic projections from lateral white matter (LWM) axons to motoneurons in neonates. However, this treatment is ineffective after postnatal day 10. Because chondroitinase ABC (ChABC) treatment restores plasticity in the adult CNS, we have added ChABC to this treatment and applied the combination to adult rats receiving a left lateral hemisection (Hx) at T8. All hemisected animals initially dragged the ipsilateral hindpaw and displayed abnormal gait. Rats treated with ChABC or NT3/HSV-NR2D recovered partial hindlimb locomotor function, but animals receiving combined therapy displayed the most improved body stability and interlimb coordination [Basso-Beattie-Bresnahan (BBB) locomotor scale and gait analysis]. Electrical stimulation of the left LWM at T6 did not evoke any synaptic response in ipsilateral L5 motoneurons of control hemisected animals, indicating interruption of the white matter. Only animals with the full combination treatment recovered consistent multisynaptic responses in these motoneurons indicating formation of a detour pathway around the Hx. These physiological findings were supported by the observation of increased branching of both cut and intact LWM axons into the gray matter near the injury. ChABC-treated animals displayed more sprouting than control animals and those receiving NT3/HSV-NR2D; animals receiving the combination of all three treatments showed the most sprouting. Our results indicate that therapies aimed at increasing plasticity, promoting axon growth and modulating synaptic function have synergistic effects and promote better functional recovery than if applied individually.
authors.affiliation: Centre for Brain Repair, University of Cambridge, Cambridge CB2 0PY, United Kingdom.
authors.forename: Guillermo
authors.initials: G
authors.lastname: García-Alías
authors.forename: Hayk A
authors.initials: HA
authors.lastname: Petrosyan
authors.forename: Lisa
authors.initials: L
authors.lastname: Schnell
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Horner
authors.forename: William J
authors.initials: WJ
authors.lastname: Bowers
authors.forename: Lorne M
authors.initials: LM
authors.lastname: Mendell
authors.forename: James W
authors.initials: JW
authors.lastname: Fawcett
authors.forename: Victor L
authors.initials: VL
authors.lastname: Arvanian
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001369:Axons / Q000378:metabolism* / Q000473:pathology; D001710:Biotin / Q000031:analogs & derivatives / Q000378:metabolism; D002478:Cells, Cultured; D019765:Chondroitin ABC Lyase / Q000378:metabolism*; D011508:Chondroitin Sulfate Proteoglycans / Q000378:metabolism; D003911:Dextrans / Q000378:metabolism; D004195:Disease Models, Animal; D019706:Excitatory Postsynaptic Potentials; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D049452:Green Fluorescent Proteins / Q000235:genetics; D006930:Hyperalgesia / Q000503:physiopathology; D008124:Locomotion / Q000502:physiology; D009473:Neuronal Plasticity / Q000502:physiology*; D020933:Neurotrophin 3 / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D020127:Recovery of Function / Q000502:physiology*; D013119:Spinal Cord Injuries / Q000378:metabolism* / Q000503:physiopathology*; D014162:Transfection; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D011508:Chondroitin Sulfate Proteoglycans; D003911:Dextrans; C464436:NR2D NMDA receptor; D020933:Neurotrophin 3; D016194:Receptors, N-Methyl-D-Aspartate; C076397:biotinylated dextran amine; D049452:Green Fluorescent Proteins; D001710:Biotin; D001616:beta-Galactosidase; D019765:Chondroitin ABC Lyase