title: Combined delivery of Nogo-A antibody, neurotrophin-3 and the NMDA-NR2d subunit establishes a functional 'detour' in the hemisected spinal cord.
abstract: To encourage re-establishment of functional innervation of ipsilateral lumbar motoneurons by descending fibers after an intervening lateral thoracic (T10) hemisection (Hx), we treated adult rats with the following agents: (i) anti-Nogo-A antibodies to neutralize the growth-inhibitor Nogo-A; (ii) neurotrophin-3 (NT-3) via engineered fibroblasts to promote neuron survival and plasticity; and (iii) the NMDA-receptor 2d (NR2d) subunit via an HSV-1 amplicon vector to elevate NMDA receptor function by reversing the Mg(2+)  block, thereby enhancing synaptic plasticity and promoting the effects of NT-3. Synaptic responses evoked by stimulation of the ventrolateral funiculus ipsilateral and rostral to the Hx were recorded intracellularly from ipsilateral lumbar motoneurons. In uninjured adult rats short-latency (1.7-ms) monosynaptic responses were observed. After Hx these monosynaptic responses were abolished. In the Nogo-Ab + NT-3 + NR2d group, long-latency (approximately 10 ms), probably polysynaptic, responses were recorded and these were not abolished by re-transection of the spinal cord through the Hx area. This suggests that these novel responses resulted from new connections established around the Hx. Anterograde anatomical tracing from the cervical grey matter ipsilateral to the Hx revealed increased numbers of axons re-crossing the midline below the lesion in the Nogo-Ab + NT-3 + NR2d group. The combined treatment resulted in slightly better motor function in the absence of adverse effects (e.g. pain). Together, these results suggest that the combination treatment with Nogo-Ab + NT-3 + NR2d can produce a functional 'detour' around the lesion in a laterally hemisected spinal cord. This novel combination treatment may help to improve function of the damaged spinal cord.
authors: Brain Research Institute, University and ETH of Zurich, Zurich, Switzerland.
authors: Lisa
authors: L
authors: Schnell
authors: Arsen S
authors: AS
authors: Hunanyan
authors: William J
authors: WJ
authors: Bowers
authors: Philip J
authors: PJ
authors: Horner
authors: Howard J
authors: HJ
authors: Federoff
authors: Miriam
authors: M
authors: Gullo
authors: Martin E
authors: ME
authors: Schwab
authors: Lorne M
authors: LM
authors: Mendell
authors: Victor L
authors: VL
authors: Arvanian
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D001522:Behavior, Animal / Q000502:physiology; D005260:Female; D006801:Humans; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009046:Motor Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D009185:Myelin Proteins / Q000276:immunology*; D020933:Neurotrophin 3 / Q000494:pharmacology* / Q000627:therapeutic use; D000070798:Nogo Proteins; D021122:Protein Subunits / Q000494:pharmacology* / Q000627:therapeutic use; D011597:Psychomotor Performance; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000627:therapeutic use*; D013116:Spinal Cord / Q000187:drug effects* / Q000473:pathology; D013119:Spinal Cord Injuries / Q000188:drug therapy / Q000473:pathology* / Q000503:physiopathology
chemical_list: D000911:Antibodies, Monoclonal; D009185:Myelin Proteins; C464436:NR2D NMDA receptor; D020933:Neurotrophin 3; D000070798:Nogo Proteins; D021122:Protein Subunits; C000603199:RTN4 protein, human; D016194:Receptors, N-Methyl-D-Aspartate; C000603197:Rtn4 protein, rat