Combined delivery of Nogo-A antibody, neurotrophin-3 and the NMDA-NR2d subunit establishes a functional ‘detour’ in the hemisected spinal cord

Brain Research Institute, University and ETH of Zurich, Zurich, Switzerland.
European Journal of Neuroscience (Impact Factor: 3.18). 10/2011; 34(8):1256-67. DOI: 10.1111/j.1460-9568.2011.07862.x
Source: PubMed


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.

Download full-text


Available from: Lorne Mendell,
40 Reads
  • Source
    • "The behavioral data were correlated with the highest number of sprouting axons in the spinal cord and multisynaptic responses in the motor-neurons. Similar results could be found if anti-Nogo-A antibodies were combined with NT-3 and the NMDA-NR2D subunit (Schnell et al., 2011). Furthermore, the combinatorial treatment of acutely applied anti-Nogo-A antibody followed by delayed Chondroitinase ABC treatment starting 3 weeks after spinal cord injury, and forelimb grasp training starting at 4 weeks was much more effective in terms of functional recovery , sprouting and axonal regeneration than the single treatments (Rehme et al., 2011). "
    [Show abstract] [Hide abstract]
    ABSTRACT: After stroke the central nervous system reveals a spectrum of intrinsic capacities to react as a highly dynamic system which can change the properties of its circuits, form new contacts, erase others, and remap related cortical and spinal cord regions. This plasticity can lead to a surprising degree of spontaneous recovery. It includes the activation of neuronal molecular mechanisms of growth and of extrinsic growth promoting factors and guidance signals in the tissue. Rehabilitative training and pharmacological interventions may modify and boost these neuronal processes, but almost nothing is known on the optimal timing of the different processes and therapeutic interventions and on their detailed interactions. Finding optimal rehabilitation paradigms requires an optimal orchestration of the internal processes of re-organization and the therapeutic interventions in accordance with defined plastic time windows. In this review we summarize the mechanisms of spontaneous plasticity after stroke and experimental interventions to enhance growth and plasticity, with an emphasis on anti-Nogo-A immunotherapy. We highlight critical time windows of growth and of rehabilitative training and consider different approaches of combinatorial rehabilitative schedules. Finally, we discuss potential future strategies for designing repair and rehabilitation paradigms by introducing a "3 step model": determination of the metabolic and plastic status of the brain, pharmacological enhancement of its plastic mechanisms, and stabilization of newly formed functional connections by rehabilitative training.
    Frontiers in Human Neuroscience 06/2014; 7:911. DOI:10.3389/fnhum.2013.00911 · 3.63 Impact Factor
  • Source
    • "Long term intrathecal treatment with neurotrophins can also promote the development of novel functional pathways in the spinal cord, specifically the formation of functional detours around zones of injury both in neonatal (Arvanian et al., 2006) and adult rats (García-Alías et al., 2011; Schnell et al., 2011). In adults the neurotrophin works best if supplemented with agents that overcome the inhibitory effect of the tissue on axonal growth, e.g., anti Nogo or chondroitinase (reviewed in Fawcett et al., 2012), and provision of NMDA subunit NR2D to bring these receptors back to their juvenile state (Arvanian et al., 2004). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Work early in the last century emphasized the stereotyped activity of spinal circuits based on studies of reflexes. However, the last several decades have focused on the plasticity of these spinal circuits. These considerations began with studies of the effects of monoamines on descending and reflex circuits. In recent years new classes of compounds called growth factors that are found in peripheral nerves and the spinal cord have been shown to affect circuit behavior in the spinal cord. In this review we will focus on the effects of neurotrophins, particularly nerve growth factor (NGF), brain derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3), on spinal circuits. We also discuss evidence that these molecules can modify functions including nociceptive behavior, motor reflexes and stepping behavior. Since these substances and their receptors are normally present in the spinal cord, they could potentially be useful in improving function in disease states and after injury. Here we review recent findings relevant to these translational issues.
    Frontiers in Neural Circuits 06/2014; 8:59. DOI:10.3389/fncir.2014.00059 · 3.60 Impact Factor
  • Source
    • "To examine synaptic pathways through dCST and VLF, we performed an acute focal dorsal column lesion followed by a lateral hemisection at T 8 , i.e., between stimulating and recording electrodes, ipsilateral to the recording/stimulation side, respectively (see Fig. 1B). We performed an acute lesion of the dorsal column to interrupt the transmission through dorsal corticospinal fibers (described in Alstermark et al. 2004) and an acute lateral hemisection to interrupt transmission through lateral white matter (described in Schnell et al. 2011). Each acute lesion was performed after recording from several neurons in the same rat. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Transmission through descending pathways to lumbar motoneurons, although important for voluntary walking in humans and rats, has not been fully understood at the cellular level in contusion models. Major descending pathways innervating lumbar motoneurons include those at corticospinal tract and ventrolateral funiculus (VLF). We examined transmission and plasticity at synaptic pathways from dorsal corticospinal tract (dCST) and VLF to individual motoneurons located in ventral horn and interneurons located in dorsomedial grey matter at lumbar segments following thoracic chronic contusion in adult anesthetized rats. To accomplish this we used intracellular electrophysiological recordings and performed acute focal spinal lesions during the recordings. We directly demonstrate that after thoracic T10 chronic contusion the disrupted dCST axons spontaneously form new synaptic contacts with individual motoneurons, extending around the contusion cavity, through spared ventrolateral white matter. These detour synaptic connections are very weak and strengthening these connections in order to improve function may be a target for therapeutic interventions following SCI. We found that degradation of scar-related chondroitin sulfate proteoglycans using the enzyme ChondroitinaseABC (ChABC) combined with adeno-associated viral (AAV) vector-mediated prolonged delivery of neurotrophin NT-3 (AAV-NT3) strengthened these spontaneously formed connections in contused spinal cord. Moreover, ChABC/AAV-NT3 treatment induced the appearance of additional detour synaptic pathways innervating dorsomedial interneurons. Improved transmission in ChABC/AAV-NT3 treated animals associated with increased immunoreactivity of 5-HT-positive fibers in lumbar dorsal and ventral horns. Improved locomotor function assessed with automated Catwalk highlights the physiological significance of these novel connections.
    Journal of Neurophysiology 07/2013; 110(8). DOI:10.1152/jn.00427.2013 · 2.89 Impact Factor
Show more