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In macaques with a partial spinal hemisection, can BDNF with an antibody neutralizing Nogo-A promote the growth of primary afferents, act on the transfer of sensory information and improve sensory-motor behaviours

English title In macaques with a partial spinal hemisection, can BDNF with an antibody neutralizing Nogo-A promote the growth of primary afferents, act on the transfer of sensory information and improve sensory-motor behaviours
Applicant Wannier Thierry Marcel Joseph
Number 118357
Funding scheme Project funding (Div. I-III)
Research institution Département de Médecine Université de Fribourg
Institution of higher education University of Fribourg - FR
Main discipline Neurophysiology and Brain Research
Start/End 01.10.2007 - 30.04.2011
Approved amount 206'255.00
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Keywords (6)

primate; spinal cord injury; regeneration; neurotrophin; nogo-A; recovery

Lay Summary (English)

Lead
Lay summary
Patients suffering from a spinal cord injury and who are now sitting in a roll chair know it only too well: their spinal cord does not repair spontaneously and medicine is presently poorly armed to help! One reason accounting for this situation in the adult central nervous system is the presence in the whole brain and spinal cord of growth inhibitory substances, such as that what scientists call "Nogo" and which hinders the growth of the lines interconnecting distant nervous cells, the axons. Without these lines, which have been damaged by the injury, the spinal cord remains divided into two parts which are not communicating. Thus, the signals from the brain do not travel further from the lesion and cannot act on the severed portion of the spinal cord. Various laboratories are working to find out if an injured spinal cord can be repaired if the inhibitory action of Nogo is neutralized. In recent years, axonal growth has been obtained in rats subjected to a spinal cord lesion by blocking the action of Nogo. Not only was the growth sufficient to build a bridge over the lesion, but some functional improvements have also been found. While the results from the rat experiments were encouraging, their direct translation to clinic was hazardous. For instance, this technique promotes the growth of axons but does not ensure that in human the growing axons will not build aberrant circuits with an overall deleterious effect. Therefore, before starting clinical trials, additional data had to be gained to make certain that the treatment also favors regeneration and recovery in primates, and also to reduce the risks that it could have a negative impact on patients. Our investigations in non-human primates have demonstrated that the treatment leads to some anatomical repair of spinal cords which were paralleled by functional recovery. Moreover, no adverse effects of the treatment have been observed. Our data have contributed at the launch of a clinical trial. Quantitative analysis of the effects of the anti-Nogo-A treatment on the growth of corticospinal fibres have show that this growth is rather local and of limited strength in the macaque. Because investigations in the rat have shown that the combination of substances improving the growth of axons and of a treatment blocking the action of Nogo effectively leads to an extended growth of axons over longer distance, the question arise as to whether this observation remains valid for the macaque, and if a further improvement of recovery can be obtained. We are presently following investigations on this topic. Specifically, we search to clarify whether combining the anti-Nogo-A treatment with the application of the neurotrophic substance BDNF (Brain Derived Neurotrophic Factor) fosters the growth capacity of CS neurones, reverses the axotomy driven changes in rubrospinal and corticospinal neurones, and improves functional recovery. Because of the limited number of animals used and of the compression of the spinal cord in two animals, additional data are required to reach firm conclusions. The present investigations shall not only deliver these additional data, but also gain original information regarding the effects of the treatment on the growth of primary sensory afferents as well as on the transmission and use of sensory signal. This issue is perceived as being of prime importance by paraplegic patients, who do not wish to only regain motor capacity, but also to recover normal sensation. The experiments start by training adult macaque monkeys to perform a battery of tasks designed to assess manual dexterity and sensory-motor control. When the animals master the tasks, they are anaesthetized and a portion of their spinal cord is cut on one side. The lesion is set so as to interrupt a bundle of nerve fibers projecting directly from the brain to the spinal cord and which is prominent in primates and humans. The section of these fibres is known to permanently disable the generation of precise fine finger movements. The section also interrupts fibres conveying sensory information towards the brain. A subgroup of lesioned animals are treated with a combination of BDNF and of an antibody directed against Nogo, whereas the other subgroup of lesioned animals, called control animals hereafter, receive a control antibody which does not interfere with Nogo and no BDNF. The day after the surgery, the animals show a loss of motor ability for the hand affected by the lesion. Weeks later, they recover most of their capacity to walk, climb or jump, and little distinguish these animals from intact animals. However, if their dexterity is thoroughly tested using quantitative analysis, a clear difference emerged. A simple but powerful test consists in presenting to the animals a board with wells filled with small food pellets. The wells are elongated and orientated either horizontally or vertically. The monkey has to retrieve the pellets, a task which depends upon the ability to perform small precise finger movements. From the time required to get the pellets, from the capacity to get them out of both vertical and horizontal holes, and from the way the fingers are used, a picture of the recovery level can be obtained. In general, the control animals are able to retrieve food pellets out of the vertical holes, but retrieval from the horizontal slots remains particularly difficult. The movements are considerably slowed down, and the position of the fingers is also abnormal. In contrast, the anti-Nogo-A/BDNF treated animals recover faster and to substantially better levels. In anti-Nogo-A treated animals, in parallel to the enhancement of motor recovery, a partial reconstruction of the lesioned corticospinal tract caudal to the lesion was observed. This possibly represents the anatomical substrate accounting for the enhanced functional rehabilitation. Ongoing analysis shall clarify whether this growth enhancement can also be observed in the anti-Nogo-A/BDNF treated animals, and whether the combination treatment extends the growth in these animals. By evaluating whether a combination of BDNF and of the anti-Nogo-A antibody lead to better functional recovery in primates, these investigations may contribute to introduce a safe and effective method to bridge a spinal lesion in human subjects.
Direct link to Lay Summary Last update: 21.02.2013

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Associated projects

Number Title Start Funding scheme
104061 Does a BDNF treatment protect corticospinal and rubrospinal neurons from the secondary damages in spinalized monkey and add to the functional recovery obtained with an anti-Nogo treatment? 01.08.2004 Project funding (Div. I-III)

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