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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?

English title 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?
Applicant Wannier Thierry Marcel Joseph
Number 104061
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 01.08.2004 - 30.09.2007
Approved amount 248'300.00
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Keywords (6)

primate; spinal cord injury; regeneration; BDNF; Nogo; neurotrophins

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 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. Thereby the repertoire of movements that one can generate becomes limited. Various laboratories are working to find out if an injured spinal cord can be repaired if the inhibitory action of Nogo is neutralized. Among them, the laboratory of Prof. M. Schwab in Zürich has investigated this question in the rat with a technique which consists of neutralizing Nogo by "covering" it with another substance, in this case, with an antibody specifically attaching to Nogo. Used on isolated nervous cells, this technique promotes the growth of axons. Used in rats subjected to a spinal cord lesion, a limited but consistent growth of axons has been observed. In this case, not only is the growth sufficient to build a bridge over the lesion, but some functional improvements have also been found. This is therefore one among other techniques which may ultimately find its way to clinic and help patients to recover better from a spinal cord injury.

If the results from the rat experiments are encouraging, their direct translation to human is 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, if safe clinical trials are the final goal, supporting data should first be obtained by repairing spinal cords of non-human primates (monkeys), in a species which shares much of the organisation and complexity of the human spinal cord. The aim of our study is to investigate this question using macaque monkeys as a model.

A group of adult macaque monkeys (macaca fascicularis) is first trained to perform a battery of motor tasks, testing essentially the manual dexterity. 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 axons (the dorsolateral funiculus) which is prominent in primates and humans, and whose section is known to permanently disable the generation of precise fine finger movements. A subgroup of lesioned animals are treated with 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.

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 manual dexterity is thoroughly tested using quantitative analysis, a clear difference emerged. A simple but powerful test consists in presenting a board with wells filled with small food pellets to the animals. 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 difficult. The movements are considerably slowed down, and the position of the fingers is also abnormal: the thumb is not moved actively, but remains flexed in the palm and is only used as a passive substrate on which the forefinger clinched the pellet. This is indicative of a strategy of substitution rather than of a real recovery of normal finger movements. In contrast, the anti-Nogo treated animals recover faster and to substantially better levels. They are able to grasp pellets out of both vertical and horizontal wells, and though somewhat slower than normal. Also the way to use the fingers appear closer to normal: the thumb is moved in opposition to the forefinger and the pellet held between their tips. Also in two other motor tasks requiring motor dexterity, the level of recovery is considerably higher for the anti-Nogo treated animals. However, when testing the motor capacity of the hind limb, both animals show similar limited levels of recovery.

In parallel to the enhancement of motor recovery by anti-Nogo treatment, anatomical investigations on the same monkeys allowed to demonstrate that anti-Nogo treatment promotes a reconstruction of the lesioned corticospinal track caudal to the lesion, possibly representing the anatomical support for the enhanced functional rehabilitation.

These are encouraging results, suggesting for the first time that, by blocking the action of Nogo, one can help the spinal cord of primates to re-establish some severed connections and thereby to recover in part from an injury. In this respect, our observations are in agreement with those previously obtained in rats. Another important observation derived from these experiments is that the anti-Nogo treated monkeys do not exhibit signs of pain, epilepsy or unusual behaviour, indicating that the treatment does not produce undesired marked secondary effects. In summary, these data in monkeys pave the way towards safer pilot clinical tests in human subjects, although this model in monkeys remains crucial in order to address the fundamental issue of the mechanisms involved in the re-growth of transected axons favoured by the anti-Nogo treatment.
Direct link to Lay Summary Last update: 21.02.2013

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Associated projects

Number Title Start Funding scheme
118357 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 01.10.2007 Project funding (Div. I-III)

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