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Thread: Dr.Young, question about axonregeneration

  1. #1
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    Dr.Young, question about axonregeneration

    If I remember correctly you always said axons have to grow all the way down to L1-2 to get functional recovery of the legs.But the people of the "IN-1" trial told me it isn't necessary that the axons grow all the way. They said the regenerating axons make connections at higher levels with existing axons and that would be sufficient for functional recovery of the legs.In any case would that be an explanation for the quick recovery in the Lima trial because axons could by far not grow down that quickly according to the estimated growth rates.
    What's your opinion on this?
    And if you think it makes sense do people still need about 10% existing axons to be able to walk or does this make the existing axons more powerfull so that less than 10% would also be sufficient.

  2. #2
    Pecla, my statements related to getting walking back. Perhaps the scientists that you spoke to was referring to reinnervation of segments close to the injury site. I agree that short distance regeneration may restore some segments close to the injury site. I am not sure that they (or you) mean by axons making connections with axons. While axo-axonic synapses have been observed in some animals, this is unlikely to be a mechanism of recovery for the lower spinal cord for the following reasons:

    1. Presumably the injury has damaged most of the descending axons from the injury site to the lower spinal cord (or else the person would not be paralyzed). Therefore, there should be few or no descending axons for the regenerating axons to connect to.

    2. There are some neurons in the spinal cord that send axons from the cervical spinal segments to the lumbar spinal cord. It is possible that regenerating axons may contact some of these neurons mediating intraspinal tracts and convey their signals to the lower spinal cord through that route. However, this would not be true if the injury is in the thoracic spinal cord. In any case, it seems to be a rather roundabout way of trying to convey messages to the lower spinal cord and unlikely to be efficient.

    I am not sure why this possibility is being raised for IN-1. After all, the promise and hope of IN-1 was that it would block the white matter growth inhibitors that prevent long distance growth of axons. Schwab saw long distance growth of axons in rats when he treated them IN-1.

    By the way, many studies have now shown that IN-1 strongly stimulate surviving axons crossing the injury site to send out collaterals and innervate more neurons. So, one possible mechanism of action of IN-1 is that it allows the surviving axons to contact and control more neurons.

    I have been thinking that OEG may do the same thing and this might explain the early recovery seen by Huang in Beijing. After all, he is injecting the cells above and below the injury site and not at the injury site itself.

    Wise.

  3. #3
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    Dr.Young, unfortunately I haven't discussed it with them.I had some additional questions after I had an extensive call which I've e-mailed and one of there answers was that the axons didn't have to grow all the way to L1-2 but could make connections at higher levels to recover leg function.So I guess they meant axo-axonic synapses(if that's what it is is called).
    So if I understand you right the "IN-1" could indeed make the axons more powerful, but not as a result of new regenerating axons which makes connections with existing axons but because of a change in the existing axons themselves.It's the first time I hear about such mechanism and it could indeed be an explanation for the quick recoveries in Lisbon and Beijng.

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    Hello Pecla - do you have any new info about the IN1 trials?

  5. #5
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    Duuhh. Just saw your update below.....

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    IP, I posted an update yesterday in the "IN-1 update" topic at the same time as this topic.I don't know if you missed it.

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    Thanks so much for getting the info. To me, the functional recovery sounds promising, and it's great Novartis' big pockets are funding it. Maybe in 2007, 2008 they'll have some drug out and available that we can 'marinate' our spinal cord in.

  8. #8
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    ip, let's hope so.You don't have to thank me it is a pleasure for me if I can collect some info to contribute to this great site.

  9. #9
    Is that drug being used in the genetic engineering SCI cells?

  10. #10
    Some abstracts:

    • Bareyre FM, Haudenschild B and Schwab ME (2002). Long-lasting sprouting and gene expression changes induced by the monoclonal antibody IN-1 in the adult spinal cord. J Neurosci 22:7097-110. Summary: Lesion-induced plasticity of the rat corticospinal tract (CST) decreases postnatally, simultaneously with myelin appearance. In adult rats, compensatory sprouting can be induced by the monoclonal antibody (mAb) IN-1 raised against the growth inhibitory protein Nogo-A. In this study, we examined separately the fate of sensory and motor corticospinal fibers after mAb IN-1 application. Intact adult rats treated with the IN-1 antibody exhibited an increase of aberrant CST projections, i.e., sensory fibers projecting into the ventral horn and motor fibers projecting dorsally. Unilateral lesion of the CST [pyramidotomy (PTX)] in the presence of mAb IN-1 triggered a progressive reorganization of the sprouting of the remaining CST across the midline, with sensory fibers projecting gradually into the denervated dorsal horn and motor fibers projecting into the denervated ventral horn. In unilaterally denervated spinal cords, aberrant sprouts were only transient and disappeared by 6 weeks, whereas midline crossing fibers ending in the appropriate target region were stabilized and persisted over the entire study period. Within the spinal cord, IN-1 antibody treatment was associated with upregulation of growth factors (BDNF, VEGF), growth-related proteins (actin, myosin, GAP-43), and transcription factors (STATs), whereas pyramidotomy induced an enhanced expression of guidance molecules (semaphorins and slits) as well as neurotrophic factors (BDNF, IGFs, BMPs). These gene expression changes may contribute to attraction, guidance, and stabilization of sprouting CST fibers. Brain Research Institute, Department of Biology, University of Zurich, ETH Zurich, 8057 Zurich, Switzerland. florence.bareyre@access.unizh.ch
    • Blochlinger S, Weinmann O, Schwab ME and Thallmair M (2001). Neuronal plasticity and formation of new synaptic contacts follow pyramidal lesions and neutralization of Nogo-A: a light and electron microscopic study in the pontine nuclei of adult rats. J Comp Neurol 433:426-36. Summary: Regeneration and compensatory sprouting are limited after lesions in the mature mammalian central nervous system in contrast to the developing central nervous system (CNS). After neutralization of the growth inhibitor Nogo-A, however, massive sprouting and rearrangements of fiber connections occurred after unilateral pyramidal tract lesions in adult rats: Corticofugal fibers from the lesioned side crossed the midline of the brainstem and innervated the contralateral basilar pontine nuclei. To determine whether these newly sprouted fibers formed synaptic contacts, we analyzed the corticofugal fibers in the basilar pontine nuclei contralateral to the lesion by light and electron microscopy 2 weeks after pyramidotomy and treatment with the Nogo-A-inhibiting monoclonal antibody IN-1 (mAb IN-1). The mAb IN-1, but not a control antibody, led to structural changes in the basilar pons ipsilateral and contralateral to the lesion site. Fibers sprouted across the pontine midline and terminated topographically. They established asymmetric synaptic contacts with the characteristics of normal corticopontine terminals. These results show that adult CNS fibers are able to sprout and to form new synaptic contacts after a lesion when a growth-permissive microenvironment is provided. Brain Research Institute, University of Zurich and Swiss Federal Institute of Technology-Zurich, CH-8057 Zurich, Switzerland.
    • Fouad K, Dietz V and Schwab ME (2001). Improving axonal growth and functional recovery after experimental spinal cord injury by neutralizing myelin associated inhibitors. Brain Res Brain Res Rev 36:204-12. Summary: Injuries of the spinal cord often result in an irretrievable loss of motor and sensory functions of all body parts situated below the lesion site. Functional recovery is restricted mainly due to the limited regeneration and plasticity of injured axons in the adult central nervous system. Over the last few years different experimental approaches have led to axonal growth and functional benefits in animal models. This review focuses on the effects of the neutralization of myelin-associated neurite growth inhibitors, in particular Nogo-A, using the monoclonal antibody IN-1. Acute mAb IN-1 treatment of adult CNS lesioned rats results in extensive plastic changes of neuronal connections and regenerative fiber growth. In two different lesion paradigms (i.e. pyramidal tract lesion and incomplete spinal cord lesion in adult rats), the mAb IN-1-treated animals always showed a higher degree of recovery in various behavioral tests. These observations, together with electrophysiological results, suggest that neuronal CNS circuits of mAb IN-1-treated animals can be rearranged, and that sprouting and regenerating axons form functionally meaningful connections. Brain Research Institute, University of Zurich and Department of Biology ETH Zurich, Winterthurerstrasse 190, CH-8057, Zurich, Switzerland.
    • Merkler D, Metz GA, Raineteau O, Dietz V, Schwab ME and Fouad K (2001). Locomotor recovery in spinal cord-injured rats treated with an antibody neutralizing the myelin-associated neurite growth inhibitor Nogo-A. J Neurosci 21:3665-73. Summary: The limited plastic and regenerative capabilities of axons in the adult mammalian CNS can be enhanced by the application of a monoclonal antibody (mAb), IN-1, raised against the myelin-associated neurite growth inhibitor Nogo-A. The aim of the present study was to investigate the effects of this treatment on the functional recovery of adult rats with a dorsal over-hemisection of the spinal cord. Directly after injury, half of the animals were implanted with mAb IN-1-secreting hybridoma cells, whereas the others received cells secreting a control antibody (anti-HRP). A broad spectrum of locomotor tests (open field locomotor) score, grid walk, misstep withdrawal response, narrow-beam crossing) was used to characterize locomotor recovery during the 5 weeks after the injury. In all behavioral tests, the recovery in the mAb IN-1-treated group was significantly augmented compared with the control antibody-treated rats. EMG recordings of flexor and extensor muscles during treadmill walking confirmed the improvement of the locomotor pattern in the mAb IN-1-treated rats; step-cycle duration, rhythmicity, and coupling of the hindlimbs were significantly improved. No differences between the two groups with regard to nociception were observed in the tail flick test 5 weeks after the operation. These results indicating improved functional recovery suggest that the increased plastic and regenerative capabilities of the CNS after Nogo-A neutralization result in a functionally meaningful rewiring of the motor systems. Department of Neuromorphology, Brain Research Institute, University and Swiss Federal Institute of Technology Zurich, 8057 Zurich, Switzerland.
    • Papadopoulos CM, Tsai SY, Alsbiei T, O'Brien TE, Schwab ME and Kartje GL (2002). Functional recovery and neuroanatomical plasticity following middle cerebral artery occlusion and IN-1 antibody treatment in the adult rat. Ann Neurol 51:433-41. Summary: Stroke is a prevalent and devastating disorder, and no treatment is currently available to restore lost neuronal function after stroke occurs. One unique therapy that may improve functional recovery after stroke is blockade of the neurite inhibitory protein Nogo-A with the monoclonal antibody IN-1, through enhancement of neuroanatomical plasticity from uninjured areas of the central nervous system. In the present study, we combined IN-1 treatment with an ischemic lesion (permanent middle cerebral artery occlusion) to determine the effect of Nogo-A neutralization on cortical plasticity and functional recovery. We report here that, following ischemic stroke and treatment with IN-1, adult rats demonstrated functional recovery on a forelimb-reaching task and new cortico-efferent projections from the opposite, unlesioned hemisphere. These results support the efficacy of Nogo-A blockade as a treatment for ischemic stroke and implicate plasticity from the unlesioned hemisphere as a mechanism for recovery. Neurology and Research Services, Hines Veterans Affairs Hospital, Hines, IL 60153, USA.
    • Schwab ME (2002). Increasing plasticity and functional recovery of the lesioned spinal cord. Prog Brain Res 137:351-9. Summary: In vitro assays have shown that adult CNS tissue, in particular oligodendrocytes and myelin, contains several molecular constituents (Nogo-A/NI-220, MAG, several proteoglycans) which exert neurite growth inhibitory activity. Elimination of oligodendrocytes or myelin, or application of antibodies against some of these constituents enhance regenerative growth and compensatory sprouting of lesioned and unlesioned fiber tracts in spinal cord and brain. Enhanced growth is paralleled by various degrees of functional recovery. Department of Neuromorphology, Brain Research Institute, University of Zurich, Swiss Federal Institute of Technology, Winterthurerstr. 190, 8057 Zurich, Switzerland. schwab@hifo.unizh.ch

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