Functional recovery after spinal cord injury: basic science meets clinic

doi:10.1016/S0166-2236(00)01893-2

Trends in Neurosciences

Volume 24, Issue 8, 1 August 2001, Pages 437-439

https://doi.org/10.1016/S0166-2236(00)01893-2 Get rights and content

Abstract

Functional Recovery after Spinal Cord Injury. Held at Ascona, Monte Verità, Switzerland; 1–5 April, 2001. Organizers: Volker Dietz, Martin E. Schwab and Karim Fouad.

Section snippets

Inhibition by myelin

The role of a well-characterized myelin-associated inhibitor, the recently cloned Nogo-A (Ref. 3), was illustrated by Martin Schwab (Brain Research Institute, University of Zurich, Switzerland) and his group. The Nogo gene encodes three protein products (Nogo-A, B and C), which represent the fourth subgroup of the reticulon family. The transmembrane protein Nogo-A is a component of CNS myelin and is recognized by the monoclonal antibody IN-1, which promotes axonal regeneration and functional

Modulation of the immune response

Although there is long-standing evidence that unspecific immunostimulation by LPS (lipopolysaccharide) mimicking bacterial infections can be beneficial for the neuroregenerative outcome, in recent years inflammation has been attributed to wide aspects of secondary injury phenomena, such as lipid peroxidation, cell membrane damage, free radical formation and edema formation.

One answer to all questions?

In order to anticipate future clinical intervention it was noteworthy that approaches that block even a single CNS inhibitor enhance the growth state of neurons and lead to a remarkable regenerative axonal growth under experimental conditions. In conclusion, a combination of strategies will be the most promising way for a successful therapy after spinal cord injury. Although, it will increase the need (1) to clearly distinguish epi-phenomena from effector cascades and (2) to identify the

Key conference outcomes

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Nogo-A blocking might promote prevailing plasticity.
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Need for the identification of the most effective, less harmful cellular substrate (olfactory ensheathing cells, Schwann cells, serotinergic cells) for cell transplantation strategy.
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Therapeutic immunization: are pro-regenerative effects a result of cellular or antibody-mediated effects?
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Insufficient comparability of clinical endpoint measurements to distinguish intrinsic regenerative potential from effects of therapeutic intervention.

References (6)

O. Behar
Putting the spinal cord together again
Neuron
(2000)
D.W. Huang
A therapeutic vaccine approach to stimulate axon regeneration in the adult mammalian spinal cord
Neuron
(1999)
P.J. Horner et al.
Regenerating the damaged central nervous system
Nature
(2000)

There are more references available in the full text version of this article.

Cited by (5)

Permissive and Repulsive Cues and Signalling Pathways of Axonal Outgrowth and Regeneration
2008, International Review of Cell and Molecular Biology
Citation Excerpt :
For example, p75NTR, the common neurotrophin low affinity receptor; the netrin‐1 receptors DCC, UNC5H1, UNC5H2, and UNC5H3; the androgen receptor (AR); RET, the receptor for GDNF (glial cell line‐derived neurotrophic factor); integrins such as αvβ3 and α5β1, and the receptor for sonic hedgehog, patched (Ptc) (Mehlen and Bredesen, 2004). Works by Monnier and colleagues (Monnier et al., 2002; Schwab et al., 2001, 2005a,b) have shown that RGMa is highly expressed in the human adult nervous system and at the site of CNS injury. For example, following focal cerebral ischemia and traumatic brain injury, RGMa was found to increase in expression in the lesion site and in the penumbral area, both in neurons and in leucocytes infiltrating the lesion site (Schwab et al., 2005a,b).
Successful axonal outgrowth in the adult central nervous system (CNS) is central to the process of nerve regeneration and brain repair. To date, much of the knowledge on axonal guidance and outgrowth comes from studies on neuritogenesis and patterning during development where distal growth cones constantly sample the local environment and respond to specific physical and trophic influences. Opposing permissive (e.g., growth factors) and hostile signals (e.g., repulsive cues) are processed, leading to growth cone remodelling, and a concomitant restructuring of the cytoskeleton, thereby permitting pioneering extension and a potential for establishing synaptic connections. Repulsive cues, such as semaphorins, ephrins and myelin‐secreted inhibitory glycoproteins, act through their respective receptors to affect the collapsing or turning of growth cones via several pathways, such as the Rho GTPases signalling which precipitates the cytoskeletal changes. One of the direct modulators of microtubules is the family of brain‐specific proteins, collapsin response mediator protein (CRMP). Exciting evidence emerged recently that cleavage of CRMPs in response to injury‐activated proteases, such as calpain, signals axonal retraction and neuronal death in adult post‐mitotic neurons, while blocking this signal transduction prevents axonal retraction and death following excitotoxic insult and cerebral ischemia. Regeneration is minimal in injured postnatal CNS, albeit the occurrence of some limited remodelling in areas where synaptic plasticity is prevalent. Frequently in the absence of axonal regeneration, there is not only an inevitable loss of functional connections, but also a loss of neurons, such as through the actions of dependence receptors. Deciphering the cues and signalling pathways of axonal guidance and outgrowth may hold the key to fully understanding nerve regeneration and brain repair, thereby opening the way for developing potential therapeutics.
Experimental strategies to promote spinal cord regeneration - An integrative perspective
2006, Progress in Neurobiology
Detailed pathophysiological findings of secondary damage phenomena after spinal cord injury (SCI) as well as the identification of inhibitory and neurotrophic proteins have yielded a plethora of experimental therapeutic approaches. Main targets are (i) to minimize secondary damage progression (neuroprotection), (ii) to foster axon conduction (neurorestoration) and (iii) to supply a permissive environment to promote axonal sprouting (neuroregenerative therapies). Pre-clinical studies have raised hope in functional recovery through the antagonism of growth inhibitors, application of growth factors, cell transplantation, and vaccination strategies. To date, even though based on successful pre-clinical animal studies, results of clinical trials are characterized by dampened effects attributable to difficulties in the study design (patient heterogeneity) and species differences. A combination of complementary therapeutic strategies might be considered pre-requisite for future synergistic approaches. Here, we line out pre-clinical interventions resulting in improved functional neurological outcome after spinal cord injury and track them on their intended way to bedside.
Affinity for, and localization of, PEG-functionalized silica nanoparticles to sites of damage in an ex vivo spinal cord injury model
2012, Journal of Biological Engineering
Co-culture of astrocytes with neurons from injured brain: A time-dependent dichotomy
2011, Neural Regeneration Research
A chemical screen identifies novel compounds that overcome glial-mediated inhibition of neuronal regeneration
2010, Journal of Neuroscience

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Trends in Neurosciences

Research updateFunctional recovery after spinal cord injury: basic science meets clinic

Abstract

Section snippets

Inhibition by myelin

Modulation of the immune response

One answer to all questions?

Key conference outcomes

Neuron

Neuron

Regenerating the damaged central nervous system

Nature

Research update
Functional recovery after spinal cord injury: basic science meets clinic