Nogos

Compensatory plasticity and functional recovery can be enhanced in the injured adult central nervous system through blockade of Nogo-A 525... 

Nogo-A is a potent inhibitor of neurite growth and blocks axonal regeneration in the central nervous system. Early in vitro experiments showed that neurite outgrowth was impeded across a culture dish coated with CNS myelin whereas neurites would actively grow on a... 

FIGURE 30-4 Isoforms of Nogo. Nogo-A, B and -C have a common carboxy terminus of about 180 amino acids (the common domain - blue contains Nogo-66). Nogo -A and -B share an amino terminus of about 172 amino acids (green). 

Nogo-A neutralizing antibodies lead to axonal growth and functional recovery in vivo. After cell culture experiments, the next step was to show the ability to block myelin inhibitors and achieve axonal regrowth after spinal cord injury. The monoclonal antibody IN-1 was initially raised against myelin fractions enriched for... 

Nogo-A. Treatment with IN-1 promoted axonal regeneration and behavioral recovery in rats after thoracic spinal cord injury. These exciting results have since been confirmed using local intrathecal pump infusions of recombinant IN-1 Fab fragments or novel anti-Nogo-A antibodies [9]. 

A third myelin inhibitory protein, OMgp, is a GPI-linked protein expressed by oligodendrocytes [18], OMgp is a relatively minor component of myelin, believed to be localized to the paranodal loops, next to the node of Ranvier. OMgp contains a leucine-rich repeat (LRR) domain and a C-terminal domain with serine/threonine repeats. Like MAG, OMgp is also found in the PNS. Like Nogo, OMgp is also expressed in adult neurons. 

To date, the possible roles played by these inhibitors that are found within neurons is not known. In one recent study a high degree of Nogo-A expression was found in... 

Another important aspect of this study was that the time window for starting the treatment was extended to 1 week after stroke, demonstrating that anti-Nogo therapy is effective even beyond the time of acute brain damage. These findings open the possibility of treatment options for those suffering from chronic brain or spinal cord injuries. 

Even in the case of spinal cord injury where application of anti-Nogo antibodies results in regeneration of the cut axons, an additional important element for functional recovery is enhanced fiber growth from the unlesioned fibers, i.e. compensatory plasticity, as discussed above. After high corticospinal tract injury in the rat at the level of the medullary pyramid and treatment with anti-Nogo antibodies, rubrospinal pathways were shown to sprout into deafferented areas of the spinal cord, resulting in high levels of functional recovery, i.e. a functional switch in the remodeled pathway [42]. 

Schwab, M. E. Nogo and axon regeneration. Curr. Opin. Neurobiol. 14 118-124, 2004. 

Chen, M. S., Huber, A. B., Van Der Haar, M. E. etal. Nogo-A is a myelin-associated neurite outgrowth inhibitor and an antigen for monoclonal antibody IN-1. Nature 403 434-439, 2000. 

Oertle, T., Van Der Haar, M. E., Bandtlow, C. E. et al. Nogo-A inhibits neurite outgrowth and cell spreading with three discrete regions. /. Neurosci. 23 5393-5406,2003. 

Fournier,A E., Grandpre,T., Strittmatter, S. M. Identification of a receptor mediating Nogo-66 inhibition of axonal regeneration. Nature 409 341-346,2001. 

Sicotte, M., Tsatas, O., Jeong, S. Y., Cai, C-Q., He, Z. and David, S. Immunization with myelin or recombinant Nogo-66/MAG promotes axon regeneration and sprouting after corticospinal tract lesions in the spinal cord. Mol. Cell. Neurosci. 23 251-263, 2003. 

Wang,K. C.,Koprivica,V.,Kim, J.A etal. Oligodendrocyte-myelin glycoprotein is a Nogo receptor ligand that inhibits neurite outgrowth. Nature 417 941-944,2002. 

Li, S. and Strittmatter, S. M. Delayed systemic Nogo-66 receptor antagonist promotes recovery from spinal cord injury. /. Neurosci. 23 4219-4227, 2003. 

Wiessner, C., Bareyre, F. M., Allegrini, P. R. etal. Anti-Nogo-A antibody infusion 24 hours after experimental stroke improved behavioral outcome and corticospinal plasticity in normotensive and spontaneously hypertensive rats. J. Cereb. Blood Flow Metab. 23 154-165, 2003. 

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