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Targeting the Nogo Receptor to Treat Central Nervous System Injuries

Key Points

  • There is a large unmet need for treatments for conditions such as spinal cord injury, traumatic head injury and stroke, which are all characterized by axonal damage in the central nervous system (CNS).

  • Promoting axon regrowth could be an attractive strategy to treat such injuries, but a key barrier has been the inability of CNS neurons to regenerate their axons after injury, which is generally attributed to the presence of growth inhibitors present in CNS myelin.

  • Three inhibitors of axonal regeneration have been identified in CNS myelin: Nogo, myelin-associated glycoprotein (Mag) and oligodendrocyte myelin glycoprotein (Omgp). These myelin proteins induce growth cone collapse and inhibit neurite outgrowth.

  • Recently, it has been demonstrated that these inhibitory molecules all act through the Nogo receptor (NgR), making NgR a focal point for modulating axonal regrowth.

  • In this review, we discuss recent advances in the understanding of the biological role of NgR and the relevance of these findings to a novel drug discovery strategy of promoting CNS axonal regrowth for treating CNS injuries.

Abstract

Axonal damage is a key pathology in many injuries of the central nervous system (CNS), such as spinal cord injury, traumatic brain injury and stroke, as well as in multiple sclerosis. An attractive drug discovery strategy to treat such conditions is to search for agents that promote CNS axonal regeneration. Historically, limited knowledge concerning the basis of poor CNS regeneration has precluded a rational drug discovery approach for promoting axonal regeneration. The recent identification of the Nogo receptor, which interacts with inhibitory myelin protein, established the crucial role of this molecular pathway in mediating the inhibitory effects of CNS myelin. This provides an unprecedented opportunity to manipulate adult CNS axonal regeneration. The development of therapeutics targeting the Nogo receptor has the potential to promote functional recovery and reverse the devastating consequences of CNS injuries.

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Figure 1: CNS myelin inhibits neurite extension in vitro.
Figure 2: The Nogo receptor and inhibition of axon regeneration.
Figure 3: Axonal regeneration promoted by delayed systemic treatment with a NgR peptide antagonist.

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Correspondence to Daniel H. S. Lee.

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DATABASES

LocusLink

BDNF

MAG

OMgp

NGF

NgR

NgRh1

NgRh2

NogoA

NT-3

FURTHER INFORMATION

Encyclopedia of Life Sciences

Traumatic central nervous system injury

Glossary

MYELIN SHEATH

The sheets of membranes derived from oligodendrocytes wrapping around nerve fibres in the central nervous system that provide trophic support and facilitate nerve impulse transmission. Detergent extraction of these membranes yields a protein mixture named myelin that inhibits neurite outgrowth and induces growth cone collapse.

GROWTH CONE COLLAPSE

The tips of the growing axons and neurites are characterized by a fan-shaped structure (laminopodia) accompanied by several outgrowths (filapodia). Together, these structures form the growth cone of an axon or neurite. When a growing axon comes into contact with an unfavourable environment, the growth cone changes in morphology, shrinking to form a stump. This phenomenon is generally described as growth cone collapse, and is indicative of halted neurite growth.

BBB SCORE

A 21-point scale of behavioural scoring for assessment of open-field locomotion abilities.

LEUCINE-RICH REPEATS

Small protein domains comprising 23 amino-acid residues that are characterized by the dominant presence of leucine residues. Examples include NgR, NgRh1, NgRh2 and OMgp.

DORSAL ROOT GANGLION

DRG. Groups of sensory neuron cell bodies that correspond to a particular level of the spinal cord. These neurons are frequently used in culture assays to assess neurite outgrowth or growth cone collapse.

INTRATHECAL DELIVERY

Direct delivery of a molecule via a catheter or needle inserted under the dura of the spinal cord, thereby bypassing the blood–brain barrier. The molecule subsequently becomes distributed via the cerebral spinal fluid to different parts of the spinal cord and can reach the brain.

BDA TRACING

Biotinylated dextran acetate (BDA) is a stable, non-metabolized, low-molecular-mass compound that after injection into the motor cortex is transported along the axons. The molecule can be detected in tissue sections using appropriately tagged strepavidin (for example, conjugated with horse radish peroxidase) for labelling nerve fibres.

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Lee, D., Strittmatter, S. & Sah, D. Targeting the Nogo Receptor to Treat Central Nervous System Injuries. Nat Rev Drug Discov 2, 872–879 (2003). https://doi.org/10.1038/nrd1228

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