Spinal Cord Lesion Study

• Potential Regenerative Strategies within the CNS with Attention to the Hippocampus

Project Background

Researchers have found that neurons in the central nervous system fail to regenerate after having been lesioned. This issue is relevant to countless neurological disorders including: traumatic brain injury (TBI), spinal cord injury, amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS). When considering neural regeneration it is critical to examine the differences between peripheral nervous system (PNS) and central nervous system (CNS) damage. After a lesion to the PNS, axons can re-grow and re-innervate targets. From the site of the lesion, the portion of the axon proximal to the soma regenerates a growth cone, which has the potential to grow back to the target. The portion of the axon distal to the soma from the site of the lesion degrades away into the extracellular space. In the PNS after a lesion, Schwann cells revert to an embryonic state producing axon stimulating factors including laminin and Nerve Growth Factor (NGF) which promote axonal re-grow. PNS axonal re-growth limitations include misdirected routing and atrophied targets. After a neuron is lesioned in the CNS, the distal nerve terminal and distal segment of the axon degenerates. Myelinating cells shed myelin and dedifferentiate while immune cells, macrophages and microglia, infiltrate and phagocyte debris. The Proximal portion of axon survives; the cut end of axon re-heals and reforms growth cone. After the CNS lesion, fibroblast reactive gliosis occurs which causes increased production of glia, resulting in a glial scar. The proximal axon tip reforms but fails to grow due to the glial scar and turns into a retraction bulb. Therefore, lesioned CNS neurons fail to regenerate because of reactive gliosis, misguided axonal growth, atrophied post-synaptic targets and CNS inhibition by oligodendrocytes, the myelin producing cell within the CNS. There are at least 3 factors secreted by oligodendrocytes that inhibit axonal re-growth, these factors include: Myelin Associated Glycoprotein (MAG), OMGP and Nogo. Nogo is a protein secreted by oligodendrocytes that inhibits axonal growth cones from re-growing. Research has shown that the use of Nogo knockouts or Nogo antibodies may stimulate re-growth with a CNS lesion such as a stroke.

Ideas for Neuronal Re-growth after CNS Lesions

Insertion of developmental CNS growth factors:

• NGF
• Brain Derived Neurotrophic Factor (BDNF)
• Embryonic Epithelial Progenitor cells
• Noggin

Inhibit adult CNS axonal growth inhibition

• Nogo Inhibition
  
• Repulsive guidance molecule (RGMa) antibody
  

Inhibition of reactive gliosis
Transplantation of Stem cells
Combinatorial Therapy

Proposed Experimental Design

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