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by Greg Kopanski

Introduction

The nervous system is an exceptionally complicated network of 100 billion cells with trillions of synapses between them. It can be divided into two main parts, the peripheral nervous system and the central nervous system. The peripheral nervous system is responsible for the sending and receiving of communications from the central nervous system to the rest of the body. The central nervous system contains the brain and spinal cord. Both systems can undergo damage to the axons that prevents signal transduction. Particularly with the PNS, the body has a repair process that clears damage and eventually re-innervates the target site to reestablish the neural pathway.



Anatomy

Understanding the basic anatomy of a neuron is necessary to learn the mechanisms of its regeneration. Each neuron contains a cell body containing a nucleus. Around the cell body are many treelike dendrites, small branching projections that receive action potentials and send electrical signals toward the cell body. Also attached to the cell body is a single axon, a long unbranched projection that sends electrical impulses away from the cell. Surrounding this axon are glial cells which produce a myelin sheath at established intervals. This sheath protects the axon and greatly improves the speed of conduction down the axon to the terminal branches. At these terminal branches the neuron synapses with its target, possibly a muscle, sensory receptor or other neuron, and it ‘passes along’ the action potential.

neuronpicusethis.jpg

http://www.simplypsychology.pwp.blueyonder.co.uk/neuron.jpg

PNS vs CNS

Neurons in the PNS are much more capable of responding to cellular damage and regenerate, restoring some but likely not all of their previous function. According to the current research, there are two primary reasons why the PNS is more effective at restoring a damaged connection than the CNS.

1.) Neural regrowth cannot bridge cysts or scar tissue that frequently forms after spinal cord damage.

2.) The CNS is hostile to axon growth by containing many growth inhibiting proteins. These proteins are found in the CNS myelin to prevent unintended growth, but they also prevent reconstruction of a neural circuit.

Neuron Regeneration Stages

A severed or damaged neuron typically repairs itself using a ten step process.

Step 1 - Cell Body Response

The cell nucleus decentralizes immediately after the injury.

Step 2 - Metabolic Reaction

Ribosomes collect around the nucleus for increased protein synthesis and energy production

Step 3 - Immune Response

Macrophages attack and consume the Schwann cells of the severed distal segment.

Step 4 - Nervous System Reaction

The neurons surrounding the damaged neuron send sprouts to innervate the target of the damaged neuron in order to regain some sensation.

Step 5 - Enzymatic Action

The axon of the severed distal segment is broken down by various enzymes

Step 6 - Rapid Cell Division

The last Schwann cell at the end of the proximal end rapidly divides in chains leading in different directions.

Step 7 - Formation of Growth Path

One of the Schwann cell chains reaches the damaged neuron’s target site and it becomes the new growth path.

Step 8 - Axon Growth and Death of Extra Schwann Cells

The axon extends from the proximal ending through the Schwann cell growth path. The other unlinked Schwann cell extensions are consumed by macrophages.

Step 9 - Death of Sprouts

The sprouts to the target site from the axons of nearby neurons die after the damaged neuron resumes innervation of the target site.

Step 10 - Return to Normal

The nucleus returns to its original position and the number of ribosomes surrounding it decreases after re-innervation.



An animation of these stages is shown here:

animatedsequence.gif

http://staff.jccc.net/aalarabi/nranim.gif

Factors Influencing Success

The ability of a neuron to self repair is dependent on a number of factors. The patient’s age and health are not surprisingly strongly correlated with the body’s ability to regenerate neurons. Furthermore, the location of the injury is important in predicting the likelihood of a successful self repair. Typically, new axons grow no more than 1 mm per day. An injury to the nerve at the site of the ankle will need to regenerate the axon all the way to the toe. The greater the distance is between an injury site and the neural target, generally the less successful the outcome. Lastly, the type of injury can also affect the body’s ability to repair it. A clean cut from a stabbing or puncture wound has a better success rate of repair than a crushing wound. This is partly due to the additional complications involving surrounding tissue, tendon and joint damage commonly associated with a crushing injury. A crushing wound typically has a greater degree of inflammation and scar tissue, both of which can inhibit axon regrowth.


Surgical Repair

In cases where PNS damage is perceived to be too great for the body’s self repairing mechanisms, there exists the surgical option. Surgeons are able to reattach neurons with relative ease, particularly in cases of a clean break. In situations where a clean break has not occurred the surgeons typically cut the neural endings in order to create one. The primary method of reattaching nerves is using one or many nerve grafts from a donor nerve elsewhere in the body that will more easily repair. Most often this donor nerve is the sural nerve located on the calf. The graft is cut to size and sewn in using an operating microscope to replace the missing section of the nerve at the injury site.

Before the graft on a sciatic nerve injury:

ungraftedsurgery.jpg

http://www.columbianeurosurgery.org/wp-content/2009/11/ngr1_lg-300x126.jpg

After the graft:

graftedsurgery.jpg

http://www.columbianeurosurgery.org/wp-content/2009/11/ngr2_lg-300x156.jpg

A recent alternative to this technique utilizes a small bioabsorbable tube called Neurolac. The two severed nerve ends are placed on either side of the tube. The severed proximal end grows into the tube to reconnect the pathway, having been attracted by the chemical signals sent out by the distal end.

neurolac.jpg

http://81.26.223.58/~polyganics/indexe371.html?id=18

Current Research on CNS Regeneration


The majority of scientist’s understanding of neural regeneration involves the PNS. However, some studies suggest that the CNS can regenerate after injury and is capable of creating new cells. The idea that the neurons in the brain are not finite or irreplaceable is still a relatively new one, arising in the late turn of the century. For decades prior to this, the scientific community held the widespread belief that the number of CNS cells is unchanged from birth. Two recent studies counter this claim, one conducted by UCSF researchers and another published in Nature Journal. Furthermore, an article titled “Spinal Cord Injury: Treatments and Rehabilitation” using information from the National Institute of health is a good resource outlining the most current research and theories regarding spinal cord re-innervation. The mechanisms uniquely inhibiting CNS growth are discussed in detail along with references to several trial drugs that show promise in assisting axon repair and regeneration.


Quiz


Multiple Choice
1. Which cell produces myelin?
a) Myelinite
b) Pacinian Corpuscle
c) Schwann Cell

2. Which of the following is a true statement?
a) Axons can easily regrow through scar tissue
b) The spinal cord is part of the PNS
c) There is only one growth path during reconstruction

3. Which of the following is not a factor affecting neuron regrowth?
a) obesity
b) age
c) location of injury

True or False
4. A crushing wound is the easiest to repair
5. Nearby neurons send permanent fibers to the damaged neurons' target site
6. Skin cells can be used as neural grafts during surgery
7. The more distal the injury site, the more likely it can be repaired

Essay Questions

Describe the process which a neuron regrows, labeling each step accordingly
Why is a clean puncture wound more likely to re-innervate?
Why do neurons not regrow easily in the spinal cord?

Answers
C,C,A,F,F,F,T

Glossary

Schwann Cell- A cell that covers the nerve fibers in the peripheral nervous system and forms the myelin sheath
Neuron- A cell of the nervous system designed to conduct nerve impulses
Axon- The usually long process of a nerve fiber that generally conducts impulses away from the body of the nerve cell
Dendrite- A branched protoplasmic extension of a nerve cell that conducts impulses from adjacent cells inward toward the cell body
Myelin- A white fatty material, composed chiefly of lipids and lipoproteins, that encloses certain axons and nerve fibers.
Graft- Material, especially living tissue or an organ, surgically attached to or inserted into a bodily part to replace a damaged part or compensate for a defect.
Enzyme- Any of numerous proteins or conjugated proteins produced by living organisms and functioning as biochemical catalysts.
Macrophage- Any of the large phagocytic cells of the reticuloendothelial system.
Action Potential- A momentary change in electrical potential on the surface of a cell that occurs when it is stimulated, resulting in the transmission of an electrical impulse.

Note: The above definitions were found using the 2009 American Heritage Dictionary

References

Belcher, Harry. Nerve Grafts. Retrieved May 11, 2010 from http://www.pncl.co.uk/~belcher/information/Nerve%20graft.pdf

Gebroe, Linda. (2005, December 1). UCSF study finds nerve regeneration is possible in spinal cord injuries. UCSF Medical Center Publication. Retrieved May 11, 2010 from http://news.ucsf.edu/releases/ucsf-study-finds-nerve-regeneration-is-possible-in-spinal-cord-injuries/

Iskandar, BJ, Resnick, DK, et als. (2004, August) Folic acid supplementation enhances repair mechanism in the adult CNS. Annals of Neurology. 56(2):221-7.

MedicineNet. Spinal Cord Injury: Treatments and Rehabilitation. Retrieved May 11, 2010 from http://www.medicinenet.com/spinal_cord_injury_treatments_and_rehabilitation/page8.htm

Olson, Lars. (1997) Regeneration in the adult central nervous system: Experimental repair strategies. Nature Medicine. 3, 1329 - 1335. Retrieved May 11, 2010 from http://www.nature.com/nm/journal/v3/n12/abs/nm1297-1329.html

Winfree, Christopher J. Overview of Nerve Graft Repair. Columbia University Medical Center Publication. Retrieved May 11, 2010 from http://www.columbianeurosurgery.org/specialties/peripheral-nerve/problems-and-treatments/nerve-injuries/onerve-graft-repair/