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First Published 26 January 2011

 

Lucia Notterpek Ph.D, leads Florida researchers who are focusing on damaged nerve coating as key to finding a cure for trigeminal neuralgia

 

 

 

Lucia Notterpek and Douglas Anderson at Facial Pain Research Foundation

Board Meeting January 7, 2011

 

One known culprit behind the piercing, repetitive pain of trigeminal neuralgia is damage to myelin, the waxy coating that insulates nerve fibers against electrical signals

that are transmitted from cell to cell. Loss of myelin on the trigeminal nerve causes a short circuit that results in facial pain.

To define how myelin defects cause havoc in the nervous system, University of Florida Neuroscience Professor Lucia Notterpek, Ph.D., is leading studies of myelin biology and disease. She is addressing basic questions about healthy myelin, which is vital to the normal rapid movement of electrical impulses through the nerve pathways, and about various nerve disorders, including hereditary demyelinating neuropathies, which result from myelin defects or deficiency. She seeks information that will aid the development of ways to repair or rebuild myelin in order to cure trigeminal neuralgia and other demyelinating diseases.

In one project, she is carrying out experiments in mice aimed at defining the role of myelin-producing genes in nerve disease, and in another more clinically oriented study, she is evaluating the effectiveness of various pharmaceutical compounds designed to protect nerves. New and better compounds are urgently needed for trigeminal neuralgia, since all medications currently prescribed for this disorder have side effects ranging from bothersome to intolerable.

“We’re finding genetically altered mice are a very good model for investigating myelin damage,” said Notterpek, who also chairs the Department of Neuroscience at UF’s College of Medicine. “We have a known genetic defect—specifically a deficiency of the peripheral myelin protein 22 gene that is linked to myelin damage. We can induce temporary nerve compression that mimics the condition in classic trigeminal neuralgia, and we can measure sensory response in the animals. Later, after sacrificing the mice, we can analyze the status of the nerves at the molecular level.”

Co-investigator, Andrew Ahn, M.D., Ph.D., an assistant professor of neurology, neuroscience and anesthesiology specializing in the treatment of headache and facial pain, has expertise in assessing pain behaviors in mice. By measuring behavioral responses to mildly uncomfortable stimuli such as heat, researchers can detect abnormal pain behaviors in mice in comparison to responses by healthy mice. Ahn said the sensory responses observed and measured in mice cannot be directly equated to human pain, but a series of behavioral approaches aimed at analyzing the animals’ sensitivity to various physical stimuli can be used to approximate various aspects of pain in humans.

Currently, Notterpek seeks to figure out how the PMP22 gene normally works to help produce myelin, and what happens in disease conditions to cause this gene to get stuck in nerve cells rather than traveling to the myelin sheath where it is needed. She refers to this problem as “mistrafficking or abnormal expression of genes, like a traffic jam in part of the nervous system.”

 

 

She said daily, repeated observations of mice with known myelin defects reveal a puzzling observation: under the same testing conditions using the same type of stimuli, some of the mice show hypersensitive responses that indicate discomfort, while others show delayed sensory response. In a testing procedure now well-practiced in the UF lab, mice are placed in a clear box while a researcher shines a warm light on their feet, creating a situation similar to walking barefoot on hot sand. The hypersensitive mice move their feet within two to three seconds, while other mice don’t seem to be bothered by the warmness of the light for longer times. The responses of the animals are monitored and recorded by a computer for subsequent analysis. Notterpek said correlating specific gene deficiencies or gene abnormalities to myelin damage and to indications of pain requires long, tedious research that can involve behavioral assessments in hundreds of mice.

 

In previous studies that resulted in two published papers, she discovered that mice generally have to reach a certain age before they show signs of myelin deterioration—similar to the way TN most often affects people over age 50. Now she and Ahn are investigating how myelin damage in different parts of the nervous system may result in different levels of discomfort. They note, for example, that longer nerves such as those in the hind legs are more susceptible to damage than the shorter nerves.

Notterpek also is testing a hypothesis that the peripheral nerves in mice with PMP22 gene deficiency are more sensitive to injury, and require little provocation to initiate myelin injury. She seeks to determine the least amount of nerve damage needed to trigger loss of myelin in normal mice, and in mice that are deficient in the PMP22 gene. At the close of each study, the mice are sacrificed, and the nerve is removed and examined microscopically to assess the status of the myelin. The researchers also measure the levels of molecules involved in both the myelin sheath pathway and the pain pathway.  

In parallel studies supported by a grant from the National Institutes of Health, the UF team is testing specific nerve-protective compounds—one well established drug and others newly developed. Through a new pilot study, they are beginning to investigate additional commercially available compounds and dietary supplements that may affect the pathways believed to be important to normal myelin formation. They are just starting to test the effects of these compounds on cells that make myelin.

Notterpek’s myelin research is funded in small part by the TNA-Facial Pain Association, which has its national headquarters in Gainesville. She and Ahn currently carry out the TNA-FPA-supported research with one lab technician and the help of non-salaried students on scholarships. They hope to publish the first major manuscript on their findings in 2011.

Although Notterpek has only been at UF for 11 years, her studies of myelin damage and myelin restoration began almost 20 years ago while she served as a research assistant at the Gladstone Institutes of the University of California San Francisco. After entering the doctoral program in neuroscience at UCLA, she completed her thesis on a topic related to multiple sclerosis. She earned her Ph.D. in 1994, followed by a five-year postdoctoral fellowship in neurobiology at Stanford University. Coincidentally about this time, neuroscientists first identified the PMP22 gene and several other genes that play a role in eroding or chipping away myelin from nerves.

While at Stanford, she became involved in a project aimed at determining more precisely how the PMP22 gene may be implicated in myelin injury. When she left Stanford in 1999, she took this project to the University of Florida where she has been working on nerve damage ever since. Her large research program is aimed at translating discoveries in the mice to applications in patients with trigeminal neuralgia and with hereditary demyelinating neuropathies. In both conditions, damage to myelin disrupts the normal transmission of nerve impulses.

Eminent Scholar Douglas K. Anderson, Ph.D., who formerly chaired UF’s Department of Neuroscience and who supports plans for Notterpek’s research, suggests several approaches to myelin repair might be tested in the myelin-deficient mice. One approach would involve patching the demyelinated region of the trigeminal nerve with myelin-producing cells derived from adult or embryonic stem cells, or with the patient’s own Schwann cells, provided these cells do not carry a genetic defect that produces unstable myelin. (Myelin is made up of Schwann cells.)

Anderson also proposes, “Gene therapy might be used to deliver genes that produce endogenous factors known to control pain and/or to knock out genes found to be involved in causing pain. With this approach, it might be possible to manage the pain of TN without actually repairing, or even identifying, the defect producing the pain.”

Anderson is a trustee and scientific advisor for The Facial Pain Research Foundation, who is helping to establish its international consortium of scientists working to cure nerve-generated facial pain. He is internationally known in scientific circles for his development of the first effective medication for acute spinal cord injury and for his pioneering studies of embryonic tissue transplants to halt complicated wounds associated with paralyzing spinal cord injury in people.

 

 

 

 

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