NEWS FROM SICKKIDS – 15.12.2005

Researchers identify key protein involved in neuropathic pain

TORONTO (December 15, 2005) — A team of researchers led by Université Laval and The Hospital for Sick Children (SickKids) has discovered a protein that plays a major role in neuropathic pain. This discovery, published in the December 16 issue of Nature, paves the way for the development of new diagnostics and treatments for chronic pain.

Neuropathic pain is a common and severely disabling state that affects millions of people worldwide. Many people suffering from neuropathic pain appear normal, but are in agony experiencing lightning-like pain known as allodynia.

This type of pain can alter perception to a point where previously innocuous or even pleasurable stimuli applied to the skin or tissues become extremely painful. It may be experienced after nerve injury or from diseases that affect peripheral nerve function such as diabetes, shingles, or cancer.

After a peripheral nerve injury there is a biophysical change in spinal cord cells called microglia. Microglia are typically considered to be immune cells in the nervous system, but have now been proven to be involved in neuropathic pain.

“We knew that microglia had to communicate with nerve cells in the pain-processing network in the spinal cord. However the mechanism for this communication was not known,” said Dr. Michael Salter, co-principal investigator, senior scientist at SickKids, professor of Physiology at the University of Toronto (U of T), and director of the U of T Centre for the Study of Pain. “We discovered that the microglia talk to the nerves cells by releasing Brain-Derived Neurotropic Factor (BDNF).”

When BDNF was injected into the spinal cords of normal mice it resulted in allodynia. When the team made manipulations to block or intercept BDNF signaling from the microglia the in nerve-injured mice the allodynia was reversed.

“We established that the microglia cause chloride ions to increase inside the nerve cells and that BDNF is the mystery mediator,” said Dr. Yves De Koninck, co-principal investigator, professor, Department of Psychiatry, Université Laval and director of the Division of Cellular Neurobiology at the Centre de recherche Université Laval Robert-Giffard. “Thus, not only did we discover that BDNF is the chemical mediator, but we also determined how BDNF works.”

By a still unknown mechanism, nerve injury results in activation of P2X4 receptors on the microglia, which causes the release of BDNF. BDNF then disrupts inhibition in the spinal cord, which causes spinal relay neurons to send an abnormal signal to pain-processing neural networks in the brain, ultimately causing the experience of aberrant pain.

The research team hopes that this new information on neuropathic pain can be applied to diagnostics. “Effective pain diagnosis is nearly as big a challenge as developing effective pain therapeutics,” added Dr. Salter, also Canada Research Chair in Neuroplasticity and Pain. “The gold standard for diagnosing neuropathic pain is history and physical examination. But many people want objective proof that something is pathophysiologically different. We are hoping to develop a probe that can measure the response of microglia in people with peripheral nerve injury.”

The team is also looking for ways to devise new kinds of therapeutics, as there is not presently any effective treatment for neuropathic pain.

“This is an important discovery for the millions of Canadians who suffer from debilitating chronic pain that cannot currently be treated. The cost to society is equally devastating and is estimated in the billions of
dollars annually,” said the Honourable Michael H. Wilson, chair of
NeuroScience Canada, one of the funders of this research through the Brain Repair Program, which includes $1.5 million to the team led by Dr. Michael Salter. NeuroScience Canada’s funding partners on the team grant led by Dr. Salter include the Canadian Institutes of Health Research and the Ontario Neurotrauma Foundation.

“With the work of Drs. Salter and De Koninck, we can now focus the research on developing drugs that will target the class of cells responsible for chronic pain. This represents an important shift that could soon provide patients with effective treatments and allow them to be active again in our society,” added Mr. Wilson.

Other members of the research team include co-lead authors Dr. Simon Beggs of SickKids and Dr. Jeffrey Coull of McGill University, Dominic Boudreau, Dominick Bovin and Dr. Claude Gravel of Université Laval, Drs. Makoto Tsuda and Kazuhide Inoue of Kyushu University, Japan.

This research was supported by the Canada Research Chairs Program, the Canadian Institutes of Health Research, Fonds de la recherche en santé du Québec, Neuroscience Canada and SickKids Foundation.

Located in Quebec’s historic capital city, Université Laval is one of Canada’s leading research universities, ranking 6th among the country’s 93 university-level institutions in terms of research funding, with more than $250 million devoted to research last year.

The Hospital for Sick Children, affiliated with the University of Toronto, is Canada’s most research-intensive hospital and the largest centre dedicated to improving children’s health in the country. Its mission is to provide the best in family-centred, compassionate care, to lead in scientific and clinical advancement, and to prepare the next generation of leaders in child health. For more information, please visit www.sickkids.ca.


For more information, please contact:
Chelsea Gay, Public Affairs
The Hospital for Sick Children
(416) 813 5045
chelsea.gay@sickkids.ca

News from SickKids - 01.12.2005

Researchers discover a protein responsible for shaping the nervous system

TORONTO — A team of researchers led by The Hospital for Sick Children (SickKids), the University of Toronto (U of T) and Cold Spring Harbor Laboratory have discovered a protein that is responsible for shaping the nervous system. This research was made possible with the support of a $1.5-million NeuroScience Canada Brain Repair Program team grant that enabled scientists from across Canada to work together and fast track their research. This research is reported in the December 8, 2005 issue of
the journal Neuron.

“We discovered that p63 is the major death-promoting protein for nerve cells during fetal and post-natal development,” said Dr. David Kaplan, the paper’s senior author, senior scientist at SickKids, professor of
Molecular Genetics, Medical Genetics & Microbiology at U of T, Canada Research Chair in Cancer and Neuroscience, and co-team leader on the NeuroScience Canada Brain Repair Program grant with Dr. Freda Miller of SickKids. “Proteins such as p63 that regulate beneficial cell death processes during development may cause adverse affects later in life by making us more sensitive to injury and disease.”

At birth, the nervous system has twice the number of nerve cells than needed. The body disposes of the excess cells by eliminating those that go to the wrong place or form weak or improper connections. If this process does not happen, the nervous system cannot function properly. The expression of the p63 protein guides the nervous system in disposing of the ineffective nerve cells. The protein is from the p53

family of tumour suppressor proteins that is mutated in many human cancers.

While p63 is involved in determining which nerve cells die, the research team also suspects that it determines whether nerve cells die when injured or in neurological and neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases.

“The discovery of this new protein represents hope for thousands of people affected by neurological and neurodegenerative disorders, such as multiple sclerosis, Parkinson’s, Alzheimer’s and schizophrenia, as well as spinal cord injury,” says the Honourable Michael H. Wilson, Chair of NeuroScience Canada, a national umbrella organization for neuroscience research, whose Brain Repair Program helped support this research. “Because this protein is responsible for the death of nervous systems cells, understanding how we could inhibit its functions could represent survival for many patients across Canada.”

Ten million Canadians of all ages will be affected by a disease, disorder or injury of the brain, spinal cord or nervous system. These conditions number more than 1,000. Fifty per cent of all Canadians — about 15 million people — have had a brain disorder impact their family. Based on Health Canada data, the economic burden of these disorders is conservatively estimated at 14 per cent of the total burden of disease, or $22.7 billion annually; however, when disability is included, the economic burden reaches 38 per cent or more, according to the World Health Organization. However, despite the magnitude of the problem, neuroscience research, with just $100 million total in operating grants in Canada annually, is still greatly under funded in this country.

To this end, future research for the research team involves testing whether p63 is the key protein that determines whether nerve cells die when injured or in neurodegenerative diseases, and will identify drugs that will prevent p63 from functioning that may be used to treat these conditions.

Other members of the research team include Dr. Freda Miller, Canada Research Chair in Developmental Neurobiology, Dr. W. Bradley Jacobs, Daniel Ho and Dr. Fanie Barnabe-Heider, all from SickKids, Dr. William Keyes and Dr. Alea Mills from Cold Spring Harbor Laboratory in Cold Spring Harbor, New York, and Dr. Jasvinder Atwal and Dr. Gregory Govani of Dr. Miller’s and Kaplan’s former group from McGill University.

This research was also supported by the Canadian Institutes of Health Research, the National Science and Engineering Research Council of Canada, a McGill Major Studentship, a McGill Tomlinson fellowship, the Canada Research Chairs Program and SickKids Foundation.

Founded in 1988, NeuroScience Canada is Canada’s umbrella organization and voice for the neurosciences. Through partnering with the public, private and voluntary sectors, NeuroScience Canada connects the knowledge and resources available in this area to accelerate neuroscience research and funding, and maximize the output of Canada’s world-class scientists and researchers. The mission of NeuroScience Canada’s Brain Repair Program is to fast-track neuroscience research in order to develop treatments and therapies more quickly. Through the Brain Repair Program, NeuroScience Canada and its donors and partners have already invested $4.5 million to research teams conducting breakthrough work in the area of brain repair. The goal of the Brain Repair Program is to initially fund five teams, for a total investment of $8 million.

The Hospital for Sick Children, affiliated with the University of Toronto, is Canada's most research intensive hospital and the largest centre dedicated to improving children's health in the country. Its mission is to provide the best in family-centred, compassionate care, to lead in scientific and clinical advancement, and to prepare the next generation of leaders in child health. For more information, please visit www.sickkids.ca.