Blood clotting protein may inhibit spinal cord regeneration

Fibrinogen, a blood-clotting protein found in circulating blood, has been found to inhibit the growth of central nervous system neuronal cells, a process that is necessary for the regeneration of the spinal cord after traumatic injury. The findings by researchers at the University of California, San Diego (UCSD) School of Medicine, may explain why the human body is unable to repair itself after most spinal cord injuries.

The study, led by Katerina Akassoglou, Ph.D., assistant professor in UCSD’s Department of Pharmacology, is the first evidence that when blood leaks into the nervous system, the blood protein contributes to the neurons’ inability to repair themselves. The findings, which show the molecular link between vascular and neuronal damage during injury to the central nervous system, was published in the online issue of the Proceedings of the National Academy of Sciences on July 2.

The research team studied three types of spinal cord injuries in mice and rats which resulted in cellular and vascular damage, and leakage of fibrinogen from the blood vessels. Once injured, neurons cannot be repaired because of various inhibitors that are present in the brain and the spinal cord after damage, which results in a patient’s paralysis. The researchers were surprised at the massive deposits of fibrinogen found at the sites of injury. That discovery led them to investigate the protein’s effect on neuronal cells’ ability to regenerate.

“Our study shows that fibrinogen directly affects neurons by inhibiting their ability for repair,” said Akassoglou. Fibrinogen – contained in the blood which leaks at the site of injury – begins the process of inhibiting axonal growth by binding to the beta 3 integrin receptor. This binding, in turn, induces the activation of another receptor on the neuronal cells, called the epidermal growth factor receptor. When the second receptor is activated, it inhibits the axonal growth. Other inhibitors have been identified that use the same epidermal growth factor receptor, but this is the first blood-derived inhibitor that has been found.

The discovery may open the door to a possible strategy to improving recovery after spinal cord injury by discovering a way to block activation of neuronal receptors by fibrinogen. Identifying the specific inhibitors that impede the repair process could provide ways to regenerate and connect the damaged nerves and initiate recovery from paralysis after spinal cord injury.

“Inhibiting the damaging effects of fibrinogen on neurons may potentially facilitate repair in the nervous system after injury” said Akassoglou. A similar mechanism could be at work in other neurological diseases that result in paralysis, such as multiple sclerosis or hemorrhagic stroke, where blood vessels break and bleed into the brain. She added that such a therapeutic approach wouldn’t interfere with fibrinogen’s essential role in coagulation, because its blood-clotting mechanism depends on binding with a different receptor.

Debra Kain | EurekAlert!
Informationen: www.ucsd.edu

NEOUCOM professor seeks cure to neurodegenerative disease

Priscilla Tasker

Issue date: 3/20/07 Section: News

Neurodegenerative diseases such as Alzheimer's disease, multiple sclerosis, Parkinson's disease and others affect more than 20 million people worldwide.

Researchers at Northeastern Ohio Universities College of Medicine and Pharmacy in Rootstown, have been conducting research to develop a drug that could stop the processes that cause such diseases. The focus of the research is a molecule called NGP1-01, which has the potential to treat several factors that result in the deterioration of neurons in the brain, said Dr. Neels Van der Schyf, founding chair of NEOUCOM and professor at Kent State.

"Each individual has 80 to 90,000 dopaminergic neurons," Van der Schyf said. "Now that sounds like a lot, but you reach your peak in your early 20s. After that they start to die down one by one."

Dopaminergic neurons control brain functions including voluntary movement and behaviors associated with stress, mood and addiction, according to the National Center for Biotechnology Information Web site. Loss of this type of neuron is characteristic of Parkinson's disease.

A person may lose up to 80 percent of those neurons and still operate normally, never knowing that something is happening. Symptoms of a neurodegenerative disease would begin to surface when the neurons are depleted to about 20 percent, Van der Schyf said.

The theory behind the drug research is that the neurodegeneration can be slowed down before reaching that 20 percent range.

"Arguably if we could catch an individual with 30 percent of the (neurons) still intact we could probably prevent the neurodegeneration and have them live out a normal life," Van der Schyf said.

NGP1-01 has the potential to treat certain causes of neurodegeneration because of its ability to cross the blood-brain barrier. This means that the molecule is able to access cells in the brain, which is a rare discovery, Van der Schyf said.

The molecule's mechanism as a calcium-channel blocker balances the calcium influx in the brain cells that leads to the deterioration of the neurons, he said. It also has the ability to weaken or lessen excitotoxicity in the brain. Excitotoxicity refers to an excessive release of the chemical that transports messages from cell to cell, according to the Harvard Center for Neurodegeneration and Repair.

"If we have a mechanism by where we could very effectively and accurately diagnose an individual's propensity to develop Parkinson's, I believe we that have the tools to prevent that," Van der Schyf said, "Here's the dilemma, you may argue that OK, it's great to give a drug to everybody because we already know that the drug's going to prevent (it), but you don't know what the drug's going to do elsewhere. It may cause heart problems, it may do all kinds of things, which is why we cannot do that ethically."

In 2004, Vioxx, an inflammatory medication produced by Merck Inc., was pulled from the market because a study had found a higher rate of heart attack and stroke in patients who were on the drug.

"It was never discovered when they went to market, so we need to be extremely careful when giving any kind of molecule to a group of people," Van der Schyf said.

The Food and Drug Administration has strict rules for developing and marketing new drugs, he said. On average it takes about 12 years of research and clinical trials before the FDA approves a drug, and additional post-marketing studies are required as well, according to the Alliance Pharmaceutical Corp. Web site.

NGP1-01 is still in the pre-clinical testing phase of drug development, and researchers are testing the affect of the molecule in mice.

About five of nearly 5,000 drugs enter clinical trials (human testing sequences), according to Alliance Pharmaceutical's Web site, but only one of the five drugs receives approval from the FDA.

NGP1-01 will probably never make it to market, Van der Schyf said, but the goal of the research is to open the doors to other discoveries in neuro-drug development.

Contact health trends and NEOUCOM reporter Priscilla Tasker at ptasker@kent.edu.