Drug helps paralysed rats walk again

Jane Sutton
Monday, 24 May 2004

Rats with spinal cord injuries regained 70% of their normal walking function with a three-part treatment aimed at regrowing nerve cells, researchers have shown.

The U.S. and Brazilian scientists grafted nerve cells, injected the rats with a special messenger molecule and an antidepressant to produce their results, which were published in the latest issue of the journal Nature Medicine.

The researchers said that their approach could one day have implications for treating human paralysis.

“[The research produced results] far greater than what we’ve seen in anything else,” said the principal researcher, Dr Mary Bartlett Bunge, from the University of Miami School of Medicine

“It opens up a potential new avenue of treatment for human spinal cord injury,” said Bunge, who declined to speculate when human trials might be attempted.

The spinal cord carries messages between the brain and the muscles through a network of nerve cells. When injury severs the network, chemical signals prevent those nerves from regrowing, resulting in paralysis.

So, regrowing nerve cells and reconnecting them has been the Holy Grail of spinal cord research.

The Miami study involved hundreds of animals with crushing injuries to the thoracic region of the spinal cord, which mainly causes loss of control of the legs.

The researchers transplanted cells known as Schwann cells from the peripheral nerves, where regeneration does occur, to create a bridge across the damaged area of the spinal cord and promote the growth of axons, the nerve fibres that transmit messages. Those cells also make the protective myelin sheath that insulates nerve fibres.

A triple approach

In earlier research, such grafts promoted the growth of new nerve fibres across and through the damaged areas of the spinal cord. But they stopped growing too soon.

So the researchers combined the grafts with two other treatments: injections of cyclic AMP, a messenger molecule that guides the nerve cells to grow their connecting fibres, and the antidepressant rolipram, which prevents the breakdown of cyclic AMP.

“The cyclic AMP hangs around longer and can be more effective,” Bunge said.

After eight weeks, the rats that did not receive the treatment could occasionally take a halting step but could not take one step after another, Bunge said.

Those that received the treatment had regained 70% of their walking function, “a striking improvement”, Bunge said. They could step consistently, and had better fine motor control and coordination.

“The hind limbs knew what the fore limbs were doing,” said Bunge.

The triple-treated animals also had more tissue in their spinal cords than those without the treatment, suggesting it had stopped the secondary tissue loss that normally occurs after a spinal cord injury, Bunge said.

And the triple-treated rats had a 500% increase in nerve fibres in the graft area, she said.

Commenting, Dr Naomi Kleitman, a program director for spinal cord injury research at the National Institute of Neurological Disorders and Stroke, said:

“Each of the pieces of the strategy have been hailed as ‘promising’ in earlier reports, but the behavioral effects were not huge. With the right combination, the sum is now proving to be much greater than the parts.”

source abc.net.au

Related Stories
Spinal injury and sport, Health Minutes News Radio 18 Aug 2003
Spinal cord injury, The Health Report Radio National 4 Dec 2000
Real hope for spinal cord injury, News in Science 27 Oct 1999

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Obese Cure?


May 10, 2004

Cutting Off Blood Supply to Fat Cells Slims Obese Mice

With 65 percent of the U.S. population overweight, the battle of the bulge seems to be one we are losing. Now researchers have unveiled a new method of attack: starving fat cells of their lifeblood in order to destroy them. Findings reported in the June issue of Nature Medicine indicate that the tactic is successful in mice.

A team lead by Wadih Arap of the University of Texas M.D. Anderson Cancer Center borrowed a technique from the fight against cancer to develop their antiobesity therapy. One approach to killing tumors is to cut off their blood supply because the proliferation of new cells requires the formation of new blood vessels, a process known as angiogenesis. Although fat cells are not malignant, they do have the ability to proliferate and expand. In addition, each cell is in contact with a number of capillaries. In the new work, the researchers identified a protein, called prohibitin, which is expressed on blood vessels that supply fat cells in obese mice. The team then paired a peptide that binds to prohibitin with a second peptide that promotes cell death.


molecular liposuction

Want to be slim? Cut your blood supply

Tim Radford, science editor

Monday May 10, 2004

The Guardian

Scientists have found a new way to make the obese slim again – by cutting off the blood supply to the layers of fat that are a health hazard for hundreds of millions of people.

The technique called “molecular liposuction” so far works only in mice. A team at the University of Houston, Texas, report in Nature Medicine today that weeks of treatment by an experimental drug restored the normal weight of mice that had doubled their size on a high-fat “cafeteria” diet.

“If even a fraction of what we found in mice relates to human biology, then we are cautiously optimistic that there may be a new way to think about reversing obesity,” said Renata Pasqualini, of the University of Texas at Houston.

Obesity is now one of the biggest problems in world health. Almost one American in three is seriously overweight. One British male in four is clinically obese. Even in the developing world, obesity levels are rising rapidly. Obesity has been linked to adult-onset type 2 diabetes, cardiovascular hazards and increased risks of cancer.

Health authorities have urged people to eat less, choose a diet richer in fruit and vegetables and exercise more.

Cosmetic surgeons have promoted liposuction – the drastic removal of fat – and stomach surgery. Geneticists have been trying to make a hereditary connection – because some groups of people seem to be at greater risk of obesity – and research groups have been studying the hormonal cycles linked with eating in the search for appetite-suppressing pills.

But the Texas team tried an approach already being investigated as a cancer treatment. In theory, life-threatening tumours would halt and dwindle if you could cut off the blood supply to the cancerous tissue. But fat tissue, too, depends on a steady supply of oxygen and nutrients delivered in the blood.

These fat cells are abnormally greedy for oxygen, and a pound of fat contains a mile of blood vessels, according to one estimate. Blood vessels differ according to the “postal code addresses” they serve. So the Houston scientists, based at the university’s M D Anderson cancer centre, searched for unique protein markers that would identify only those blood cells that served white adipose or fatty tissue.

They found one called prohibitin, already known to regulate cell survival and growth. They attached to it a synthetic drug already known from cancer trial to cause a cell to self-destruct.

Then they injected it into mice that had become grossly overweight on a high-fat, sugary diet. Within four weeks, the mice had reached their normal weight again. The fat had been reabsorbed and metabolised.

Other collaborators looked for evidence of toxic or unpleasant side effects – such as fat accumulation in the liver and blood – and found none. But further trials are needed.

“White adipose tissue is unique because it resembles a tumour in that it can rapidly expand.

“For such rapid expansion, there must be a very active production of blood vessels to deliver oxygen, and in fact every single fat cell is encased by capillaries,” said Mikhail Kolonin, who led the research at Houston.


Cancer strategy to treat obesity

Mice fight the flab

Cancer strategy could be used to treat obesity.

10 May 2004


Chubby mice have shaped up with a new slimming aid, based on a technique used in cancer therapy that destroys blood vessels. The researchers say that after clinical trials on humans this may become a useful weapon in the war on obesity.

One promising technique for treating cancer involves starving a tumour of the nutrients it needs to grow. The most effective way to do this is by killing off the blood vessels that supply the cancer cells. This technique is currently being evaluated in clinical trials.

In the same way, each fat cell relies on a network of capillaries to deliver the chemicals it needs to reproduce and grow. So Mikhail Kolonin and his colleagues from the University of Texas and Baylor College of Medicine, Texas, reasoned that if they could kill off these blood vessels, the fat cells would die too.

To do this, they targeted a molecule called prohibitin. It is present on the surface of fat cells, but not other types of cells, and it helps to regulate the growth of surrounding blood vessels. The researchers took a fragment of protein that binds to prohibitin, and attached it to another protein fragment that is used in cancer therapy to kill blood vessels.

In order to test whether the composite molecule works to destroy fat, the researchers fed two groups of mice a high calorie diet. Once the mice were overweight, the researchers injected the molecule under their skin each day for four weeks. The animals treated with the protein fragment ate less food and lost 30% of their original weight, but remained healthy1.

“It is an approach with great potential,” says Peter Carmeliet, a biologist from Flanders Interuniversity Institute for Biotechnology in Belgium. He points out that fat cells grow into much bigger masses than tumours, so this starvation technique could potentially work even better against obesity than cancer.


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