Animal study examines method for restoring brain cells killed by stroke or other neurological diseases.
Giving 3K3A-APC to mice with stroke-induced brain damage dramatically increased the production of new neurons (labeled in red) from neural stem cells implanted next to the injured area.Berislav Zlokovic, M.D., Ph.D., USC
Scientists and clinicians have long dreamed of helping the injured brain repair itself by creating new neurons, and an innovative NIH-funded study published today in Nature Medicine may bring this goal much closer to reality. A team of researchers has developed a therapeutic technique that dramatically increases the production of nerve cells in mice with stroke-induced brain damage.
The therapy relies on the combination of two methods that show promise as treatments for stroke-induced neurological injury. The first consists of surgically grafting human neural stem cells into the damaged area, where they mature into neurons and other brain cells. The second involves administering a compound called 3K3A-APC, which the scientists have shown helps neural stem cells grown in a petri dish develop into neurons. However, it was unclear what effect the molecule, derived from a human protein called activated protein-C (APC), would have in live animals.
A month after their strokes, mice that had received both the stem cells and 3K3A-APC performed significantly better on tests of motor and sensory functions compared to mice that received neither or only one of the treatments. In addition, many more of the stem cells survived and matured into neurons in the mice given 3K3A-APC.
“This USC-led animal study could pave the way for a potential breakthrough in how we treat people who have experienced a stroke,” added Jim Koenig, Ph.D., a program director at the NIH’s National Institute of Neurological Disorders and Stroke (NINDS), which funded the research. “If the therapy works in humans, it could markedly accelerate the recovery of these patients.”
The researchers induced stroke-like brain damage in mice by disrupting blood flow to a specific part of their brains. One week later – the equivalent of several months in humans – the team inserted the stem cells next to the dead tissue and then gave the mice several infusions of either a placebo or 3K3A-APC.
“When you give these mice 3K3A-APC, it works much better than stem cells alone,” said Berislav Zlokovic, M.D., Ph.D., the University of Southern California professor who led the research. “We showed that 3K3A-APC helps the cells convert into neurons and make structural and functional connections with the host’s nervous system.”
To confirm that the stem cells were responsible for the animals’ improved function, the researchers used a targeted toxin to kill the neurons that had developed from them in another group of mice given the combination therapy. These mice showed the same improved performance on the tests of sensory and motor functions prior to being given the toxin but lost these gains afterwards, suggesting that the neurons that grew from the implanted cells were necessary for the improvements.
In a separate experiment, the team examined the connections between the neurons that developed from the stem cells in the damaged brain region and nerve cells in a nearby region called the primary motor cortex. The mice given the stem cells and 3K3A-APC had many more neuronal connections, called synapses, linking these areas than mice given the placebo. In addition, when the team stimulated the mice’s paws with a mechanical vibration, the neurons that grew from the stem cells responded much more strongly in the treated animals.
“That means the transplanted cells are being functionally integrated into the host’s brain after treatment with 3K3A-APC,” Dr. Zlokovic explained. “No one in the stroke field has ever shown this, so I believe this is going to be the gold standard for future studies.”
3K3A-APC is currently being studied in a NINDS-funded Phase II clinical trial to determine if it can reduce the death of neurons deprived of blood flow immediately following a stroke. As a result of the new mouse study, Dr. Zlokovic and his team, including co-first authors Yaoming Wang and Zhen Zhao, now hope to pursue another Phase II clinical trial to test whether the combination of neural stem cell grafts and 3K3A-APC can stimulate the growth of new neurons in human stroke patients to improve function. If that trial succeeds, it may be possible to test the treatment’s effects on other neurological conditions, such as spinal cord injuries, for which stem cell therapies are being investigated.
The study was supported by the NIH (NS090904, NS075345, HL052246, HL031950) with additional funding provided by the National Natural Science Foundation of China, the Adelson Medical Research Foundation, the New York State Stem Cell Research Board, the Novo Nordisk Foundation, the Lundbeck Foundation, the National Multiple Sclerosis Society, and the ALS Association.
The NINDS is the nation’s leading funder of research on the brain and nervous system. The mission of NINDS is to seek fundamental knowledge about the brain and nervous system and to use that knowledge to reduce the burden of neurological disease.
The National Heart, Lung, and Blood Institute provides global leadership for a research, training, and education program to promote the prevention and treatment of heart, lung, and blood diseases and enhance the health of all individuals so that they can live longer and more fulfilling lives.
About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.
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Wang et al. 3K3A-activated protein C stimulates postischemic neuronal repair by human neural stem cells in mice. Nature Medicine. August 22, 2016. DOI: 10.1038/nm.4154.
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