New hybrid drug, derived from common spice, may protect, rebuild brain cells after stroke

ScienceDaily (Feb. 11, 2011) — Whether or not you're fond of Indian, Southeast Asian and Middle Eastern food, stroke researchers at Cedars-Sinai Medical Center think you may become a fan of one of their key spices.

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The scientists created a new molecule from curcumin, a chemical component of the golden-colored spice turmeric, and found in laboratory experiments that it affects mechanisms that protect and help regenerate brain cells after stroke. Research scientist Paul A. Lapchak, Ph.D., director of Translational Research in the Department of Neurology at Cedars-Sinai Medical Center, is presenting these findings at the American Heart Association International Stroke Conference in Los Angeles.

Only one drug is now approved for ischemic stroke, which occurs when a clot blocks blood flow to the brain. Commonly called a "clot-busting drug," tissue plasminogen activator (tPA) is injected intravenously to dissolve clots and reinstate blood flow. If blood and oxygen are restored in time, consequences of the stroke, such as speech, memory, movement and other impairments, may be reduced.

The new curcumin-hybrid compound -- CNB-001 -- does not attack clots but instead repairs stroke damage at the molecular level that feed and support the all-important brain cells, neurons.

Curcumin has been studied for its potential to treat brain injury and disease, and while the substance itself looks promising, it has several drawbacks, especially as an emergency stroke treatment, which must be quick to be effective: It is not well absorbed in the body, fails to reach its target in high concentrations, becomes depleted quickly, and is blocked from entering the brain by a natural protective mechanism called the blood-brain barrier.

"CNB-001 has many of the same benefits of curcumin but appears to be a better choice of compound for acute stroke because it crosses the blood-brain barrier, is quickly distributed in the brain, and moderates several critical mechanisms involved in neuronal survival," Lapchak says, adding that he and his colleagues expect the new drug to move to human clinical trials soon.

When brain tissue is deprived of blood and oxygen, a cascading series of interrelated events triggers at the molecular level, breaking down the normal electrical and chemical "signaling pathways" responsible for nourishing and supporting neurons. The environment quickly becomes toxic, killing brain cells and destroying their support structures.

Theoretically, interrupting these harmful events and restoring normal pathway function could prevent cell death and the memory and behavioral deficits that result, but it will take a cocktail of drugs or a drug capable of targeting many mechanisms to correct the many pathways damaged by stroke, Lapchak says. CNB-001protects brain cells from damage by repairing four major pathways. One mechanism also plays a major role in the growth and survival of neurons.

The drug reduced stroke-caused "motor deficits" -- problems of muscle and movement control -- in this laboratory study. It was effective when administered up to an hour after stroke, which correlates with about three hours in humans, the same time frame for which tPA is currently approved.

Lapchak and colleagues at the Salk Institute for Biological Studies used the same laboratory rabbit model to mimic human stroke that earlier researchers had employed before the clot-busting drug tPA entered clinical trials. Patrick D. Lyden, M.D., chairman of Cedars-Sinai's Department of Neurology, helped lead a major trial that resulted in the Food and Drug Administration's 1996 approval of tPA, still considered the stroke treatment gold standard.

Those who cook Indian, Thai, Malay and Persian dishes know turmeric well for its zesty flavor, use in curries and for the rich color it imparts to food. Turmeric also has a long history of use in Ayurvedic and Chinese traditional medicine.

Grants from the National Institute of Neurological Disorders and Stroke, part of the National Institutes of Health, supported the CNB-001 study (NS060685 to PAL).

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Multiple sclerosis blocked in mouse model: Barring immune cells from brain prevents symptoms

ScienceDaily (Mar. 7, 2011) — Scientists have blocked harmful immune cells from entering the brain in mice with a condition similar to multiple sclerosis (MS).

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According to researchers from Washington University School of Medicine in St. Louis, this is important because MS is believed to be caused by misdirected immune cells that enter the brain and damage myelin, an insulating material on the branches of neurons that conduct nerve impulses.

New insights into how the brain regulates immune cell entry made the accomplishment possible. Washington University scientists had borrowed an anti-cancer drug in development by the company ChemoCentryx simply to test their theories.

"The results were so dramatic that we ended up producing early evidence that this compound might be helpful as a drug for MS," says Robyn Klein, MD, PhD, associate professor of pathology and immunology, of medicine and of neurobiology. "The harmful immune cells were unable to gain access to the brain tissue, and the mice that received the highest dosage were protected from disease."

ChemoCentryx is now testing the drug in Phase I safety trials. The study is published in The Journal of Experimental Medicine.

Klein and her colleagues discovered a chemical stairway that immune cells have to climb down to enter the brain. Immune cells that exit the blood remain along the vessels on the tissue side, climbing down from the meninges into the brain where they can then cross additional barriers and attack myelin on the branches of neurons.

"The effect of immune cell entry into the brain depends on context," Klein says. "In the case of viral infection, immune cell entry is required to clear the virus. But in autoimmune diseases like multiple sclerosis, their entry is associated with damage so we need to find ways to keep them out."

The stairway is located on the tissue side of the microvasculature, tiny vessels that carry blood into the central nervous system. The steps are made of a molecule called CXCL12 that localizes immune cells, acting like stairs that slow them down so that they can be evaluated to determine if they are allowed to enter the brain. Klein's lab previously discovered that the blood vessel cells of the microvasculature display copies of this molecule on their surfaces.

Klein also found that MS causes CXCL12 to be pulled inside blood vessel cells in humans and mice, removing the stairway's steps and the checkpoints they provide. In the new paper, she showed that blocking the internalization of the molecule prevented immune cells from getting into the brain and doing harm.

Work by another lab called Klein's attention to CXCR7, a receptor that binds to CXCL12. She showed that the receptor is made by the same cells in the microvasculature that display CXCL12. They watched the receptor take copies of CXCL12 and dump them in the cells' lysosomes, pockets for breakdown and recycling of molecules the cell no longer needs.

"After it dumps its cargo in the lysosome, the receptor can go right back to the cell surface to pull in another copy of CXCL12," Klein says. "There likely exists an equilibrium between expression and disposal of CXCL12. Some of the proteins expressed by the immune cells in MS patients affect CXCR7 expression and activity, disrupting the equilibrium and stripping the steps from this immune cell stairway we're studying."

Klein contacted researchers at ChemoCentryx, who were developing a blocker of the CXCR7 receptor as a cancer treatment. When they gave it to the mouse model of MS, immune cells stopped at the meninges.

Klein also found that immune factors could cause microvasculature cells to make more or less of CXCR7, ramping up or down the number of steps on the chemical stairway. She is currently investigating additional immune factors that impact on CXCR7 activity within the blood vessel cell. Whether a given factor promotes or suppresses the receptor may also differ depending upon what part of the brain is being considered.

"One of the biggest questions in MS has been why the location, severity and progression of disease varies so much from patient to patient," Klein says. "Getting a better understanding of how these factors regulate immune cell entry will be an important part of answering that question."

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Anti-depressants boost brain cells after injury in early studies

ScienceDaily (Apr. 22, 2011) — Anti-depressants may help spur the creation and survival of new brain cells after brain injury, according to a study by neurosurgeons at the University of Rochester Medical Center.

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Jason Huang, M.D., and colleagues undertook the study after noticing that patients with brain injuries who had been prescribed anti-depressants were doing better in unexpected ways than their counterparts who were not taking such medications. Not only did their depression ease; their memory also seemed improved compared to patients not on the medication.

"We saw these patients improving in multiple ways -- their depression was improved, but so were their memory and cognitive functioning. We wanted to look at the issue more, so we went back to the laboratory to investigate it further," said Huang, associate professor of Neurosurgery and chief of Neurosurgery at Highland Hospital, an affiliate of the University of Rochester Medical Center.

The team's findings were published online recently in the Journal of Neurotrauma.

Huang said many patients who have a traumatic brain injury also experience depression -- by some estimates, half of such patients are depressed. Doctors aren't sure whether the depression is a byproduct of the sudden, unfortunate change in circumstances that patients find themselves in, or whether the depression is a direct consequence of brain damage.

Previous research by other groups indicated that anti-depressants help generate new brain cells and keep them healthy in healthy animals. That, together with the experience of his patients, led Huang to study the effects of the anti-depressant imipramine (also known as Tofranil) on mice that had injuries to their brains.

Scientists found that imipramine boosted the number of neurons in the hippocampus, the part of the brain primarily responsible for memory. By one measure, mice treated with imipramine had approximately 70 percent more neurons after four weeks than mice that did not receive the medication.

That change was borne out on behavioral tests as well. The team tested mice by using what scientists call a novel object recognition test. Like human infants, mice tend to spend more time sizing up objects that they haven't encountered before -- or don't remember encountering -- than they do objects that they've seen before. This gives scientists a way to measure a mouse's memory.

The team found that mice that had been treated with imipramine had a better memory. They were more likely to remember objects they had seen previously and so spent more time exploring truly novel objects, compared to mice that did not receive the compound.

The benefits did not extend to the motor skills of the mice -- a finding that parallels what neurosurgeons like Huang have seen in their patients on anti-depressants, who don't show improved mobility after use of the medications.

Scientists aren't sure whether the drug helps spur the creation of more new neurons, or whether it helps newly created neurons survive -- or both. Some of the team's evidence indicates that the drug helps immature stems evolve into useful cells such as neurons and astrocytes, and to travel to the exact areas of the brain where they're needed.

In addition to sorting out those questions, investigators will try to identify the molecular pathway that prompts the brain to create more neurons in response to anti-depressants. The team suspects that a molecule known as BDNF or brain-derived neurotrophic factor may play a role.

Huang notes that one of his mentors, co-author Douglas H. Smith, M.D., of the University of Pennsylvania, has found that a brain injury itself also seems to prompt the brain to create more brain cells, perhaps as a way to compensate for injury.

"The brain has an intrinsic mechanism to repair itself to a certain extent," said Huang. "Our goal is to learn more about that mechanism and improve it, to help patients recover even more brain function than they can now, even with extensive work and rehabilitation."

Some of Huang's work is based on his experiences treating soldiers and civilians while working for four months as a neurosurgeon with the U.S. Army Reserve in Iraq, as well as more than a decade of experience treating patients affected by incidents like motor vehicle accidents.

He said that traumatic brain injury -- an injury experienced by approximately 1.4 million Americans each year -- must be treated aggressively. Often this involves surgery to relieve pressure on the brain, other procedures to protect the brain against immediate further injury, and then rehabilitation for months or years.

"It's exciting that the study involves a drug that is already safe and approved by FDA and is used clinically. If we could add a medication to the treatment regimen -- even a slight improvement would be a big gain for these patients. It's our hope that the work will ultimately make a difference in patient care," added Huang, who is also a scientist in the Center for Neural Development and Disease.

In addition to Huang, other authors at Rochester include post-doctoral associates Xiaodi Han, M.D., Ph.D., Jing Tong, M.D., and Jiankai Yang, M.D.; neurosurgery resident Arash Farahvar, M.D.,; and undergraduate Ernest Wang. Other authors include Jun Zhang, M.D., of the Chinese PLA General Hospital in Beijing; Uzma Samadani, M.D., Ph.D., of New York University; and Douglas H. Smith, M.D., of the University of Pennsylvania.

The work was funded by the National Institute of Neurological Disorders and Stroke and by the University of Rochester.

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