New TBI treatments

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Public release date: 14-Dec-2010

Contact: Kirchweger

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Salk Institute

Compound derived from curry spice is neuroprotective against stroke and

traumatic brain injury

LA JOLLA, CA--A synthetic derivative of the curry spice turmeric, made by

scientists at the Salk Institute for Biological Studies, dramatically

improves the behavioral and molecular deficits seen in animal models of

ischemic stroke and traumatic brain injury (TBI). Two new studies suggest

that the novel compound may have clinical promise for these conditions,

which currently lack good therapies.

Ischemic stroke is the leading cause of disability and the third leading

cause of death of older people in the United States, while TBI is the

leading cause of death and disability in both civilians and military

personnel under the age of 45; in particular, it is the major cause of

disability in veterans returning from Iraq and Afghanistan. In both

conditions, those who survive frequently have serious behavioral and memory

deficits. The only FDA-approved treatment for stroke is tissue plasminogen

activator (TPA), which is effective only in about 20 percent of cases. There

is no clinically documented treatment for TBI.

In earlier studies, R. Schubert. Ph.D., and Pamela Maher, Ph.D., in

the Salk Cellular Neurobiology Laboratory had developed a series of new

compounds using a novel drug discovery paradigm that starts with natural

products derived from plants; it then calls for selecting synthetic

derivatives that show efficacy in multiple assays testing protection against

various aspects of the nerve cell damage and death that occur in brain

injuries and in age-associated neurodegenerative diseases. One compound,

called CNB-001, which was derived from curcumin, the active ingredient in

the spice turmeric, proved highly neuroprotective in all of the assays; it

also enhanced memory in normal animals.

While the Salk group has a great deal of expertise in age-associated

neurological diseases such as Alzheimer's, they do not run animal models of

TBI and stroke. " To test the prediction that drugs from our new drug

discovery scheme will work in multiple models of CNS disease and trauma, "

Schubert explains, " we undertook a series of experiments to assay the drugs

in collaboration with researchers at Cedars-Sinai and UCLA, who are leaders

in the fields of stroke and TBI, respectively, and appreciate the potential

for therapeutics based on natural products and their derivatives. "

Employing the same animal model of stroke that was used to develop TPA,

Lapchak, Ph.D., of the Department of Neurology at the Burns and

Research Institute at Cedars-Sinai Medical Center in Los Angeles,

collaborated with Schubert's team in a study that showed that CNB-001 was at

least as effective as TPA in preventing the behavioral deficits caused by

stroke. The study, published in the Dec. 2, 2010 edition of the Journal of

Neurochemistry, also demonstrated that unlike TPA, which reduces clotting in

the blood vessels of the brain, the Salk compound has a direct protective

effect on nerve cells within the brain. Maher has found that it maintains

specific cell signaling pathways required for nerve cell survival.

Similarly, in a study to be published in early 2011 in Neurorehabilitation

and Neural Repair, Gomez-Pinilla, Ph.D., and his colleagues in the

Department of Physiological Science and Division of Neurosurgery at the

University of California, Los Angeles used a rodent model of TBI to

demonstrate that CNB-001 dramatically reversed the behavioral deficits in

both locomotion and memory that accompany the brain injury. As with stroke,

CNB-001 was again found to maintain the critical signaling pathways required

for nerve cell survival, as well as the connections between nerve cells that

are lost with the injury.

The results of these two studies, which used two distinct models of brain

injury, indicate that the Salk compound has clinical potential in conditions

where there is currently no effective treatment.

" Existing drug therapies for complex neurological conditions such as stroke

and Alzheimer's disease target only one aspect of the condition, while in

fact many different factors contribute to the pathology, " observes Schubert.

" In the drug discovery program our lab uses at Salk, drug candidates must

show efficacy in tissue culture models of several aspects of the condition

before they are introduced into animal models. We believe that this approach

is making an important difference in the discovery of effective drugs. "

In related work, Maher used the same drug discovery paradigm to identify a

compound that is effective in animal models of Huntington's disease.

" Although these brain disorders appear very different, they share common

changes in the nerve cells, which suggests that compounds that prevent these

changes will be effective in multiple disorders, " she notes.

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In addition to Schubert and Gomez-Pinilla, Aiguo Wu, Ph.D., and Zhe Ying of

the UCLA Department of Physiological Science contributed to the TBI study.

Both studies were supported by the National Institutes of Health;

Gomez-Pinilla's study received additional funding from the Craig Neilsen

Foundation.

About the Salk Institute for Biological Studies

The Salk Institute for Biological Studies is one of the world's preeminent

basic research institutions, where internationally renowned faculty probe

fundamental life science questions in a unique, collaborative, and creative

environment. Focused both on discovery and on mentoring future generations

of researchers, Salk scientists make groundbreaking contributions to our

understanding of cancer, aging, Alzheimer's, diabetes, and infectious

diseases by studying neuroscience, genetics, cell and plant biology, and

related disciplines.

Faculty achievements have been recognized with numerous honors, including

Nobel Prizes and memberships in the National Academy of Sciences. Founded in

1960 by polio vaccine pioneer Jonas Salk, M.D., the Institute is an

independent nonprofit organization and architectural landmark.

Louis N. Molino, Sr. CET

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