http://med.stanford.edu/ism/2012/april/stroke.html

APRIL 24, 2012   1 162Study points to potential treatment for stroke
BY BRUCE GOLDMAN

 
Marion Buckwalter
Stanford University School of Medicine neuroscientists have demonstrated, in
a study published online April 24 in Stroke, that a compound mimicking a key
activity of a hefty, brain-based protein is capable of increasing the
generation of new nerve cells, or neurons, in the brains of mice that have
had strokes. The mice also exhibited a speedier recovery of their athletic
ability.

These results are promising, because the compound wasn't administered to the
animals until a full three days after they had suffered strokes, said the
study's senior author, Marion Buckwalter, MD, PhD, an assistant professor of
neurology and neurological sciences. This means that the compound works not
by limiting a stroke's initial damage to the brain, but by enhancing
recovery.

This is of critical significance, said Buckwalter, a practicing clinical
neurologist who often treats recently arrived stroke patients in Stanford
Hospital's intensive care unit.

"No existing therapeutic agents today enhance recovery from stroke,"
Buckwalter said. "The only approved stroke drug, tissue plasminogen
activator, can bust up clots that initially caused the stroke but does
nothing to stimulate the restoration of brain function later." Furthermore,
to be effective, tPA has to be given within four and a half hours after a
stroke has occurred, she added. "In real life, many people don't get to the
hospital that quickly. They may live alone or have their stroke while
sleeping, or they and the people close to them didn't recognize the stroke's
symptoms well enough to realize they'd just had one."

Related News 
> Buckwalter enjoys deciphering the mysteries of stroke 
> Study identifies small molecules mimicking key brain growth factor 
Looking for an alternative, Buckwalter chose to focus on a compound called
LM22A-4, which had shown promise in previous research. LM22A-4 is a small
molecule whose bulk is less than one-seventieth that of the brain protein it
mimics: brain-derived neurotrophic factor, a powerful and long-studied nerve
growth factor. BDNF is critical during the development of the nervous system
and known to be involved in important brain functions including memory and
learning.

Stem-cell therapy, while an exciting prospect, is a relatively invasive and
expensive way to replace lost or damaged tissue. A drug that could achieve
similar results in such a delicate and complex organ as the brain would be a
welcome development.

"This small molecule stimulates the brain's own stem cells to form new
neurons and therefore may be achieving many of the same things a stem-cell
transplant would achieve, albeit with a less spectacular technology," said
Frank Longo, MD, PhD, professor and chair of neurology and neurological
sciences and a co-author of the study. "It represents an entirely new
approach for treating conditions for which we have nothing now."

Longo, who is the George E. and Lucy Becker Professor in Medicine, and his
laboratory colleagues identified LM22A-4 as a potential BDNF mimic in 2011,
in collaboration with neurologist Stephen Massa, MD, PhD, at the University
of California-San Francisco. (Massa is also listed as a study co-author.) 

About 800,000 people suffer a stroke each year in the United States, making
it the nation's leading cause of long-term disability. The older we get, the
more susceptible to stroke we become, and the harder it is for us to
recover. One contributing factor, some have hypothesized, is that BDNF
production in the brain tapers off as we get older.

In the new study, Buckwalter's team induced severe strokes on one side of
the brain in adult laboratory mice that had been previously trained in
several distinct athletic tasks. Three days afterward, the researchers
administered once-daily intranasal doses of LM22A-4 in a solution to one
group of the mice, while giving another group (who had suffered strokes as
severe as those in the first group) a similar dose of the same solution
without any LM22A-4 in it. Delaying the first dose for three days better
tests the ability of this treatment to help stroke patients in the real
world, Buckwalter said.

Dosing proceeded for 10 weeks, while the scientists monitored both the
animals' recovery of their motor skills and the numbers of new nerve cells
in areas of the mice's brains that had been damaged by strokes.

Mice receiving LM22A-4 regained their athletic prowess considerably more
quickly than those given the dummy solution: both the accuracy of their foot
placement and the swing speed of the limb on the side of their bodies
affected by the stroke improved more rapidly. Moreover, analysis revealed
twice as many new nerve cells in these mice's stroke-affected brain areas,
at six and 10 weeks after the event, than in those of their LM22A-4-denied
counterparts.

For recovering patients, walking speed is critical, said Buckwalter. "A
major factor in their ability to retain their independence and regain their
self-confidence lies in their recovering the ability to get around on their
feet," she said.

The promise of LM22A-4, for stroke and possibly other indications as well,
turns on both its resemblance to and its difference from the protein BDNF.

Reduced BDNF Ievels in the brain are observed as well in neurological
disorders such as Alzheimer's and Huntington's disease, said Longo. And in
October 2011, Ahmad Salehi, MD, PhD, clinical associate professor of
psychiatry and behavioral sciences at Stanford, and his collaborators found
that different variants of the gene coding for BDNF are associated with
correspondingly different rates at which cognitive ability declines with
age.

The notion of pharmacologically increasing the brain's stores of BDNF, while
tempting, is impractical, said Longo. "Being a protein, BDNF has a very
short half-life in the blood before it's degraded, and it penetrates the
blood-brain barrier very poorly," he said. "Plus, not all of the many things
this complex protein does are really understood, or necessarily even
helpful."

No molecule as small as LM22A-4 could possibly perform all the functions of
the gigantic, many-faceted BDNF protein that it imitates. But this
limitation may work to its advantage. Importantly, LM22A-4 binds to and
activates only one of two major cell-surface receptors for BDNF found in
nerve cells. The receptor LM22A-4 activates is associated with BDNF's
long-known ability to foster the survival of newborn nerve cells, while the
receptor it doesn't activate has been shown to respond to BDNF stimulation
by inducing the death of nerve cells - helpful, perhaps, during early
development when the brain needs to prune redundant nerve circuitry produced
in a series of growth spurts, but presumably counterproductive after a
stroke, when new nerve-cell growth and connectivity need to be encouraged.
In addition, LM22A-4 has a longer half-life in the body and has superior
ability to get into the brain than BDNF does. These differences may make
LM22A-4 better-suited for drug development than a compound that stimulated
both receptors.

The University of North Carolina at Chapel Hill and UCSF, where Longo worked
before coming to Stanford, hold the patent for LM22A-4 for use in treating
stroke. While at UNC, Longo also founded PharmatrophiX, a company focused on
the commercial development of small molecules similar to and including
LM22A-4.

The Stroke study's first author was Jullet Han, a technician in Buckwalter's
lab. Other Stanford co-authors are postdoctoral scholars Kristian Doyle,
PhD, and Kereshmeh Taravosh-Lahn, PhD; graduate student Egle Cekanaviciute;
and laboratory technicians Julia Pollak, Mohammad Siddiqui, Alex Hahn,
Jeremy Goodman,and Britta Jones, all of the Buckwalter laboratory; and Tao
Yang, PhD, a senior scientist in Longo's lab. 

Funding was provided by the National Institute for Neurological Disorders
and Stroke, the Stanford Stroke Center, Taube Philanthropies, the Koret
Foundation, the Jean Perkins Foundations and the U.S. Department of Veterans
Affairs.

Information about the medical school's Department of Neurology and
Neurological Sciences, which also supported the work, is available at
http://neurology.stanford.edu/. 

PRINT MEDIA CONTACT 
Bruce Goldman | Tel (650) 725-2106 
[log in to unmask] BROADCAST MEDIA CONTACT 
M.A. Malone | Tel (650) 723-6912 
[log in to unmask] Stanford University Medical Center integrates
research, medical education and patient care at its three institutions -
Stanford University School of Medicine, Stanford Hospital & Clinics and
Lucile Packard Children's Hospital. For more information, please visit the
Office of Communication & Public Affairs site at
http://mednews.stanford.edu/.
You are Here:
Stanford Medicine > School of Medicine > News > Inside Stanford Medicine
Navigation for This Section: News  

 
     
 
    
All School of Medicine News 
Inside Stanford Medicine 
Video News 
1:2:1 Podcast Scope Blog Featured Topics 
School of Medicine Events 
Stanford Medicine Magazine 
Stanford Medicine Newsletter 
RSS Feeds 
Office of Communication 
& Public Affairs Site Navigation:
Education Overview Admissions Financial Aid Registrar Student Life
Educational Programs & Services (EPS) Diversity at School of Medicine Office
of Diversity & Leadership Center of Excellence in Diversity in Medical
Education Biosciences Diversity Programs Diversity in Postdoctoral Training
Lane Medical Library Degree Programs Masters Programs MD Program
Multiple-Degree Programs PhD Programs Primary Care Associate Program
Non-Degree Programs PGSP-Stanford PsyD Consortium Postdoctoral Scholars
Residencies and Clinical Fellowships Summer Programs Undergraduate
Opportunities Visiting Clerkships Professional Development Career Center
Continuing Medical Education Continuing Studies at Stanford Academic
Resources Academic Calendar Course Catalog Curriculum Web Portal (MD)
Evaluations (MD) IT Services Libraries Student Support Learning & Knowledge
Center Research Overview Breakthroughs Faculty & Researcher Profiles
Clinical Trials Lane Medical Library Seminar Calendar Ways to Give Resources
for Investigators Core Research Facilities Lane Medical Library Web-based
Research Tools Research Management Group NIH, NSF & Stanford Forms Funding
Opportunities IRB (Human Subjects) OTL (Tech. Licensing) Research Policy
Handbook Conflicts of Interest Update your CAP Profile Faculty Handbook
PR/Media Services Patient Care Overview Milestones in Advancing Patient Care
Faculty & Researcher Profiles Clinical Departments Medical Research Centers
Find a Physician Find a Pediatrician or Obstetrician For Referring
Physicians (Adult) For Referring Physicians (Pediatric & Obstetric) Stanford
Health Library Clinical Trials Community Overview Education in Community
Medicine Public Health Research Public Service and Community Partnerships
Stanford Global Health Diversity Initiatives at the School of Medicine
Stanford Medicine Newsletter How You Can Help Departments & Institutes
Overview Departments Institutes of Medicine Centers & Programs Faculty Labs,
A-Z Find People Community Academic Profiles Faculty Profiles Postdoctoral
Scholar Profiles Masters Student Profiles MD Student Profiles PhD Student
Profiles Other Contact Information General Contact Information Search
Stanford.Who Administration Overview School Leadership Overview School of
Medicine Dean Vice Dean Senior Associate Deans School Officers Department &
Division Chairs Faculty Senate Strategic Plan Dean's Office Home Academic
Affairs Office of Communication & Public Affairs Office of Diversity &
Leadership Global Health Office Conflict of Interest Finance &
Administration Government Relations Information Resources & Technology
Institutional Planning Medical Development Educational Programs & Services
(EPS) Dean's Newsletter Strategic Plan Contacts Finance & Administration
Home Mission Directors of Finance & Administration Facilities Planning &
Management Health & Safety Human Resources Research Management Group Visual
Arts Services Useful Links Contacts Information Resources & Technology Home
Getting Help Personal Computing Lane Library Web Support & Development
Infrastructure Services & Communications Research Technology Administrative
Systems Educational Technology Stanford Center for Clinical Informatics
Center for Immersive and Simulation-based Learning Departmental
Administration Contacts Research Administration Home Community Academic
Profiles Conflict of Interest Core Research Facilities Department,
Institutes & Labs Institutional Proposals Development HIPAA at Stanford
Institutional Review Board Research Policy Handbook Research Management
Group Stanford/Packard Center for Translational Research in Medicine
Technology Licensing Human Resources Home Benefits Job Opportunities
Relocation Services Training Lane Medical Library Media & Public Affairs
Student Support Overview Admissions Alumni Association Career Center
Continuing Medical Education Educational Programs & Services (EPS) Financial
Aid Graduate Medical Education Lane Medical Library Postdoctoral Affairs
Registrar Faculty Support Overview Academic Affairs Conflict of Interest
Office of Diversity & Leadership Lane Medical Library Stanford Faculty
Development Center for Medical Teachers Faculty Mentoring Strategic Plan
Stanford Medicine Resources:
Stanford Medicine Getting Care Overview Find a Physician Find a Clinical
Care Center Stanford Hospital & Clinics Lucile Packard Children's Hospital
Emergency Research Overview School of Medicine News & Resources Clinical
Trials Departments, Institutes & Centers Faculty Profiles Education &
Training Overview School of Medicine Programs Admissions Continuing Medical
Education Alumni Lane Medical Library Community Overview Stanford Health
Library Community Newsletter Volunteering Public Service & Community
Partnerships Renewal & New Building Projects About Us Overview News Careers
Ways to Give Find a Person Contact Us Maps & Directions The Dean's
Newsletter Stanford University Footer Links:
Directions & Maps Contacts Jobs Strategic Plan Local Users' Home C2012
Stanford School of Medicine Terms of Use Powered by IRT

-----------------------

To change your mail settings or leave the C-PALSY list, go here:

http://listserv.icors.org/SCRIPTS/WA-ICORS.EXE?SUBED1=c-palsy