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Subject: MENTAL DECLINE THWARTED IN AGING RATS

U.S. Department of Health and Human Services 
NATIONAL INSTITUTES OF HEALTH NIH News 
National Institute of Mental Health (NIMH) <http://www.nimh.nih.gov/>
Embargoed for Release: Thursday, July 8, 2010, 12 p.m. EDT

CONTACTS: 
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Karen Silver, NIH DPCPSI, 301-435-2435, <e-mail:[log in to unmask]>

MENTAL DECLINE THWARTED IN AGING RATS
NIH Grantees Eye Neuroprotective Mechanism for Alzheimer's
 
Scientists have discovered a compound that restores the capacity to form new
memories in aging rats, likely by improving the survival of newborn neurons
in the brain's memory hub. The research, funded in part by the National
Institutes of Health, has turned up clues to a neuroprotective mechanism
that could lead to a treatment for Alzheimer's disease. 

"This neuroprotective compound, called P7C3, holds special promise because
of its medication-friendly properties," explained Steven McKnight, Ph.D.,
who co-led the research with Andrew Pieper, M.D., Ph.D., both of University
of Texas Southwestern Medical Center, Dallas. "It can be taken orally,
crosses the blood-brain barrier with long-lasting effects, and is safely
tolerated by mice during many stages of development." 

The researchers report on their findings July 9, 2010 in the journal Cell.
Their work was funded, in part, by the NIH's National Institute of Mental
Health (NIMH), a NIH Director's Pioneer Award
(http://commonfund.nih.gov/pioneer/Profiles04/McKnight.aspx) supported
through the Common Fund (http://nihroadmap.nih.gov/) and managed by the
National Institute of General Medical Sciences, and National Cancer
Institute. 

"This striking demonstration of a treatment that stems age-related cognitive
decline in living animals points the way to potential development of the
first cures that will address the core illness process in Alzheimer's
disease," said NIMH Director Thomas Insel, M.D. 

Physical activity, social, or other enriching experiences promote
neurogenesis -- the birth and maturation of new neurons. This growth takes
place in the dentate gyrus, a key area of the brain's memory hub, the
hippocampus. But even in the normal adult brain, most of these newborn
neurons die during the month it takes to develop and get wired into brain
circuitry. To survive, the cells must run a gauntlet of challenges. Newborn
hippocampus neurons fare much worse in aging-related disorders like
Alzheimer's, marked by runaway cell death.  

In hopes of finding compounds that might protect such vulnerable neurons
during this process, Pieper, McKnight and colleagues tested more than 1000
small molecules in living mice. One of the compounds, designated P7C3,
corrected deficits in the brains of adult mice engineered to lack a gene
required for the survival of newborn neurons in the hippocampus. Giving P7C3
to the mice reduced programmed death of newborn cells -- normalizing stunted
growth of branch-like neuronal extensions and thickening an abnormally thin
layer of cells by 40 percent. Among clues to the mechanism by which P7C3
works, the researchers discovered that it protects the integrity of
machinery for maintaining a cell's energy level. 

[The html version of this release contains the image:
http://www.nimh.nih.gov/images/news-items/compound-mouse.jpg]

To find out if P7C3 could similarly stem aging-associated neuronal death and
cognitive decline, the researchers gave the compound to aged rats. Rodents
treated with P7C3 for two months significantly outperformed their
placebo-treated peers on a water maze task, a standard assay of
hippocampus-dependent learning. This was traced to a threefold
higher-than-normal level of newborn neurons in the dentate gyrus of the
treated animals. Rats were used instead of mice for this phase of the study
because the genetically engineered mice could not swim.

The researchers pinpointed a derivative of P7C3, called A20, which is even
more protective than the parent compound. They also produced evidence
suggesting that two other neuroprotective compounds eyed as possible
Alzheimer's cures may work through the same mechanism as P7C3. The A20
derivative proved 300 times more potent than one of these compounds
currently in clinical trials for Alzheimer's disease. This suggested that
even more potent neuroprotective agents could potentially be discovered
using the same methods. Following up on these leads, the researchers are now
searching for the molecular target of P7C3 -- key to discovering the
underlying neuroprotective mechanism. 

[The html version of this release contains the image:
http://www.nimh.nih.gov/images/news-items/McKnightNeuroprotectiveRatDentateG
yrus.jpg]

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visit <www.nih.gov>.
-----------------------------------------
REFERENCE:

Discovery of a Pro-neurogenic, Neuroprotective Chemical. Pieper AA, Xie S,
Capota E, Estill SJ, Zhong J, Long JM, Becker GL, Huntington P, Goldman SE,
Shen CH, Capota M, Britt JK, Kotti T, Ure K, Brat DJ, Williams NS, MacMillan
KS, Naidoo J, Melito L, Hsieh J, Brabander JD, Ready JM, McKnight SL. 2010,
Jul 8. Cell 
  
##

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