Mice With Human Protein, COX-2, Exhibit Age-Related Memory Loss, Similar To Alzheimer's Disease

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Source: Johns Hopkins Medical Institutions (http://www.hopkinsmedicine.org)

http://www.sciencedaily.com/releases/2001/11/011119072232.htm

Posted 11/21/2001

Mice With Human Protein, COX-2, Exhibit Age-Related Memory Loss, Similar To

Alzheimer's Disease

 

A new player is emerging in the complex world of the brain. This player, a

protein called COX-2, appears to be

critically important in the brain's normal functioning, as evidenced by its

ability to wreak havoc in mice that have too

much of it.

These mice, engineered to make the human COX-2 protein, develop memory problems

as they age, mimicking problems seen in

Alzheimer's disease, report scientists from Johns Hopkins School of Medicine and

the biomedical research company

Pharmacia. The results are scheduled for presentation Nov. 14 at the annual

meeting of the Society for Neuroscience in

San Diego.

 

Additional studies seem to link COX-2 to loss of brain cells in animal models of

other neurologic diseases, as well,

including stroke, Parkinson's disease and Lou Gehrig's disease.

 

" The really exciting thing is that this protein is turning out to be involved in

so many things, and we already have the

means to target it, to block it, " says Katrin Andreasson, M.D., assistant

professor of neurology and neuroscience at

Johns Hopkins. " It makes it very conceivable that in the years to come we could

prevent these diseases. "

 

Drugs that reduce swelling, like ibuprofen and newer anti-inflammatories like

Celebrex and Vioxx, work by blocking

COX-2. However, Andreasson cautions that a lot of work remains to learn whether

these drugs might prevent neurological

disease or damage in people.

 

Building on their report in the Oct. 15 issue of the Journal of Neuroscience,

Andreasson's colleagues Alena Savonenko

and Alicja Markowska are to present new data at the neuroscience meeting that

shows the more COX-2 protein the mice make

in the brain, the more pronounced their memory problems and the faster those

problems develop.

 

Andreasson's colleagues measured the animals' abilities to learn and remember

using a battery of tests, including mazes

and swimming tests. The animals' behaviors in the test situations reflected how

brain levels of the human COX-2 protein

affected their learning and memory at different ages.

 

" The effect of having lots of the human COX-2 protein is remarkable in these

mice, " says Andreasson. " At age seven

months -- roughly similar to humans in their 20s and 30s -- they are fine, but

as these mice get older they exhibit

progressively greater memory deficits. These mice have real age-dependent memory

loss, and higher age-dependent loss of

brain cells that parallels the behavioral changes. "

 

Because so much is already known about the human COX-2 protein, learning more

about what it does in the brain, even the

mouse brain, is a little easier, says Andreasson. " We already have tools to see

where COX-2 is located in the brain and

in individual nerve cells, and we can also test whether it's working by

measuring levels of the molecules it makes. "

 

COX-2 helps make a group of five molecules, called prostaglandins, that send

signals to the nerve cell. Andreasson says

one of the prostaglandins may be the real culprit behind COX-2's effects on

memory and it's role in disease.

 

" If it's a prostaglandin, we can find out which is good and which is bad, and

potentially target the bad one

specifically to prevent memory loss or damage from aging or stroke or disease, "

she says. " The possibility would exist

to prevent neurological problems and to do so with fewer side effects than

blocking COX-2 itself. "

 

While targeting prostaglandins is still hypothetical, current research is

beginning to evaluate COX-2 inhibitors to

prevent or delay neurological problems. For example, an ongoing study at Johns

Hopkins and three other centers will

determine whether using these drugs can affect development of Alzheimer's

disease in older patients at high risk for it.

 

COX-2's role in exacerbating damage from strokes is another hot topic of pursuit

among neurologists and neuroscientists.

Another Hopkins presentation at the Society for Neuroscience meeting shows that

the area of the brain affected by a

stroke is much larger in mice with extra COX-2, but importantly, the study also

shows it might be possible to save a

large part of that affected area.

 

" In a stroke, a core part of the affected brain is destroyed, but there's a

region around the core that isn't

immediately destroyed, but is at high risk for damage, " explains Andreasson. " If

you can save that area, called the

penumbra, or save a large part of it, that would have huge potential to improve

recovery after stroke. "

 

While studies looking at COX-2 inhibitors in patients with stroke haven't begun,

scientists at Johns Hopkins have

started a study of people at high risk of developing Alzheimer's disease to see

if using COX-2 inhibitors can prevent or

delay that disease. Since participants in the study don't have the disease, it

will take many years for the researchers

to know for sure if there is an effect.

 

Authors on the Society for Neuroscience presentation on age-related memory loss

in COX-2 mice are Savonenko, Andreasson

and Paul Worley of Johns Hopkins, Peter Isakson of Pharmacia Research and

Development (Peapack, NJ), and Markowska,

formerly of Johns Hopkins University, now at the National Institute on Aging.

(Wednesday, Nov. 14, poster session 4-5

pm)

 

Authors on the Oct. 15 Journal of Neuroscience paper on age-related memory loss

in COX-2 mice are Andreasson, Savonenko,

Worley, Isakson and Markowska, as well as Sveta Vidensky and Walter Kaufmann of

Johns Hopkins, and Joseph Goellner, Yan

Shang and Alex Shaffer of Pharmacia Research (St. Louis). (J. Neurosci., 2001;

21(20): 8198-8209.) This study was funded

by the National Institutes of Health, the Alzheimer's Association and Pharmacia

Research and Development.

 

Authors on the analysis of stroke in the COX-2 mice are Sylvain Dore, Nobuo

Sugo, Richard Traytsman, Raymond Koehler and

Patricia Hurn of anaesthesiology and critical care medicine at Johns Hopkins;

Worley, Andreasson and Isakson. (Monday,

Nov. 12, 11 a.m. - noon poster session)

========================

 

Another potent COX-2 inhibitor...... Omega 3 EPA.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve & db=PubMed & list_uids=1\

1421736 & dopt=Abstract

J Nat Prod 2001 Jun;64(6):745-9 Related Articles, Books, LinkOut

Cox-2 inhibitory effects of naturally occurring and modified fatty acids.

Ringbom T, Huss U, Stenholm A, Flock S, Skattebol L, Perera P, Bohlin L.

Division of Pharmacognosy, Department of Medicinal Chemistry, Biomedical Centre,

Uppsala University, Box 574, SE-751 23

Uppsala, Sweden.

 

In the search for new cyclooxygenase-2 (COX-2) selective inhibitors, the

inhibitory effects of naturally occurring fatty

acids and some of their structural derivatives on COX-2-catalyzed prostaglandin

biosynthesis were investigated. Among

these fatty acids, linoleic acid (LA), alpha-linolenic acid (alpha-LNA),

myristic acid, and palmitic acid were isolated

from a CH(2)Cl(2) extract of the plant Plantago major by bioassay-guided

fractionation. Inhibitory effects of other

natural, structurally related fatty acids were also investigated: stearic acid,

oleic acid, pentadecanoic acid,

eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). Further, the

inhibitory effects of these compounds on

COX-2- and COX-1-catalyzed prostaglandin biosynthesis was compared with the

inhibition of some synthesized analogues of

EPA and DHA with ether or thioether functions.

 

The most potent COX-2-catalyzed prostaglandin biosynthesis inhibitor was

 

20:4w3 Eicosatetraenoic acid,

20:5w3 EPA

22:6w3 DHA

18:3w3 alpha-LNA

18:2w6 LA,

tetraenoic acid,

octadecatetraenoic acid,

pentaenoic acid

 

with IC(50) values ranging from 3.9 to180 microM. The modified compound 2 and

alpha-LNA were most selective toward

COX-2, with COX-2/COX-1 ratios of 0.2 and 0.1, respectively. This study shows

that several of the natural fatty acids as

well as all of the semisynthetic thioether-containing fatty acids inhibited

COX-2-catalyzed prostaglandin biosynthesis,

where alpha-LNA and compound 2 showed selectivity toward COX-2.

 

PMID: 11421736 [PubMed - indexed for MEDLINE]

 

========================

Good Health & Long Life,

Greg Watson, gowatson

USDA database (food breakdown) http://www.nal.usda.gov/fnic/foodcomp/

PubMed (research papers) http://www.ncbi.nlm.nih.gov/entrez/query.fcgi

DWIDP (nutrient analysis) http://www.walford.com/dwdemo/dw2b63demo.exe

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