It seems tamoxifen interacts with .. iron.

Public release date: 12-Sep-2007
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Contact: Susan Cahill
scah...@mail.nih.gov
301-443-4536
NIH/National Institute of Mental Health

Manic phase of bipolar disorder benefits from breast cancer medication
Tamoxifen treats mania faster than some standard medications
The medication tamoxifen, best known as a treatment for breast cancer,
dramatically reduces symptoms of the manic phase of bipolar disorder
more quickly than many standard medications for the mental illness, a
new study shows. Researchers at the National Institutes of Health's
National Institute of Mental Health (NIMH) who conducted the study
also explained how: Tamoxifen blocks an enzyme called protein kinase C
(PKC) that regulates activities in brain cells. The enzyme is thought
to be over-active during the manic phase of bipolar disorder.

By pointing to PKC as a target for new medications, the study raises
the possibility of developing faster-acting treatments for the manic
phase of the illness. Current medications for the manic phase
generally take more than a week to begin working, and not everyone
responds to them. Tamoxifen itself might not become a treatment of
choice, though, because it also blocks estrogen - the property that
makes it useful as a treatment for breast cancer - and because it may
cause endometrial cancer if taken over long periods of time.
Currently, tamoxifen is approved by the Food and Drug Administration
for treatment of some kinds of cancer and infertility, for example. It
was used experimentally in this study because it both blocks PKC and
is able to enter the brain.

Results of the study were published online in the September issue of
Bipolar Disorders by Husseini K. Manji, MD, Carlos A. Zarate Jr., MD,
and colleagues.

Almost 6 million American adults have bipolar disorder, whose symptoms
can be disabling. They include profound mood swings, from depression
to vastly overblown excitement, energy, and elation, often accompanied
by severe irritability. Children also can develop the illness.

During the manic phase of bipolar disorder, patients are in
"overdrive" and may throw themselves intensely into harmful behaviors
they might not otherwise engage in. They might indulge in risky
pleasure-seeking behaviors with potentially serious health
consequences, for example, or lavish spending sprees they can't
afford. The symptoms sometimes are severe enough to require
hospitalization.

"People think of the depressive phase of this brain disorder as the
time of risk, but the manic phase has its own dangers," said NIMH
Director Thomas R. Insel, MD. "Being able to treat the manic phase
more quickly would be a great asset to patients, not just for
restoring balance in mood, but also because it could help stop harmful
behaviors before they start or get out of control."

The three-week study included eight patients who were given tamoxifen
and eight who were given a placebo (a sugar pill); all were adults and
all were having a manic episode at the time of the study. Neither the
patients nor the researchers knew which of the substances the patients
were getting.

By the end of the study, 63 percent of the patients taking tamoxifen
had reduced manic symptoms, compared with only 13 percent of those
taking a placebo. Patients taking tamoxifen responded by the fifth day
- which corresponds with the amount of time needed to build up enough
tamoxifen in the brain to dampen PKC activity.

The researchers decided to test tamoxifen's effects on the manic phase
of bipolar disorder because standard medications used to treat this
phase, specifically, are known to lower PKC activity - but they do it
through a roundabout biochemical route that takes time. Tamoxifen is
known instead to block PKC directly. As the researchers suspected
would happen, tamoxifen's direct actions on PKC resulted in much
faster relief of manic symptoms, compared with some of the standard
medications available today.

"We now have proof of principle. Our results show that targeting PKC
directly, rather than through the trickle-down mechanisms of current
medications, is a feasible strategy for developing faster-acting
medications for mania," said Manji. "This is a major step toward
developing new kinds of medications."

Findings from another recent NIMH study strengthen the results. This
previous study showed that the risk of developing bipolar disorder is
influenced by a variation in a gene called DGKH. The gene makes a PKC-
regulating protein known to be active in the biochemical pathway
through which standard medications for bipolar disorder exert their
effects - another sign that PKC is a promising direct target at which
to aim new medications for the illness.

"Mania isn't just your average mood swing, where any of us might feel
upbeat in response to something that happens. It's part of a brain
disorder whose behavioral manifestations can severely undermine
people's jobs, relationships, and health," said Zarate. "The sooner we
can help patients get back on an even keel, the more we can help them
avoid major disruptions to their lives and the lives of people around
them."

###
For more information about bipolar disorder, visit the NIMH website athtt=

The National Institute of Mental Health (NIMH) mission is to reduce
the burden of mental and behavioral disorders through research on
mind, brain, and behavior. More information is available at the NIMH
website:http://www.nimh.nih.gov/.

The National Institutes of Health (NIH) - The Nation's Medical
Research Agency - includes 27 Institutes and Centers and is a
component of the U.S. Department of Health and Human Services. It is
the primary federal agency for conducting and supporting basic,
clinical and translational medical research, and it investigates the
causes, treatments, and cures for both common and rare diseases. For
more information about NIH and its programs, visitwww.nih.gov.

Reference: Zarate Jr. CA, Singh JB, Carlson PJ, Quiroz J, Jolkovsky L,
Luckenbaugh DA, Manji HK. Efficiency of a Protein Kinase C Inhibitor
(Tamoxifen) in the Treatment of Acute Mania: A Pilot Study. Bipolar
Disorders, online ahead of print, September 2007.

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Sheng Li Xue Bao 2001 Oct;53(5):334-8

[Relationship between dopamine and iron contents in the brain of
parkinsonian rats.]

Jiang H, Chen WF, Xie JX
Medical School of Qingdao University, Qingdao 266021.

[Medline record in process]

Using fast cyclic voltammetry (FCV), atomic absorption/flame emission
spectrophotometry and high performance liquid chromatography for
electrochemical detection, we studied the change in iron content in
the
substantia nigra (SN) of 6-hydroxydopamine (6-OHDA) lesioned
Parkinsonian (PD)
rats and the toxic effect of intranigral injection of iron on DA
neurons. The
neuroprotective effect of desferrioxamine mesylate was also observed.
The
results are as follows. (1) The iron content in SN on the lesioned
side of
6-OHDA-lesioned PD rats was about three times as high as that in
unstandard PD
rats. (2) The iron content in caudate putamen (CPu) on the lesioned
side of PD
rats was not different from that on the unlesioned side. (3) DA
release as well
as the content of DA and its metabolites were significantly decreased
on the
lesioned side of PD rats. (4) In the rats pretreated with
intracerebroventricular desferrioxamine mesylate before 6-OHDA
injection, the
release and content of DA on the lesioned side were not significantly
different
from those on the unlesioned side. (5) Intranigral injection of 40
micrograms
FeCl3 resulted in a dramatic reduction of both DA release and content
in CPu.
The above results strongly suggest that 6-OHDA reduces the DA release
from CPu,
in which iron plays an important role. Elevation of iron content in SN
is one
of the mechanisms responsible for the reduction of DA content.
Desferrioxamine
mesylate may exert a protective action on dopaminergic neurons.

PMID: 11833414, UI: 21821751

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FEBS Lett. 1990 Nov 12;274(1-2):107-10.Links
Mechanism of inhibition of lipid peroxidation by tamoxifen and 4-
hydroxytamoxifen introduced into liposomes. Similarity to cholesterol
and ergosterol.
Wiseman H, Cannon M, Arnstein HR, Halliwell B.
Department of Biochemistry, University of London, King's College, UK.

The anticancer drug tamoxifen when introduced into phospholipid
liposomes during their preparation inhibited Fe(III)-ascorbate induced
lipid peroxidation to a greater extent than similarly introduced
cholesterol. Ergosterol was equipotent with tamoxifen, but much less
effective than 4-hydroxytamoxifen. Possible mechanisms underlying
these effects are discussed in relation to structural mimicry of the
sterols by these triphenylethylene drugs as membrane stabilizers
against lipid peroxidation.

PMID: 2253763 [PubMed - indexed for MEDLINE]

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