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Treatment
> Radiation
Related
Pathology
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Cancer Research 66, 11179-11186, December 1, 2006. doi:
10.1158/0008-5472.CAN-06-2740
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Abstract |
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Lithium Treatment Prevents
Neurocognitive Deficit Resulting from Cranial Irradiation
Eugenia M. Yazlovitskaya1,2,
Eric Edwards1, Dinesh
Thotala1, Allie
Fu1, Kate L.
Osusky1, William
O. Whetsell, Jr.3, Braden
Boone4, Eric T.
Shinohara1 and Dennis
E. Hallahan1,2
1Department of Radiation
Oncology, 2Vanderbilt-Ingram Cancer Center, 3Department
of Pathology, and 4Vanderbilt Microarray Shared Resource,
Vanderbilt University School of Medicine, Nashville, Tennessee --
Requests for reprints: Dennis E. Hallahan, Department of Radiation
Oncology, Vanderbilt University, 1301 22nd Avenue South, B-902 The
Vanderbilt Clinic, Nashville, TN 37232-5671. Phone: 615-343-9244; Fax:
615-343-3075; E-mail: Dennis.Hallahan@vanderbilt.edu.
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Curative cancer treatment regimens often
require cranial irradiation, resulting in lifelong
neurocognitive deficiency in cancer survivors.
This deficiency is in part related to radiation-induced apoptosis
and decreased neurogenesis in the subgranular zone of the
hippocampus.
We show that lithium treatment protects irradiated hippocampal neurons
from apoptosis and improves cognitive performance of irradiated
mice.
The molecular mechanism of this effect is mediated through
multiple pathways, including Akt/glycogen synthase kinase-3ß (GSK-3ß)
and Bcl-2/Bax.
Lithium treatment of the cultured mouse hippocampal neurons
HT-22 induced activation of Akt (1.5-fold), inhibition of
GSK-3ß (2.2-fold), and an increase in Bcl-2 protein
expression (2-fold).
These effects were sustained when cells were treated with
lithium in combination with ionizing radiation.
In addition, this combined treatment led to decreased expression
(40%) of the apoptotic protein Bax.
The additional genes regulated by lithium were identified
by microarray, such as decorin and Birc1f.
In summary, we propose lithium treatment as a novel therapy
for prevention of deleterious neurocognitive consequences
of cranial irradiation.
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© 2006 American Association for Cancer Research
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