Publication: Time-course changes in neural cell apoptosis in the rat fetal brain from dams treated with 6-mercaptopurine (6-MP)
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Date
2009
Authors
Kanemitsu, H. ; Yamauchi, Hirofumi ; Komatsu, M. ; Yamamoto, S. ; Okazaki, S. ; Nakayama, Hiroyuki
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Publisher
Murcia : F. Hernández
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DOI
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info:eu-repo/semantics/article
Description
Abstract
6-Mercaptopurine (6-MP), one of the major
drugs for the therapy of acute lymphoblastic leukemia
and autoimmune diseases, is incorporated as thioguanine
in nucleic acid and it induces cytotoxicity and
fetotoxicity. In the present study, pregnant rats were
treated with 50 mg/kg of 6-MP on 13 embryonic days
(E), and fetuses were collected from 12 to 96 h after the
treatment to examine the mechanism and time-course
changes in neural cell death in the developing brain. The
weights of fetal telencephalon and the thickness of the
dorsal telencephalic wall of the fetuses were
significantly reduced at 96 h. The number of pyknotic
neural cells in the fetal telencephalon began to increase
at 24 h, peaked at 36 h, and then gradually decreased
toward 72 h. The nuclei of most of these pyknotic cells
were stained positively by TUNEL method, which
detects DNA fragmentation. Moreover, pyknotic cells
were immunohistochemically positive for cleaved
caspase-3, one of the key executioners of apoptosis, and
the increased expression of the protein from 30 to 48 h
was confirmed by using Western blot analysis. Also,
electron microscopical features of the pyknotic cells
showed ultrastructural characteristics of apoptosis. On the other hand, the number of mitotic and BrdU-positive
neural cells in the telencephalon decreased from 30 to 72
h. These results suggest that 6-MP induced apoptotic cell
death in neural cells in the rat fetal brain is probably due
to cytotoxic action of 6-MP.
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