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Volume 16, Number 21,
Issue of November 1, 1996
pp. 6795-6806
Copyright ©1996 Society for Neuroscience
Damage, Repair, and Mutagenesis in Nuclear Genes after Mouse
Forebrain Ischemia-Reperfusion
Received June 20, 1996; revised Aug. 2, 1996; accepted Aug. 13, 1996.
Philip K. Liu1,
Chung
Y. Hsu2,
Miral Dizdaroglu3,
Robert A. Floyd4,
Yoke W. Kow5,
Asuman Karakaya3, 6,
Lois E. Rabow5, and
Jian-K. Cui1
1 Laboratory of Neurobiology, Division of Restorative
Neurology and Human Neurobiology, Baylor College of Medicine, Houston,
Texas 77030, 2 Department of Neurology, Washington
University, St. Louis, Missouri 63110, 3 Chemical Science
and Technology Laboratory, National Institute of Standards and
Technology, Gaithersburg, Maryland 20899, 4 Oklahoma
Medical Research Foundation, Oklahoma City, Oklahoma 73104-5046, 5 Department of Radiation Oncology, Emory University School
of Medicine, Atlanta, Georgia 30335, and 6 Faculty of
Pharmacy, University of Ankara, Ankara, Turkey
To determine whether oxidative stress after cerebral
ischemia-reperfusion affects genetic stability in the brain, we
studied mutagenesis after forebrain ischemia-reperfusion in Big Blue
transgenic mice (male C57BL/6 strain) containing a reporter
lacI gene, which allows detection of mutation frequency.
The frequency of mutation in this reporter lacI gene
increased from 1.5 to 7.7 (per 100,000) in cortical DNA after 30 min of
forebrain ischemia and 8 hr of reperfusion and remained elevated at 24 hr reperfusion. Eight DNA lesions that are characteristic of DNA damage
mediated by free radicals were detected. Four mutagenic lesions
(2,6-diamino-4-hydroxy-5-formamidopyrimidine, 8-hydroxyadenine,
5-hydroxycytosine, and 8-hydroxyguanine) examined by gas
chromatography/mass spectrometry and one corresponding
8-hydroxy-2 -deoxyguanosine by a method of HPLC with electrochemical
detection increased in cortical DNA two- to fourfold
(p < 0.05) during 10-20 min of
reperfusion. The damage to  -actin and DNA polymerase- genes was
detected within 20 min of reperfusion based on the presence of
formamidopyrimidine DNA N-glycosylase-sensitive
sites. These genes became resistant to the glycosylase within 4-6 hr
of reperfusion, suggesting a reduction in DNA damage and presence of
DNA repair in nuclear genes. These results suggest that nuclear genes
could be targets of free radicals.
Key words:
apoptosis;
brain;
mutation;
dementia;
oxidative
stress;
stroke
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