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Increased postischemic brain injury in mice deficient in uracil-DNA glycosylase
Matthias Endres, … , Andreas Meisel, Rudolf Jaenisch
Matthias Endres, … , Andreas Meisel, Rudolf Jaenisch
Published June 15, 2004
Citation Information: J Clin Invest. 2004;113(12):1711-1721. https://doi.org/10.1172/JCI20926.
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Article Neuroscience

Increased postischemic brain injury in mice deficient in uracil-DNA glycosylase

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Abstract

Uracil-DNA glycosylase (UNG) is involved in base excision repair of aberrant uracil residues in nuclear and mitochondrial DNA. Ung knockout mice generated by gene targeting are viable, fertile, and phenotypically normal and have regular mutation rates. However, when exposed to a nitric oxide donor, Ung–/– fibroblasts show an increase in the uracil/cytosine ratio in the genome and augmented cell death. After combined oxygen-glucose deprivation, Ung–/– primary cortical neurons have increased vulnerability to cell death, which is associated with early mitochondrial dysfunction. In vivo, UNG expression and activity are low in brains of naive WT mice but increase significantly after reversible middle cerebral artery occlusion and reperfusion. Moreover, major increases in infarct size are observed in Ung–/– mice compared with littermate control mice. In conclusion, our results provide compelling evidence that UNG is of major importance for tissue repair after brain ischemia.

Authors

Matthias Endres, Detlev Biniszkiewicz, Robert W. Sobol, Christoph Harms, Michael Ahmadi, Andreas Lipski, Juri Katchanov, Philipp Mergenthaler, Ulrich Dirnagl, Samuel H. Wilson, Andreas Meisel, Rudolf Jaenisch

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Figure 5

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Effects of focal-brain ischemia in Ung–/–, Ung+/–, and Ung+/+ littermate...
Effects of focal-brain ischemia in Ung–/–, Ung+/–, and Ung+/+ littermate mice. (A) Brain lesion volume and (B) lesion areas in Ung–/– mice compared with Ung+/– and Ung+/+ WT littermate mice after 30 minutes of MCAo and 72 hours of reperfusion. Brain lesion areas were determined on five anterior-posterior serial coronal H&E-stained cryostat sections (20 ∝m); mean ± SEM of 10 to 15 animals per group; **P < 0.01, ***P < 0.005, ANOVA and Tukey post hoc test. (C) Typical H&E-stained 20 ∝m brain sections from Ung–/– and Ung+/+ littermate mice. Scale bar: 3 mm. (D) Neurological sensory-motor deficits were determined after 72 hours and scored from 0 (no deficit) to 3 (severe); *P < 0.05, ANOVA on ranks (Kruskall Wallis). (E) The development of left and right posterior communicating arteries (PcomA) was determined in carbon black_perfused brains as follows: 0, absent; 1, present but poorly developed (hypoplastic); and 2, well formed; mean ± SEM from eight animals per group; ANOVA on ranks (Kruskall Wallis). (F) The distance from midline of the line of anastomoses between the ACA and the MCA was determined in carbon black_perfused brains; mean ± SEM from eight animals per groups. ANOVA and Tukey post hoc test.

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