Advertisement

Translational Stroke Research

, Volume 2, Issue 1, pp 42–50 | Cite as

Manganese Superoxide Dismutase Deficiency Exacerbates Ischemic Brain Damage Under Hyperglycemic Conditions by Altering Autophagy

  • Suresh L. Mehta
  • Yanling Lin
  • Wenge Chen
  • Fengshan Yu
  • Luyi Cao
  • Qingping He
  • Pak H. Chan
  • P. Andy Li
Article

Abstract

Both preischemic hyperglycemia and suppression of SOD2 activity aggravate ischemic brain damage. This study was undertaken to assess the effect of SOD2 mutation on ischemic brain damage and its relation to the factors involved in autophagy regulation in hyperglycemic wild-type (WT) and heterozygous SOD2 knockout (SOD2–/+) mice subjected to 30-min transient focal ischemia. The brain samples were analyzed at 5 and 24 h after recirculation for ischemic lesion volume, superoxide production, and oxidative DNA damage and protein levels of Beclin 1, damage-regulated autophagy modulator (DRAM), and microtubule-associated protein 1 light chain 3 (LC3). The results revealed a significant increase in infarct volume in hyperglycemic SOD2–/+ mice, and this was accompanied with an early (5 h) significant rise in superoxide production and reduced SOD2 activity in SOD2–/+ mice as compared to WT mice. The superoxide production is associated with oxidative DNA damage as indicated by colocalization of the dihydroethidium (DHE) signal with 8-OHdG fluorescence in SOD2–/+ mice. In addition, while ischemia in WT hyperglycemics increased the levels of autophagy markers Beclin 1, DRAM, and LC3, ischemia in hyperglycemic, SOD2-deficient mice suppressed the levels of autophagy stimulators. These results suggest that SOD2 knockdown exacerbates ischemic brain damage under hyperglycemic conditions via increased oxidative stress and DNA oxidation. Such effect is associated with suppression of autophagy regulators.

Keywords

Cerebral ischemia SOD2 Hyperglycemia Oxidative stress Autophagy 

Notes

Acknowledgments

This work was supported by NIH grant 7R01DK075476. The BRITE is partially funded by the Golden Leaf Foundation.

References

  1. 1.
    Li PA, Siesjö BK. Role of hyperglycaemia-related acidosis in ischaemic brain damage. Acta Physiol Scand. 1997;161:567–80.CrossRefPubMedGoogle Scholar
  2. 2.
    Muranyi M, Ding C, He Q, Lin Y, Li PA. Streptozotocin-induced diabetes causes astrocyte death after ischemia and reperfusion injury. Diabetes. 2006;55:349–55.CrossRefPubMedGoogle Scholar
  3. 3.
    Kamada H, Yu F, Nito C, Chan PH. Influence of hyperglycemia on oxidative stress and matrix metalloproteinase-9 activation after focal cerebral ischemia/reperfusion in rats: relation to blood–brain barrier dysfunction. Stroke. 2007;38:1044–9.CrossRefPubMedGoogle Scholar
  4. 4.
    Sugawara T, Chan PH. Reactive oxygen radicals and pathogenesis of neuronal death after cerebral ischemia. Antioxid Redox Signal. 2003;5:597–607.CrossRefPubMedGoogle Scholar
  5. 5.
    Murakami K, Kondo T, Kawase M, Li Y, Sato S, Chen SF, et al. Mitochondrial susceptibility to oxidative stress exacerbates cerebral infarction that follows permanent focal cerebral ischemia in mutant mice with manganese superoxide dismutase deficiency. J Neurosci. 1998;18:205–13.PubMedGoogle Scholar
  6. 6.
    Hara T, Nakamura K, Matsui M, Yamamoto A, Nakahara Y, Suzuki-Migishima R, et al. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature. 2006;441:885–9.CrossRefPubMedGoogle Scholar
  7. 7.
    Adhami F, Liao G, Morozov YM, Schloemer A, Schmithorst VJ, Lorenz JN, et al. Cerebral ischemia–hypoxia induces intravascular coagulation and autophagy. Am J Pathol. 2006;169:566–83.CrossRefPubMedGoogle Scholar
  8. 8.
    Scherz-Shouval R, Shvets E, Fass E, Shorer H, Gil L, Elazar Z. Reactive oxygen species are essential for autophagy and specifically regulate the activity of Atg4. EMBO J. 2007;26:1749–60.CrossRefPubMedGoogle Scholar
  9. 9.
    Rami A, Langhagen A, Steiger S. Focal cerebral ischemia induces upregulation of Beclin 1 and autophagy-like cell death. Neurobiol Dis. 2008;29:132–41.CrossRefPubMedGoogle Scholar
  10. 10.
    Li PA, Gisselsson L, Keuker J, Vogel J, Smith ML, Kuschinsky W, et al. Hyperglycemia-exaggerated ischemic brain damage following 30 min of middle cerebral artery occlusion is not due to capillary obstruction. Brain Res. 1998;804:36–44.CrossRefPubMedGoogle Scholar
  11. 11.
    Crapo JD, McCord JM, Fridovich I. Preparation and assay of superoxide dismutases. Meth Enzymol. 1978;53:382–93.CrossRefPubMedGoogle Scholar
  12. 12.
    Copin JC, Gasche Y, Chan PH. Overexpression of copper/zinc superoxide dismutase does not prevent neonatal lethality in mutant mice that lack manganese superoxide dismutase. Free Radic Biol Med. 2000;28:1571–6.CrossRefPubMedGoogle Scholar
  13. 13.
    Li PA, He QP, Hu BR, Siesjö BK. Phosphorylation of extracellular signal-regulated kinase after transient cerebral ischemia in hyperglycemic rats. Neurobiol Dis. 2001;8:127–35.CrossRefPubMedGoogle Scholar
  14. 14.
    Kim GW, Kondo T, Noshita N, Chan PH. Manganese superoxide dismutase deficiency exacerbates cerebral infarction after focal cerebral ischemia/reperfusion in mice: implications for the production and role of superoxide radicals. Stroke. 2002;33:809–15.CrossRefPubMedGoogle Scholar
  15. 15.
    Fujimura M, Morita-Fujimura Y, Kawase M, Copin JC, Calagui B, Epstein CJ, et al. Manganese superoxide dismutase mediates the early release of mitochondrial cytochrome C and subsequent DNA fragmentation after permanent focal cerebral ischemia in mice. J Neurosci. 1999;19:3414–22.PubMedGoogle Scholar
  16. 16.
    Nishikawa T, Edelstein D, Du XL, Yamagishi S, Matsumura T, Kaneda Y, et al. Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature. 2000;404:787–90.CrossRefPubMedGoogle Scholar
  17. 17.
    Keller JN, Kindy MS, Holtsberg FW, St Clair DK, Yen HC, Germeyer A, et al. Mitochondrial manganese superoxide dismutase prevents neural apoptosis and reduces ischemic brain injury: suppression of peroxynitrite production, lipid peroxidation, and mitochondrial dysfunction. J Neurosci. 1998;18:687–97.PubMedGoogle Scholar
  18. 18.
    Du X, Matsumura T, Edelstein D, Rossetti L, Zsengellér Z, Szabó C, et al. Inhibition of GAPDH activity by poly(ADP-ribose) polymerase activates three major pathways of hyperglycemic damage in endothelial cells. J Clin Invest. 2003;112:1049–57.PubMedGoogle Scholar
  19. 19.
    Wakade C, Khan MM, De Sevilla LM, Zhang QG, Mahesh VB, Brann DW. Tamoxifen neuroprotection in cerebral ischemia involves attenuation of kinase activation and superoxide production and potentiation of mitochondrial superoxide dismutase. Endocrinology. 2008;149:367–79.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Suresh L. Mehta
    • 1
  • Yanling Lin
    • 2
  • Wenge Chen
    • 1
    • 3
  • Fengshan Yu
    • 4
  • Luyi Cao
    • 1
  • Qingping He
    • 1
  • Pak H. Chan
    • 4
  • P. Andy Li
    • 1
  1. 1.Department of Pharmaceutical Sciences, Biomanufacturing Research Institute and Technology Enterprise (BRITE)North Carolina Central UniversityDurhamUSA
  2. 2.Reproductive Biogenesis InstituteUniversity of Hawaii School of MedicineHonoluluUSA
  3. 3.Department of Laser Therapeutics, Affiliated Hospital, College of Clinical SciencesNingxia Medical UniversityNingxiaPeople’s Republic of China
  4. 4.Department of NeurosurgeryStanford University School of MedicineStanfordUSA

Personalised recommendations