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The Role of Autophagy in Ischaemic Stroke: Friend or Foe?

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Advancement in the Pathophysiology of Cerebral Stroke

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Abstract

Autophagy is an evolutionarily conserved process of cellular self-degradation and recycling of redundant cytoplasmic entities by lysosomal enzymes. Moreover, autophagy also plays critical roles in controlling several biochemical and molecular neuronal physiology such as growth, survival and metabolism. The autophagy process constantly occurs at basal level under normal physiological conditions and gets increased during stress conditions such as starvation and hypoxia. In neuronal cells, it is a vital homeostasis mechanism that helps in the maintenance of protein quality control. In various neurological disorders, several crucial pro-survival and anti-apoptotic effects of autophagy have been reported. However, the function of autophagy in ischaemic stroke (IS) is highly controversial and still debated. Some reports show that it protects neurons during IS, while others advocate it to be neurodegenerative. Thus, the present chapter deals with the possible function of autophagy in ischaemic stroke along with the discussion of various factors influencing the action of autophagy in ischaemic stroke.

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References

  1. Chu, C. T. (2008, February). Eaten alive. The American Journal of Pathology, 172(2), 284–287.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Lakhan, S. E., Kirchgessner, A., & Hofer, M. (2009). Inflammatory mechanisms in ischemic stroke: Therapeutic approaches. Journal of Translational Medicine, 7(1), 97.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Cowan, F., Rutherford, M., Groenendaal, F., Eken, P., Mercuri, E., Bydder, G. M., et al. (2003, March). Origin and timing of brain lesions in term infants with neonatal encephalopathy. The Lancet, 361(9359), 736–742.

    Article  Google Scholar 

  4. Block, F. (1999, June). Global ischemia and behavioural deficits. Progress in Neurobiology, 58(3), 279–295.

    Article  CAS  PubMed  Google Scholar 

  5. Ouyang, Y. B., & Giffard, R. G. (2012). ER-mitochondria crosstalk during cerebral ischemia: Molecular chaperones and ER-mitochondrial calcium transfer. International Journal of Cell Biology, 2012, 1–8.

    Article  CAS  Google Scholar 

  6. Carron, S. F., Alwis, D. S., & Rajan, R. (2016, June). Traumatic brain injury and neuronal functionality changes in sensory cortex. Frontiers in Systems Neuroscience, 10, 47. Available from: http://journal.frontiersin.org/Article/10.3389/fnsys.2016.00047/abstract

    Google Scholar 

  7. Petty, G. W., Brown, R. D., Whisnant, J. P., Sicks, J. D., O’Fallon, W. M., & Wiebers, D. O. (2000, May 1). Ischemic stroke subtypes: A population-based study of functional outcome, survival, and recurrence. Stroke, 31(5), 1062–1068.

    Article  CAS  PubMed  Google Scholar 

  8. Sanganalmath, S. K., Gopal, P., Parker, J. R., Downs, R. K., Parker, J. C., & Dawn, B. (2017, February). Global cerebral ischemia due to circulatory arrest: Insights into cellular pathophysiology and diagnostic modalities. Molecular and Cellular Biochemistry, 426(1–2), 111–127.

    Article  CAS  PubMed  Google Scholar 

  9. Ye, Y., Perez-Polo, J. R., & Birnbaum, Y. (2010, October). Protecting against ischemia-reperfusion injury: Antiplatelet drugs, statins, and their potential interactions: Ye et al. The Annals of the New York Academy of Sciences, 1207(1), 76–82.

    Article  CAS  PubMed  Google Scholar 

  10. Balucani, C., Levine, S. R., Khoury, J. C., Khatri, P., Saver, J. L., & Broderick, J. P. (2016, April). Acute ischemic stroke with very early clinical improvement: A National Institute of Neurological Disorders and Stroke recombinant tissue plasminogen activator stroke trials exploratory analysis. Journal of Stroke and Cerebrovascular Diseases, 25(4), 894–901.

    Article  PubMed  Google Scholar 

  11. Barreto, A. D., Fanale, C. V., Alexandrov, A. V., Gaffney, K. C., Vahidy, F. S., Nguyen, C. B., et al. (2016, August). Prospective, open-label safety study of intravenous recombinant tissue plasminogen activator in wake-up stroke: Safety study of wake-up stroke thrombolysis. Annals of Neurology, 80(2), 211–218.

    Article  CAS  PubMed  Google Scholar 

  12. Green, A. R., & Shuaib, A. (2006, August). Therapeutic strategies for the treatment of stroke. Drug Discovery Today, 11(15–16), 681–693.

    Article  CAS  PubMed  Google Scholar 

  13. Fisher, M. (2011, January 1). New approaches to neuroprotective drug development. Stroke, 42, S24–S27.

    Article  PubMed  Google Scholar 

  14. Dirnagl, U., Iadecola, C., & Moskowitz, M. A. (1999, September). Pathobiology of ischaemic stroke: An integrated view. Trends in Neurosciences, 22(9), 391–397.

    Article  CAS  PubMed  Google Scholar 

  15. Mongin, A. A. (2007, December). Disruption of ionic and cell volume homeostasis in cerebral ischemia: The perfect storm. Pathophysiology, 14(3–4), 183–193.

    Article  CAS  PubMed  Google Scholar 

  16. Simard, J. M., Kent, T. A., Chen, M., Tarasov, K. V., & Gerzanich, V. (2007, March). Brain oedema in focal ischaemia: Molecular pathophysiology and theoretical implications. The Lancet Neurology, 6(3), 258–268.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Chen, H., Yoshioka, H., Kim, G. S., Jung, J. E., Okami, N., Sakata, H., et al. (2011, April 15). Oxidative stress in ischemic brain damage: Mechanisms of cell death and potential molecular targets for neuroprotection. Antioxidants & Redox Signaling, 14(8), 1505–1517.

    Article  CAS  Google Scholar 

  18. Sanderson, T. H., Reynolds, C. A., Kumar, R., Przyklenk, K., & Hüttemann, M. (2013, February). Molecular mechanisms of ischemia–reperfusion injury in brain: Pivotal role of the mitochondrial membrane potential in reactive oxygen species generation. Molecular Neurobiology, 47(1), 9–23.

    Article  CAS  PubMed  Google Scholar 

  19. Deb, P., Sharma, S., & Hassan, K. M. (2010, June). Pathophysiologic mechanisms of acute ischemic stroke: An overview with emphasis on therapeutic significance beyond thrombolysis. Pathophysiology, 17(3), 197–218.

    Article  CAS  PubMed  Google Scholar 

  20. Ford, A. L., An, H., Vo, K. D., Lin, W., & Lee, J.-M. (2012, June). Defining the ischemic penumbra using hyperacute neuroimaging: Deriving quantitative ischemic thresholds. Translational Stroke Research, 3(2), 198–204.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Kleinschnitz, C., Fluri, F., & Schuhmann, M. (2015). Animal models of ischemic stroke and their application in clinical research. Drug Design, Development and Therapy, 9, 3445.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Tamura, A., Graham, D. I., McCulloch, J., & Teasdale, G. M. (1981, March). Focal cerebral ischaemia in the rat: 1. Description of technique and early neuropathological consequences following middle cerebral artery occlusion. Journal of Cerebral Blood Flow & Metabolism, 1(1), 53–60.

    Article  CAS  Google Scholar 

  23. Longa, E. Z., Weinstein, P. R., Carlson, S., & Cummins, R. (1989, January). Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke, 20(1), 84–91.

    Article  CAS  PubMed  Google Scholar 

  24. Schmid Elsaesser, R., Zausinger, S., Hungerhuber, E., Baethmann, A., & Reulen, H. J. (1998, October). A critical reevaluation of the intraluminal thread model of focal cerebral ischemia: Evidence of inadvertent premature reperfusion and subarachnoid hemorrhage in rats by laser-Doppler flowmetry. Stroke, 29(10), 2162–2170.

    Article  CAS  PubMed  Google Scholar 

  25. Belayev, L., Alonso, O. F., Busto, R., Zhao, W., Ginsberg, M. D., & Hsu, C. Y. (1996, September 1). Middle cerebral artery occlusion in the rat by intraluminal suture: Neurological and pathological evaluation of an improved model. Stroke, 27(9), 1616–1623.

    Article  CAS  PubMed  Google Scholar 

  26. Howells, D. W., Porritt, M. J., Rewell, S. S., O’Collins, V., Sena, E. S., Van der Worp, H. B., et al. (2010, August). Different strokes for different folks: The rich diversity of animal models of focal cerebral ischemia. Journal of Cerebral Blood Flow and Metabolism, 30(8), 1412–1431.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Kuroiwa, T., Xi, G., Hua, Y., Nagaraja, T. N., Fenstermacher, J. D., & Keep, R. F. (2009, January 1). Development of a rat model of photothrombotic ischemia and infarction within the caudoputamen. Stroke, 40(1), 248–253.

    Article  PubMed  Google Scholar 

  28. Watson, B. D., Dietrich, W. D., Busto, R., Wachtel, M. S., & Ginsberg, M. D. (1985, May). Induction of reproducible brain infarction by photochemically initiated thrombosis. Annals of Neurology, 17(5), 497–504.

    Article  CAS  PubMed  Google Scholar 

  29. Yanagisawa, M., Kurihara, H., Kimura, S., Goto, K., & Masaki, T. (1988, December). A novel peptide vasoconstrictor, endothelin, is produced by vascular endothelium and modulates smooth muscle Ca2+ channels. Journal of Hypertension, 6(4), S188–S191.

    Article  CAS  PubMed  Google Scholar 

  30. Hughes, P. M., Anthony, D. C., Ruddin, M., Botham, M. S., Rankine, E. L., Sablone, M., et al. (2003, December). Focal lesions in the rat central nervous system induced by endothelin-1. Journal of Neuropathology and Experimental Neurology, 62(12), 1276–1286.

    Article  CAS  PubMed  Google Scholar 

  31. Frost, S. B., Barbay, S., Mumert, M. L., Stowe, A. M., & Nudo, R. J. (2006, May). An animal model of capsular infarct: Endothelin-1 injections in the rat. Behavioural Brain Research, 169(2), 206–211.

    Article  CAS  PubMed  Google Scholar 

  32. Albers, G. W. (1995, February). Antithrombotic agents in cerebral ischemia. The American Journal of Cardiology, 75(6), 34B–38B.

    Article  CAS  PubMed  Google Scholar 

  33. DiNapoli, V. A., Rosen, C. L., Nagamine, T., & Crocco, T. (2006, June). Selective MCA occlusion: A precise embolic stroke model. Journal of Neuroscience Methods, 154(1–2), 233–238.

    Article  PubMed  Google Scholar 

  34. Zhang, Z., Zhang, R. L., Jiang, Q., Raman, S. B. K., Cantwell, L., & Chopp, M. (1997, February). A new rat model of thrombotic focal cerebral ischemia. Journal of Cerebral Blood Flow and Metabolism, 17(2), 123–135.

    Article  PubMed  Google Scholar 

  35. Orset, C., Macrez, R., Young, A. R., Panthou, D., Angles-Cano, E., Maubert, E., et al. (2007, October 1). Mouse model of in situ thromboembolic stroke and reperfusion. Stroke, 38(10), 2771–2778.

    Article  PubMed  Google Scholar 

  36. Overgaard, K., Sereghy, T., Pedersen, H., & Boysen, G. (1994, May). Effect of delayed thrombolysis with rt-PA in a rat embolic stroke model. Journal of Cerebral Blood Flow and Metabolism, 14(3), 472–477.

    Article  CAS  PubMed  Google Scholar 

  37. Zhang, L., Zhang, Z. G., Zhang, C., Zhang, R. L., & Chopp, M. (2004, November 11). Intravenous administration of a GPIIb/IIIa receptor antagonist extends the therapeutic window of intra-arterial tenecteplase-tissue plasminogen activator in a rat stroke model. Stroke, 35(12), 2890–2895.

    Article  CAS  PubMed  Google Scholar 

  38. Eskelinen, E. L. (2005, April). Maturation of autophagic vacuoles in mammalian cells. Autophagy, 1(1), 1–10.

    Article  CAS  PubMed  Google Scholar 

  39. Mijaljica, D., Prescott, M., & Devenish, R. J. (2011, July). Microautophagy in mammalian cells: Revisiting a 40-year-old conundrum. Autophagy, 7(7), 673–682.

    Article  CAS  PubMed  Google Scholar 

  40. PeriyasamyThandavan, S., Jiang, M., Schoenlein, P., & Dong, Z. (2009, August). Autophagy: Molecular machinery, regulation, and implications for renal pathophysiology. The American Journal of Physiology - Renal Physiology, 297(2), F244–F256.

    Article  CAS  Google Scholar 

  41. Kiffin, R. (2004, September 1). Activation of chaperone-mediated autophagy during oxidative stress. Molecular Biology of the Cell, 15(11), 4829–4840.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Glick, D., Barth, S., & Macleod, K. F. (2010, May). Autophagy: Cellular and molecular mechanisms. The Journal of Pathology., 221(1), 3–12.

    Article  CAS  PubMed  Google Scholar 

  43. Marzella, L., Ahlberg, J., & Glaumann, H. (1981). Autophagy, heterophagy, microautophagy and crinophagy as the means for intracellular degradation. Virchows Archives B, Cell Pathology Including Molecular Pathology, 36(2–3), 219–234.

    Article  CAS  Google Scholar 

  44. Klionsky, D. J. (2007, November). Autophagy: From phenomenology to molecular understanding in less than a decade. Nature Reviews Molecular Cell Biology, 8(11), 931–937.

    Article  CAS  PubMed  Google Scholar 

  45. Ravikumar, B., Sarkar, S., Davies, J. E., Futter, M., Garcia-Arencibia, M., Green-Thompson, Z. W., et al. (2010, October 1). Regulation of mammalian autophagy in physiology and pathophysiology. Physiological Reviews, 90(4), 1383–1435.

    Article  CAS  PubMed  Google Scholar 

  46. Gabryel, B., Kost, A., & Kasprowska, D. (2012). Neuronal autophagy in cerebral ischemia – a potential target for neuroprotective strategies? Pharmacological Reports, 64(1), 1–15.

    Article  CAS  PubMed  Google Scholar 

  47. Carloni, S., Girelli, S., Scopa, C., Buonocore, G., Longini, M., & Balduini, W. (2010, April). Activation of autophagy and Akt/CREB signaling play an equivalent role in the neuroprotective effect of rapamycin in neonatal hypoxia-ischemia. Autophagy, 6(3), 366–377.

    Article  CAS  PubMed  Google Scholar 

  48. Singh, A. K., Kashyap, M. P., Tripathi, V. K., Singh, S., Garg, G., & Rizvi, S. I. (2016). Neuroprotection through rapamycin-induced activation of autophagy and PI3K/Akt1/mTOR/CREB signaling against amyloid-β-induced oxidative stress, synaptic/neurotransmission dysfunction, and neurodegeneration in adult rats. Molecular Neurobiology. Available from: http://link.springer.com/10.1007/s12035-016-0129-3.

  49. Wang, P., Guan, Y. F., Du, H., Zhai, Q. W., Su, D. F., & Miao, C. Y. (2012, January). Induction of autophagy contributes to the neuroprotection of nicotinamide phosphoribosyltransferase in cerebral ischemia. Autophagy, 8(1), 77–87.

    Article  CAS  PubMed  Google Scholar 

  50. Adhami, F., Liao, G., Morozov, Y. M., Schloemer, A., Schmithorst, V. J., Lorenz, J. N., et al. (2006, August). Cerebral ischemia-hypoxia induces intravascular coagulation and autophagy. The American Journal of Pathology, 169(2), 566–583.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Li, J., & McCullough, L. D. (2010, March). Effects of AMP-activated protein kinase in cerebral ischemia. Journal of Cerebral Blood Flow and Metabolism, 30(3), 480–492.

    Article  CAS  PubMed  Google Scholar 

  52. Koike, M., Shibata, M., Tadakoshi, M., Gotoh, K., Komatsu, M., Waguri, S., et al. (2008, February). Inhibition of autophagy prevents hippocampal pyramidal neuron death after hypoxic-ischemic injury. The American Journal of Pathology, 172(2), 454–469.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Wen, Y. D., Sheng, R., Zhang, L. S., Han, R., Zhang, X., Zhang, X. D., et al. (2008, August 16). Neuronal injury in rat model of permanent focal cerebral ischemia is associated with activation of autophagic and lysosomal pathways. Autophagy, 4(6), 762–769.

    Article  CAS  PubMed  Google Scholar 

  54. Xin, X. Y., Pan, J., Wang, X. Q., Ma, J. F., Ding, J. Q., Yang, G. Y., et al. (2011, July). 2-methoxyestradiol attenuates autophagy activation after global ischemia. Canadian Journal of Neurological Sciences/Journal Canadien des Sciences Neurologiques, 38(04), 631–638.

    Article  Google Scholar 

  55. Kang, C., & Avery, L. (2008, January). To be or not to be, the level of autophagy is the question: Dual roles of autophagy in the survival response to starvation. Autophagy, 4(1), 82–84.

    Article  PubMed  Google Scholar 

  56. Shi, R., Weng, J., Zhao, L., Li, X. M., Gao, T. M., & Kong, J. (2012, March). Excessive autophagy contributes to neuron death in cerebral ischemia: Autophagy in cerebral ischemia. CNS Neuroscience & Therapeutics, 18(3), 250–260.

    Article  CAS  Google Scholar 

  57. Qin, A. P., Liu, C. F., Qin, Y. Y., Hong, L. Z., Xu, M., Yang, L., et al. (2010, August). Autophagy was activated in injured astrocytes and mildly decreased cell survival following glucose and oxygen deprivation and focal cerebral ischemia. Autophagy, 6(6), 738–753.

    Article  CAS  PubMed  Google Scholar 

  58. Tu, X., Yang, W., Chen, J., Chen, Y., Chen, Q., Chen, P., et al. (2015, April). Repetitive ischemic preconditioning attenuates inflammatory reaction and brain damage after focal cerebral ischemia in rats: Involvement of PI3K/Akt and ERK1/2 signaling pathway. Journal of Molecular Neuroscience, 55(4), 912–922.

    Article  CAS  PubMed  Google Scholar 

  59. Park, H. K., Chu, K., Jung, K. H., Lee, S. T., Bahn, J. J., Kim, M., et al. (2009, February). Autophagy is involved in the ischemic preconditioning. Neuroscience Letters, 451(1), 16–19.

    Article  CAS  PubMed  Google Scholar 

  60. Yan, W., Zhang, H., Bai, X., Lu, Y., Dong, H., & Xiong, L. (2011, July). Autophagy activation is involved in neuroprotection induced by hyperbaric oxygen preconditioning against focal cerebral ischemia in rats. Brain Research, 1402, 109–121.

    Article  CAS  PubMed  Google Scholar 

  61. Carloni, S., Buonocore, G., & Balduini, W. (2008, December). Protective role of autophagy in neonatal hypoxia–ischemia induced brain injury. Neurobiology of Disease, 32(3), 329–339.

    Article  CAS  PubMed  Google Scholar 

  62. Komatsu, M., Ueno, T., Waguri, S., Uchiyama, Y., Kominami, E., & Tanaka, K. (2007, March). Constitutive autophagy: Vital role in clearance of unfavorable proteins in neurons. Cell Death and Differentiation. Available from: http://www.nature.com/doifinder/10.1038/sj.cdd.4402120.

  63. Liu, C., Gao, Y., Barrett, J., & Hu, B. (2010, October). Autophagy and protein aggregation after brain ischemia. Journal of Neurochemistry, 115(1), 68–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgement

A. K. Singh would like to acknowledge University Grants Commission, New Delhi, India, for providing financial support (F.4-2/2006(BSR)/BL/14-15/0326).

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Authors and Affiliations

  1. Department of Biochemistry, University of Allahabad, Allahabad, India

    Komal Saraswat, Raushan Kumar & Syed Ibrahim Rizvi

  2. Amity Institute of Neuropsychology and Neurosciences, Amity University Uttar Pradesh, Noida, Uttar Pradesh, India

    Abhishek Kumar Singh

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  1. Komal Saraswat
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  2. Raushan Kumar
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Editors and Affiliations

  1. School of Biomedical Engineering, Indian Institute of Technology (Banaras Hindu University), Varanasi, Uttar Pradesh, India

    Ranjana Patnaik

  2. School of Biomedical Engineering, Indian Institute of Technology (Banaras Hindu University), Varanasi, Uttar Pradesh, India

    Amit Kumar Tripathi

  3. Department of Zoology, Banaras Hindu University, Varanasi, Uttar Pradesh, India

    Ashish Dwivedi

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Saraswat, K., Kumar, R., Rizvi, S.I., Singh, A.K. (2019). The Role of Autophagy in Ischaemic Stroke: Friend or Foe?. In: Patnaik, R., Tripathi, A., Dwivedi, A. (eds) Advancement in the Pathophysiology of Cerebral Stroke. Springer, Singapore. https://doi.org/10.1007/978-981-13-1453-7_5

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