Advertisement

Mitochondrial Dysfunction in Stroke: Implications of Stem Cell Therapy

  • Deepaneeta Sarmah
  • Harpreet Kaur
  • Jackson Saraf
  • Kanchan Vats
  • Kanta Pravalika
  • Madhuri Wanve
  • Kiran Kalia
  • Anupom Borah
  • Akhilesh Kumar
  • Xin Wang
  • Dileep R. Yavagal
  • Kunjan R. Dave
  • Pallab Bhattacharya
Review Article

Abstract

Stroke is a debilitating condition which is also the second leading cause of death and disability worldwide. Despite the benefits and promises shown by numerous neuroprotective agents in animal stroke models, their clinical translation has not been a complete success. Hence, search for treatment options have directed researchers towards utilising stem cells. Mitochondria has a major involvement in the pathophysiology of stroke and a number of other conditions. Stem cells have shown the ability to transfer mitochondria to the damaged cells and to help revive cell energetics in the recipient cell. The present review discusses how stem cells could be employed to protect neurons and mitochondria in stroke and also the various mechanisms involved in neuroprotection.

Keywords

Stroke Mitochondria Reactive oxygen species Neuroprotection Tunnelling nanotubes Extracellular vesicles Cell fusion 

Notes

Funding

The authors acknowledge the Department of Science and Technology (DST), Govt. of India, for their financial support through grant (SB/YS/LS-196/2014), International Society for Neurochemistry (ISN) Return Home grant, Department of Pharmaceuticals, Ministry of Chemical and Fertilisers, Govt of India and National Institute of Pharmaceutical Education and Research (NIPER) Ahmedabad, Gandhinagar, India. The authors also want to express their thanks to the Director, NIPER Ahmedabad, for providing necessary support.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflicts of interest.

Ethical Approval

This article does not contain any studies with animals performed by any of the authors.

References

  1. 1.
    Bhatti JS, Bhatti GK, Reddy PH. Mitochondrial dysfunction and oxidative stress in metabolic disorders—a step towards mitochondria based therapeutic strategies. Biochim Biophys Acta (BBA)-Mol Basis Dise. 2017;1863(5):1066–77.CrossRefGoogle Scholar
  2. 2.
    J-A K, Wei Y, Sowers JR. Role of mitochondrial dysfunction in insulin resistance. Circ Res. 2008;102(4):401–14.CrossRefGoogle Scholar
  3. 3.
    Oyewole AO, Birch-Machin MA. Mitochondria-targeted antioxidants. FASEB J. 2015;29(12):4766–71.PubMedCrossRefGoogle Scholar
  4. 4.
    Sherratt H. Mitochondria: structure and function. Rev Neurol. 1991;147(6–7):417–30.PubMedGoogle Scholar
  5. 5.
    Liu Y, Fiskum G, Schubert D. Generation of reactive oxygen species by the mitochondrial electron transport chain. J Neurochem. 2002;80(5):780–7.PubMedCrossRefGoogle Scholar
  6. 6.
    Murphy MP. How mitochondria produce reactive oxygen species. Biochem J. 2009;417(1):1–13.PubMedCrossRefGoogle Scholar
  7. 7.
    Tschopp J, Schroder K. NLRP3 inflammasome activation: the convergence of multiple signalling pathways on ROS production? Nat Rev Immunol. 2010;10(3):210–5.PubMedCrossRefGoogle Scholar
  8. 8.
    Neri M, Fineschi V, Di Paolo M, Pomara C, Riezzo I, Turillazzi E, et al. Cardiac oxidative stress and inflammatory cytokines response after myocardial infarction. Curr Vasc Pharmacol. 2015;13(1):26–36.PubMedCrossRefGoogle Scholar
  9. 9.
    Förstermann U, Xia N, Li H. Roles of vascular oxidative stress and nitric oxide in the pathogenesis of atherosclerosis. Circ Res. 2017;120(4):713–35.PubMedCrossRefGoogle Scholar
  10. 10.
    Wang X, Wang W, Li L, Perry G, H-g L, Zhu X. Oxidative stress and mitochondrial dysfunction in Alzheimer’s disease. Biochim Biophys Acta (BBA)-Mol Basis Dis. 2014;1842(8):1240–7.CrossRefGoogle Scholar
  11. 11.
    Blesa J, Trigo-Damas I, Quiroga-Varela A, Jackson-Lewis VR. Oxidative stress and Parkinson’s disease. Front Neuroanat. 2015;9:91.PubMedPubMedCentralGoogle Scholar
  12. 12.
    Bonomini F, Rodella LF, Rezzani R. Metabolic syndrome, aging and involvement of oxidative stress. Aging Dis. 2015;6(2):109–20.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Kaur H, Sarmah D, Saraf J, Vats K, Kalia K, Borah A, et al. Noncoding RNAs in ischemic stroke: time to translate. Ann N Y Acad Sci. 2018;1421:19–36.PubMedCrossRefGoogle Scholar
  14. 14.
    Sims NR, Muyderman H. Mitochondria, oxidative metabolism and cell death in stroke. Biochim Biophys Acta (BBA)-Mol Basis Dis. 2010;1802(1):80–91.CrossRefGoogle Scholar
  15. 15.
    Sarmah D, Agrawal V, Rane P, Bhute S, Watanabe M, Kalia K, et al. Mesenchymal stem cell therapy in ischemic stroke: a meta-analysis of preclinical studies. Clin Pharmacol Ther. 2018;103(6):990–98.Google Scholar
  16. 16.
    Sarmah D, Saraf J, Kaur H, Pravalika K, Tekade RK, Borah A, et al. Stroke management: an emerging role of nanotechnology. Micromachines. 2017;8(9):262.CrossRefGoogle Scholar
  17. 17.
    Bhattacharya P, Pandey AK, Paul S, Patnaik R, Yavagal DR. Aquaporin-4 inhibition mediates piroxicam-induced neuroprotection against focal cerebral ischemia/reperfusion injury in rodents. PLoS One. 2013;8(9):e73481.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Sarmah D, Kaur H, Saraf J, Pravalika K, Goswami A, Kalia K, et al. Getting closer to an effective intervention of ischemic stroke: the big promise of stem cell. Transl Stroke Res. 2017:1–19.Google Scholar
  19. 19.
    d'Adesky N, Bhattacharya P, Schatz M, Perez-Pinzon M, Bramlett H, Raval A. Nicotine alters estrogen receptor-Beta-regulated Inflammasome activity and exacerbates ischemic brain damage in female rats. Int J Mol Sci. 2018.  https://doi.org/10.3390/ijms19051330
  20. 20.
    Smajlović D. Strokes in young adults: epidemiology and prevention. Vasc Health Risk Manag. 2015;11:157.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Chapman SN, Mehndiratta P, Johansen MC, McMurry TL, Johnston KC, Southerland AM. Current perspectives on the use of intravenous recombinant tissue plasminogen activator (tPA) for treatment of acute ischemic stroke. Vasc Health Risk Manag. 2014;10:75.PubMedPubMedCentralGoogle Scholar
  22. 22.
    Vu Q, Xie K, Eckert M, Zhao W, Cramer SC. Meta-analysis of preclinical studies of mesenchymal stromal cells for ischemic stroke. Neurology. 2014;82(14):1277–86.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Meurer WJ, Barth BE, Gaddis G, Vilke GM, Lam SH. Rapid systematic review: intra-arterial thrombectomy (“clot retrieval”) for selected patients with acute ischemic stroke. J Emerg Med. 2017;52(2):255–61.PubMedCrossRefGoogle Scholar
  24. 24.
    Pravalika K, Sarmah D, Kaur H, Wanve M, Saraf J, Kalia K, et al. Myeloperoxidase and neurological disorder: a crosstalk. ACS Chem Neurosci. 2018;9(3):421–30.PubMedCrossRefGoogle Scholar
  25. 25.
    Bhattacharya P, Pandey AK, Paul S, Patnaik R. Melatonin renders neuroprotection by protein kinase C mediated aquaporin-4 inhibition in animal model of focal cerebral ischemia. Life Sci. 2014;100(2):97–109.PubMedCrossRefGoogle Scholar
  26. 26.
    Bhattacharya P, Pandey AK, Paul S, Patnaik R. Neuroprotective potential of Piroxicam in cerebral ischemia: an in silico evaluation of the hypothesis to explore its therapeutic efficacy by inhibition of aquaporin-4 and acid sensing ion channel1a. Med Hypotheses. 2012;79(3):352–7.PubMedCrossRefGoogle Scholar
  27. 27.
    Ginsberg MD. Adventures in the pathophysiology of brain ischemia: penumbra, gene expression, neuroprotection: the 2002 Thomas Willis lecture. Stroke. 2003;34(1):214–23.PubMedCrossRefGoogle Scholar
  28. 28.
    Paciaroni M, Caso V, Agnelli G. The concept of ischemic penumbra in acute stroke and therapeutic opportunities. Eur Neurol. 2009;61(6):321–30.PubMedCrossRefGoogle Scholar
  29. 29.
    Nour M, Scalzo F, Liebeskind DS. Ischemia-reperfusion injury in stroke. Interv Neurol. 2012;1(3–4):185–99.CrossRefGoogle Scholar
  30. 30.
    Hotchkiss RS, Strasser A, McDunn JE, Swanson PE. Cell death. N Engl J Med. 2009;361(16):1570–83.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Pandey AK, Shukla SC, Bhattacharya P, Patnaik R. A possible therapeutic potential of quercetin through inhibition of μ-calpain in hypoxia induced neuronal injury: a molecular dynamics simulation study. Neural Regen Res. 2016;11(8):1247–53.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Chen GY, Nuñez G. Sterile inflammation: sensing and reacting to damage. Nat Rev Immunol. 2010;10(12):826–37.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Atchaneeyasakul K, Guada L, Ramdas K, Watanabe M, Bhattacharya P, Raval AP, et al. Large animal canine endovascular ischemic stroke models: a review. Brain Res Bull. 2016;127:134–40.PubMedCrossRefGoogle Scholar
  34. 34.
    Olmez I, Ozyurt H. Reactive oxygen species and ischemic cerebrovascular disease. Neurochem Int. 2012;60(2):208–12.PubMedCrossRefGoogle Scholar
  35. 35.
    Sanderson TH, Reynolds CA, Kumar R, Przyklenk K, Hüttemann M. Molecular mechanisms of ischemia–reperfusion injury in brain: pivotal role of the mitochondrial membrane potential in reactive oxygen species generation. Mol Neurobiol. 2013;47(1):9–23.PubMedCrossRefGoogle Scholar
  36. 36.
    Gustafsson CM, Falkenberg M, Larsson N-G. Maintenance and expression of mammalian mitochondrial DNA. Annu Rev Biochem. 2016;85:133–60.PubMedCrossRefGoogle Scholar
  37. 37.
    Kukat C, Davies KM, Wurm CA, Spåhr H, Bonekamp NA, Kühl I, et al. Cross-strand binding of TFAM to a single mtDNA molecule forms the mitochondrial nucleoid. Proc Natl Acad Sci. 2015;112(36):11288–93.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Torralba D, Baixauli F, Sánchez-Madrid F. Mitochondria know no boundaries: mechanisms and functions of intercellular mitochondrial transfer. Front Cell Dev Biol. 2016;4(107):1–11.Google Scholar
  39. 39.
    Ghezzi D, Zeviani M. Assembly factors of human mitochondrial respiratory chain complexes: physiology and pathophysiology. Adv Exp Med Biol. 2012;748:65–106.PubMedCrossRefGoogle Scholar
  40. 40.
    Dallner G, Sindelar PJ. Regulation of ubiquinone metabolism. Free Radic Biol Med. 2000;29(3–4):285–94.PubMedCrossRefGoogle Scholar
  41. 41.
    Sinha K, Das J, Pal PB, Sil PC. Oxidative stress: the mitochondria-dependent and mitochondria-independent pathways of apoptosis. Arch Toxicol. 2013;87(7):1157–80.PubMedCrossRefGoogle Scholar
  42. 42.
    Selivanov VA, Votyakova TV, Pivtoraiko VN, Zeak J, Sukhomlin T, Trucco M, et al. Reactive oxygen species production by forward and reverse electron fluxes in the mitochondrial respiratory chain. PLoS Comput Biol. 2011;7(3):e1001115.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Van Houten B, Woshner V, Santos JH. Role of mitochondrial DNA in toxic responses to oxidative stress. DNA Repair. 2006;5(2):145–52.PubMedCrossRefGoogle Scholar
  44. 44.
    Schieber M. Chandel NS. ROS function in redox signaling and oxidative stress. Curr Biol. 2014;24(10):R453–R62.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Hirsch EC, Vyas S, Hunot S. Neuroinflammation in Parkinson’s disease. Parkinsonism Relat Disord. 2012;18:S210–S2.PubMedCrossRefGoogle Scholar
  46. 46.
    Kussmaul L, Hirst J. The mechanism of superoxide production by NADH: ubiquinone oxidoreductase (complex I) from bovine heart mitochondria. Proc Natl Acad Sci. 2006;103(20):7607–12.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Lambert AJ, Brand MD. Inhibitors of the quinone-binding site allow rapid superoxide production from mitochondrial NADH: ubiquinone oxidoreductase (complex I). J Biol Chem. 2004;279(38):39414–20.PubMedCrossRefGoogle Scholar
  48. 48.
    Dong L-F, Jameson VJ, Tilly D, Cerny J, Mahdavian E, Marín-Hernández A, et al. Mitochondrial targeting of vitamin E succinate enhances its pro-apoptotic and anti-cancer activity via mitochondrial complex II. J Biol Chem. 2011;286(5):3717–28.PubMedCrossRefGoogle Scholar
  49. 49.
    Elmore S. Apoptosis: a review of programmed cell death. Toxicol Pathol. 2007;35(4):495–516.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Niizuma K, Yoshioka H, Chen H, Kim GS, Jung JE, Katsu M, et al. Mitochondrial and apoptotic neuronal death signaling pathways in cerebral ischemia. Biochim Biophys Acta (BBA)-Mol Basis Dis. 2010;1802(1):92–9.CrossRefGoogle Scholar
  51. 51.
    Saito A, Hayashi T, Okuno S, Ferrand-Drake M, Chan PH. Interaction between XIAP and Smac/DIABLO in the mouse brain after transient focal cerebral ischemia. J Cereb Blood Flow Metab. 2003;23(9):1010–9.PubMedCrossRefGoogle Scholar
  52. 52.
    Culmsee C, Zhu C, Landshamer S, Becattini B, Wagner E, Pellecchia M, et al. Apoptosis-inducing factor triggered by poly (ADP-ribose) polymerase and bid mediates neuronal cell death after oxygen-glucose deprivation and focal cerebral ischemia. J Neurosci. 2005;25(44):10262–72.PubMedCrossRefGoogle Scholar
  53. 53.
    Zhou H, Wang J, Jiang J, Stavrovskaya IG, Li M, Li W, et al. N-acetyl-serotonin offers neuroprotection through inhibiting mitochondrial death pathways and autophagic activation in experimental models of ischemic injury. J Neurosci. 2014;34(8):2967–78.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Wang X, Figueroa BE, Stavrovskaya IG, Zhang Y, Sirianni AC, Zhu S, et al. Methazolamide and melatonin inhibit mitochondrial cytochrome C release and are neuroprotective in experimental models of ischemic injury. Stroke. 2009;40(5):1877–85.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Martinvalet D, Zhu P, Lieberman J. Granzyme a induces caspase-independent mitochondrial damage, a required first step for apoptosis. Immunity. 2005;22(3):355–70.PubMedCrossRefGoogle Scholar
  56. 56.
    Philpott KL, McCarthy MJ, Klippel A, Rubin LL. Activated phosphatidylinositol 3-kinase and Akt kinase promote survival of superior cervical neurons. J Cell Biol. 1997;139(3):809–15.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Wang H-G, Pathan N, Ethell IM, Krajewski S, Yamaguchi Y, Shibasaki F, et al. Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD. Science. 1999;284(5412):339–43.PubMedCrossRefGoogle Scholar
  58. 58.
    Kroemer G, Reed JC. Mitochondrial control of cell death. Nat Med. 2000;6(5):513–9.PubMedCrossRefGoogle Scholar
  59. 59.
    Mears JA, Lackner LL, Fang S, Ingerman E, Nunnari J, Hinshaw JE. Conformational changes in Dnm1 support a contractile mechanism for mitochondrial fission. Nat Struct Mol Biol. 2011;18(1):20–6.PubMedCrossRefGoogle Scholar
  60. 60.
    Fannjiang Y, Cheng W-C, Lee SJ, Qi B, Pevsner J, McCaffery JM, et al. Mitochondrial fission proteins regulate programmed cell death in yeast. Genes Dev. 2004;18(22):2785–97.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Reznick RM, Shulman GI. The role of AMP-activated protein kinase in mitochondrial biogenesis. J Physiol. 2006;574(1):33–9.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Rodgers JT, Lerin C, Haas W, Gygi SP, Spiegelman BM, Puigserver P. Nutrient control of glucose homeostasis through a complex of PGC-1α and SIRT1. Nature. 2005;434(7029):113–8.PubMedCrossRefGoogle Scholar
  63. 63.
    Barja G. Endogenous oxidative stress: relationship to aging, longevity and caloric restriction. Ageing Res Rev. 2002;1(3):397–411.PubMedCrossRefGoogle Scholar
  64. 64.
    Civitarese AE, Carling S, Heilbronn LK, Hulver MH, Ukropcova B, Deutsch WA, et al. Calorie restriction increases muscle mitochondrial biogenesis in healthy humans. PLoS Med. 2007;4(3):e76.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Zainal TA, Oberley TD, Allison DB, Szweda LI, Weindruch R. Caloric restriction of rhesus monkeys lowers oxidative damage in skeletal muscle. FASEB J. 2000;14(12):1825–36.PubMedCrossRefGoogle Scholar
  66. 66.
    Shuaib A, Lees KR, Lyden P, Grotta J, Davalos A, Davis SM, et al. NXY-059 for the treatment of acute ischemic stroke. N Engl J Med. 2007;357(6):562–71.PubMedCrossRefGoogle Scholar
  67. 67.
    Kelso GF, Porteous CM, Coulter CV, Hughes G, Porteous WK, Ledgerwood EC, et al. Selective targeting of a redox-active ubiquinone to mitochondria within cells antioxidant and antiapoptotic properties. J Biol Chem. 2001;276(7):4588–96.PubMedCrossRefGoogle Scholar
  68. 68.
    James AM, Sharpley MS, Manas A-RB, Frerman FE, Hirst J, Smith RA, et al. Interaction of the mitochondria-targeted antioxidant MitoQ with phospholipid bilayers and ubiquinone oxidoreductases. J Biol Chem. 2007;282(20):14708–18.PubMedCrossRefGoogle Scholar
  69. 69.
    Snow BJ, Rolfe FL, Lockhart MM, Frampton CM, O'Sullivan JD, Fung V, et al. A double-blind, placebo-controlled study to assess the mitochondria-targeted antioxidant MitoQ as a disease-modifying therapy in Parkinson's disease. Mov Disord. 2010;25(11):1670–4.PubMedCrossRefGoogle Scholar
  70. 70.
    Gane EJ, Weilert F, Orr DW, Keogh GF, Gibson M, Lockhart MM, et al. The mitochondria-targeted anti-oxidant mitoquinone decreases liver damage in a phase II study of hepatitis C patients. Liver Int. 2010;30(7):1019–26.PubMedCrossRefGoogle Scholar
  71. 71.
    Oyewole AO, Wilmot M-C, Fowler M, Birch-Machin MA. Comparing the effects of mitochondrial targeted and localized antioxidants with cellular antioxidants in human skin cells exposed to UVA and hydrogen peroxide. FASEB J. 2014;28(1):485–94.PubMedCrossRefGoogle Scholar
  72. 72.
    Fang Y, Hu XH, Jia ZG, Xu MH, Guo ZY, Gao FH. Tiron protects against UVB-induced senescence-like characteristics in human dermal fibroblasts by the inhibition of superoxide anion production and glutathione depletion. Australas J Dermatol. 2012;53(3):172–80.PubMedCrossRefGoogle Scholar
  73. 73.
    J Mailloux R. Application of mitochondria-targeted pharmaceuticals for the treatment of heart disease. Curr Pharm Des. 2016;22(31):4763–79.CrossRefGoogle Scholar
  74. 74.
    Mao G, Kraus GA, Kim I, Spurlock ME, Bailey TB, Zhang Q, et al. A mitochondria-targeted vitamin E derivative decreases hepatic oxidative stress and inhibits fat deposition in mice–3. J Nutr. 2010;140(8):1425–31.PubMedCrossRefGoogle Scholar
  75. 75.
    Yin X, Manczak M, Reddy PH. Mitochondria-targeted molecules MitoQ and SS31 reduce mutant huntingtin-induced mitochondrial toxicity and synaptic damage in Huntington's disease. Hum Mol Genet. 2016;25(9):1739–53.PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Powell RD, Swet JH, Kennedy KL, Huynh TT, Murphy MP, Mckillop IH, et al. MitoQ modulates oxidative stress and decreases inflammation following hemorrhage. J Trauma Acute Care Surg. 2015;78(3):573–9.PubMedCrossRefGoogle Scholar
  77. 77.
    Manczak M, Mao P, Calkins MJ, Cornea A, Reddy AP, Murphy MP, et al. Mitochondria-targeted antioxidants protect against amyloid-β toxicity in Alzheimer’s disease neurons. J Alzheimers Dis. 2010;20(s2):S609–S31.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Jin H, Kanthasamy A, Ghosh A, Anantharam V, Kalyanaraman B, Kanthasamy AG. Mitochondria-targeted antioxidants for treatment of Parkinson's disease: preclinical and clinical outcomes. Biochim Biophys Acta (BBA)-Mol Basis Dis. 2014;1842(8):1282–94.CrossRefGoogle Scholar
  79. 79.
    Jauslin ML, Meier T, Smith RA, Murphy MP. Mitochondria-targeted antioxidants protect Friedreich Ataxia fibroblasts from endogenous oxidative stress more effectively than untargeted antioxidants. FASEB J. 2003;17(13):1972–4.PubMedCrossRefGoogle Scholar
  80. 80.
    Diener H-C, Lees KR, Lyden P, Grotta J, Davalos A, Davis SM, et al. NXY-059 for the treatment of acute stroke: pooled analysis of the SAINT I and II trials. Stroke. 2008;39(6):1751–8.PubMedCrossRefGoogle Scholar
  81. 81.
    Ley JJ, Vigdorchik A, Belayev L, Zhao W, Busto R, Khoutorova L, et al. Stilbazulenyl nitrone, a second-generation azulenyl nitrone antioxidant, confers enduring neuroprotection in experimental focal cerebral ischemia in the rat: neurobehavior, histopathology, and pharmacokinetics. J Pharmacol Exp Ther. 2005;313(3):1090–100.PubMedCrossRefGoogle Scholar
  82. 82.
    Becker DA, Ley JJ, Echegoyen L, Alvarado R. Stilbazulenyl nitrone (STAZN): a nitronyl-substituted hydrocarbon with the potency of classical phenolic chain-breaking antioxidants. J Am Chem Soc. 2002;124(17):4678–84.PubMedCrossRefGoogle Scholar
  83. 83.
    Ley JJ, Belayev L, Saul I, Becker DA, Ginsberg MD. Neuroprotective effect of STAZN, a novel azulenyl nitrone antioxidant, in focal cerebral ischemia in rats: dose–response and therapeutic window. Brain Res. 2007;1180:101–10.PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Reddy PH. Role of mitochondria in neurodegenerative diseases: mitochondria as a therapeutic target in Alzheimer’s disease. CNS Spectrums. 2009;14(S7):8–13.PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Kuzmicic J, del Campo A, López-Crisosto C, Morales PE, Pennanen C, Bravo-Sagua R, et al. Mitochondrial dynamics: a potential new therapeutic target for heart failure. Rev Esp Cardiol (English Edition). 2011;64(10):916–23.Google Scholar
  86. 86.
    Ou X, Lee MR, Huang X, Messina-Graham S, Broxmeyer HE. SIRT1 positively regulates autophagy and mitochondria function in embryonic stem cells under oxidative stress. Stem Cells. 2014;32(5):1183–94.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Godoy J, Allard C, Arrázola M, Zolezzi J, Inestrosa N. SIRT1 protects dendrites, mitochondria and synapses from Aβ oligomers in hippocampal neurons. J Alzheimers Dis Park. 2013;3(4):1–9.Google Scholar
  88. 88.
    Schenk S, McCurdy CE, Philp A, Chen MZ, Holliday MJ, Bandyopadhyay GK, et al. Sirt1 enhances skeletal muscle insulin sensitivity in mice during caloric restriction. J Clin Invest. 2011;121(11):4281–8.PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Guarente L. Sirtuins as potential targets for metabolic syndrome. Nature. 2006;444(7121):868–74.PubMedCrossRefGoogle Scholar
  90. 90.
    Yu J, Auwerx J. The role of sirtuins in the control of metabolic homeostasis. Ann N Y Acad Sci. 2009;1173(1):E10–9.PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Albiero M, Avogaro A, Fadini GP. A perspective on sirtuins in the metabolic syndrome. Metab Syndr Relat Disord. 2015;13(4):161–4.PubMedCrossRefGoogle Scholar
  92. 92.
    Elliott PJ, Jirousek M. Sirtuins: novel targets for metabolic disease. Curr Opin Investig Drugs. 2008;9(4):371–8.PubMedGoogle Scholar
  93. 93.
    Khoury N, Koronowski KB, Young JI, Perez-Pinzon MA. The NAD+-dependent family of Sirtuins in cerebral ischemia and preconditioning. Antioxid Redox Signal. 2018;28(8):691–710.PubMedCrossRefGoogle Scholar
  94. 94.
    Della-Morte D, Dave KR, DeFazio RA, Bao YC, Raval AP, Perez-Pinzon MA. Resveratrol pretreatment protects rat brain from cerebral ischemic damage via a sirtuin 1-uncoupling protein 2 pathway. Neuroscience. 2009;159(3):993–1002.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Reddy PH. Inhibitors of mitochondrial fission as a therapeutic strategy for diseases with oxidative stress and mitochondrial dysfunction. J Alzheimers Dis. 2014;40(2):245–56.PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Qi X, Qvit N, Su Y-C, Mochly-Rosen D. A novel Drp1 inhibitor diminishes aberrant mitochondrial fission and neurotoxicity. J Cell Sci. 2013;126(3):789–802.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Cassidy-Stone A, Chipuk JE, Ingerman E, Song C, Yoo C, Kuwana T, et al. Chemical inhibition of the mitochondrial division dynamin reveals its role in Bax/Bak-dependent mitochondrial outer membrane permeabilization. Dev Cell. 2008;14(2):193–204.PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Meuer K, Suppanz I, Lingor P, Planchamp V, Göricke B, Fichtner L, et al. Cyclin-dependent kinase 5 is an upstream regulator of mitochondrial fission during neuronal apoptosis. Cell Death Differ. 2007;14(4):651–61.PubMedCrossRefGoogle Scholar
  99. 99.
    Abbracchio MP, Burnstock G. Purinergic signalling: pathophysiological roles. Jpn J Pharmacol. 2001;78(2):113–45.CrossRefGoogle Scholar
  100. 100.
    Fredholm BB. Purinoceptors in the nervous system. Basic & Clinical Pharmacology & Toxicology. 1995;76(4):228–39.CrossRefGoogle Scholar
  101. 101.
    Watts LT, Lloyd R, Garling RJ, Duong T. Stroke neuroprotection: targeting mitochondria. Brain Sci. 2013;3(2):540–60.PubMedCrossRefGoogle Scholar
  102. 102.
    Williams M, Burnstock G. Purinergic neurotransmission and neuromodulation: a historical perspective. In: Jacobson, KA and Jarvis, MF, editors. Purinergic approaches in experimental therapeutics. New York: Wiley-Liss; 1997. p. 3–26.Google Scholar
  103. 103.
    Burnstock G. P2X receptors in sensory neurones. Br J Anaesth. 2000;84(4):476–88.PubMedCrossRefGoogle Scholar
  104. 104.
    Burnstock G. Physiology and pathophysiology of purinergic neurotransmission. Physiol Rev. 2007;87(2):659–797.PubMedCrossRefGoogle Scholar
  105. 105.
    Léon C, Hechler B, Freund M, Eckly A, Vial C, Ohlmann P, et al. Defective platelet aggregation and increased resistance to thrombosis in purinergic P2Y 1 receptor-null mice. J Clin Invest. 1999;104(12):1731–7.PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Fabre J-E, Nguyen M, Latour A, Keifer JA, Audoly LP, Coffman TM, et al. Decreased platelet aggregation, increased bleeding time and resistance to thromboembolism in P2Y 1-deficient mice. Nat Med. 1999;5(10):1199–202.PubMedCrossRefGoogle Scholar
  107. 107.
    Owens AP III, Mackman N. Tissue factor and thrombosis: the clot starts here. Thromb Haemost. 2010;104(03):432–9.PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Zheng W, Watts LT, Holstein DM, Prajapati SI, Keller C, Grass EH, et al. Purinergic receptor stimulation reduces cytotoxic edema and brain infarcts in mouse induced by photothrombosis by energizing glial mitochondria. PLoS One. 2010;5(12):e14401.PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Zheng W, Watts LT, Holstein DM, Wewer J, Lechleiter JD. P2Y1R-initiated, IP3R-dependent stimulation of astrocyte mitochondrial metabolism reduces and partially reverses ischemic neuronal damage in mouse. J Cereb Blood Flow Metab. 2013;33(4):600–11.PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Wu J, Holstein JD, Upadhyay G, Lin D-T, Conway S, Muller E, et al. Purinergic receptor-stimulated IP3-mediated Ca2+ release enhances neuroprotection by increasing astrocyte mitochondrial metabolism during aging. J Neurosci. 2007;27(24):6510–20.PubMedCrossRefGoogle Scholar
  111. 111.
    Rojas JC, Bruchey AK, Gonzalez-Lima F. Neurometabolic mechanisms for memory enhancement and neuroprotection of methylene blue. Prog Neurobiol. 2012;96(1):32–45.PubMedCrossRefGoogle Scholar
  112. 112.
    Wen Y, Li W, Poteet EC, Xie L, Tan C, Yan L-J, et al. Alternative mitochondrial electron transfer as a novel strategy for neuroprotection. J Biol Chem. 2011;286(18):16504–15.PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Lin A-L, Poteet E, Du F, Gourav RC, Liu R, Wen Y, et al. Methylene blue as a cerebral metabolic and hemodynamic enhancer. PLoS One. 2012;7(10):e46585.PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Huang S, Du F, Shih Y-YI, Shen Q, Gonzalez-Lima F, Duong TQ. Methylene blue potentiates stimulus-evoked fMRI responses and cerebral oxygen consumption during normoxia and hypoxia. NeuroImage. 2013;72:237–42.PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Holley AK, Bakthavatchalu V, Velez-Roman JM, St Clair DK. Manganese superoxide dismutase: guardian of the powerhouse. Int J Mol Sci. 2011;12(10):7114–62.PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Holley AK, Dhar SK, Clair DKS. Manganese superoxide dismutase vs. p53: regulation of mitochondrial ROS. Mitochondrion. 2010;10(6):649–61.PubMedCrossRefGoogle Scholar
  117. 117.
    Maier C, Hsieh L, Crandall T, Narasimhan P, Chan P. A new approach for the investigation of reperfusion-related brain injury. In: Portland press limited, vol. 34; 2006. p. 1366–9.Google Scholar
  118. 118.
    Chan PH, Kawase M, Murakami K, Chen SF, Li Y, Calagui B, et al. Overexpression of SOD1 in transgenic rats protects vulnerable neurons against ischemic damage after global cerebral ischemia and reperfusion. J Neurosci. 1998;18(20):8292–9.PubMedCrossRefGoogle Scholar
  119. 119.
    Ivanović-Burmazović I. Reactivity of manganese superoxide dismutase mimics toward superoxide and nitric oxide: Selectivity versus cross-reactivity. In: Advances in inorganic chemistry. New York: Elsevier; 2012. p. 53–95.Google Scholar
  120. 120.
    Friedel FC, Lieb D, Ivanović-Burmazović I. Comparative studies on manganese-based SOD mimetics, including the phosphate effect, by using global spectral analysis. J Inorg Biochem. 2012;109:26–32.PubMedCrossRefGoogle Scholar
  121. 121.
    Park W-C, Lim D-Y. Synthesis and SOD activity of manganese complexes of pentaaza macrocycles containing amino-and guanidino-auxiliary. Bull Kor Chem Soc. 2011;32(10):3787–9.CrossRefGoogle Scholar
  122. 122.
    Shmonin A, Melnikova E, Galagudza M, Vlasov T. Characteristics of cerebral ischemia in major rat stroke models of middle cerebral artery ligation through craniectomy. Int J Stroke. 2014;9(6):793–801.PubMedCrossRefGoogle Scholar
  123. 123.
    Huang HF, Guo F, Cao YZ, Shi W, Xia Q. Neuroprotection by manganese superoxide dismutase (MnSOD) mimics: antioxidant effect and oxidative stress regulation in acute experimental stroke. CNS Neurosci Ther. 2012;18(10):811–8.PubMedCrossRefGoogle Scholar
  124. 124.
    Kelso GF, Maroz A, Cochemé HM, Logan A, Prime TA, Peskin AV, et al. A mitochondria-targeted macrocyclic Mn (II) superoxide dismutase mimetic. Chem Biol. 2012;19(10):1237–46.PubMedCrossRefGoogle Scholar
  125. 125.
    Kondo T, Reaume AG, Huang T-T, Carlson E, Murakami K, Chen SF, et al. Reduction of CuZn-superoxide dismutase activity exacerbates neuronal cell injury and edema formation after transient focal cerebral ischemia. J Neurosci. 1997;17(11):4180–9.PubMedCrossRefGoogle Scholar
  126. 126.
    Li M, Wang W, Mai H, Zhang X, Wang J, Gao Y, et al. Methazolamide improves neurological behavior by inhibition of neuron apoptosis in subarachnoid hemorrhage mice. Sci Rep. 2016;6:35055.PubMedPubMedCentralCrossRefGoogle Scholar
  127. 127.
    Trounson A, McDonald C. Stem cell therapies in clinical trials: progress and challenges. Cell Stem Cell. 2015;17(1):11–22.PubMedCrossRefGoogle Scholar
  128. 128.
    Borlongan CV. Age of PISCES: stem-cell clinical trials in stroke. Lancet. 2016;388(10046):736–8.PubMedCrossRefGoogle Scholar
  129. 129.
    Prasad K, Sharma A, Garg A, Mohanty S, Bhatnagar S, Johri S, et al. Intravenous autologous bone marrow mononuclear stem cell therapy for ischemic stroke: a multicentric, randomized trial. Stroke. 2014;45(12):3618–24.PubMedCrossRefGoogle Scholar
  130. 130.
    Hao L, Zou Z, Tian H, Zhang Y, Zhou H, Liu L. Stem cell-based therapies for ischemic stroke. Biomed Res Int. 2014;2014:1–17.Google Scholar
  131. 131.
    Hayakawa K, Esposito E, Wang X, Terasaki Y, Liu Y, Xing C, et al. Transfer of mitochondria from astrocytes to neurons after stroke. Nature. 2016;535(7613):551–5.PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    Spees JL, Olson SD, Whitney MJ, Prockop DJ. Mitochondrial transfer between cells can rescue aerobic respiration. Proc Natl Acad Sci. 2006;103(5):1283–8.PubMedPubMedCentralCrossRefGoogle Scholar
  133. 133.
    Islam MN, Das SR, Emin MT, Wei M, Sun L, Westphalen K, et al. Mitochondrial transfer from bone-marrow-derived stromal cells to pulmonary alveoli protects against acute lung injury. Nat Med. 2012;18(5):759–65.PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Ahmad T, Mukherjee S, Pattnaik B, Kumar M, Singh S, Rehman R et al. Miro1 regulates intercellular mitochondrial transport & enhances mesenchymal stem cell rescue efficacy. EMBO J. 2014;33(9):994–1010.Google Scholar
  135. 135.
    Cho YM, Kim JH, Kim M, Park SJ, Koh SH, Ahn HS, et al. Mesenchymal stem cells transfer mitochondria to the cells with virtually no mitochondrial function but not with pathogenic mtDNA mutations. PLoS One. 2012;7(3):e32778.PubMedPubMedCentralCrossRefGoogle Scholar
  136. 136.
    Lin H-Y, Liou C-W, Chen S-D, Hsu T-Y, Chuang J-H, Wang P-W, et al. Mitochondrial transfer from Wharton's jelly-derived mesenchymal stem cells to mitochondria-defective cells recaptures impaired mitochondrial function. Mitochondrion. 2015;22:31–44.PubMedCrossRefGoogle Scholar
  137. 137.
    Acquistapace A, Bru T, Lesault PF, Figeac F, Coudert AE, Le Coz O, et al. Human mesenchymal stem cells reprogram adult cardiomyocytes toward a progenitor-like state through partial cell fusion and mitochondria transfer. Stem Cells. 2011;29(5):812–24.PubMedPubMedCentralCrossRefGoogle Scholar
  138. 138.
    Li X, Zhang Y, Yeung SC, Liang Y, Liang X, Ding Y, et al. Mitochondrial transfer of induced pluripotent stem cell-derived mesenchymal stem cells to airway epithelial cells attenuates cigarette smoke-induced damage. Am J Respir Cell Mol Biol. 2014;51(3):455–65.PubMedCrossRefGoogle Scholar
  139. 139.
    Rogers RS, Bhattacharya J. When cells become organelle donors. Physiology. 2013;28(6):414–22.PubMedCrossRefGoogle Scholar
  140. 140.
    Berridge MV, McConnell MJ, Grasso C, Bajzikova M, Kovarova J, Neuzil J. Horizontal transfer of mitochondria between mammalian cells: beyond co-culture approaches. Curr Opin Genet Dev. 2016;38:75–82.PubMedCrossRefGoogle Scholar
  141. 141.
    Liu K, Ji K, Guo L, Wu W, Lu H, Shan P, et al. Mesenchymal stem cells rescue injured endothelial cells in an in vitro ischemia–reperfusion model via tunneling nanotube like structure-mediated mitochondrial transfer. Microvasc Res. 2014;92:10–8.PubMedCrossRefGoogle Scholar
  142. 142.
    Han H, Hu J, Yan Q, Zhu J, Zhu Z, Chen Y, et al. Bone marrow-derived mesenchymal stem cells rescue injured H9c2 cells via transferring intact mitochondria through tunneling nanotubes in an in vitro simulated ischemia/reperfusion model. Mol Med Rep. 2016;13(2):1517–24.PubMedCrossRefGoogle Scholar
  143. 143.
    Plotnikov E, Khryapenkova T, Vasileva A, Marey M, Galkina S, Isaev N, et al. Cell-to-cell cross-talk between mesenchymal stem cells and cardiomyocytes in co-culture. J Cell Mol Med. 2008;12(5a):1622–31.PubMedCrossRefGoogle Scholar
  144. 144.
    Mahrouf-Yorgov M, Augeul L, Da Silva CC, Jourdan M, Rigolet M, Manin S, et al. Mesenchymal stem cells sense mitochondria released from damaged cells as danger signals to activate their rescue properties. Cell Death Differ. 2017;24:1224–38.PubMedPubMedCentralCrossRefGoogle Scholar
  145. 145.
    Moschoi R, Imbert V, Nebout M, Chiche J, Mary D, Prebet T, et al. Protective mitochondrial transfer from bone marrow stromal cells to acute myeloid leukemic cells during chemotherapy. Blood. 2016;128(2):253–64.PubMedCrossRefGoogle Scholar
  146. 146.
    Bukoreshtliev NV, Wang X, Hodneland E, Gurke S, Barroso JF, Gerdes H-H. Selective block of tunneling nanotube (TNT) formation inhibits intercellular organelle transfer between PC12 cells. FEBS Lett. 2009;583(9):1481–8.PubMedCrossRefGoogle Scholar
  147. 147.
    Rustom A, Saffrich R, Markovic I, Walther P, Gerdes H-H. Nanotubular highways for intercellular organelle transport. Science. 2004;303(5660):1007–10.PubMedCrossRefGoogle Scholar
  148. 148.
    He K, Shi X, Zhang X, Dang S, Ma X, Liu F, et al. Long-distance intercellular connectivity between cardiomyocytes and cardiofibroblasts mediated by membrane nanotubes. Cardiovasc Res. 2011;92(1):39–47.PubMedCrossRefGoogle Scholar
  149. 149.
    Sun X, Wang Y, Zhang J, Tu J, Wang X, Su X, et al. Tunneling-nanotube direction determination in neurons and astrocytes. Cell Death Dis. 2012;3(12):e438.PubMedPubMedCentralCrossRefGoogle Scholar
  150. 150.
    Lou E, Fujisawa S, Morozov A, Barlas A, Romin Y, Dogan Y, et al. Tunneling nanotubes provide a unique conduit for intercellular transfer of cellular contents in human malignant pleural mesothelioma. PLoS One. 2012;7(3):e33093.PubMedPubMedCentralCrossRefGoogle Scholar
  151. 151.
    Mittelbrunn M, Sánchez-Madrid F. Intercellular communication: diverse structures for exchange of genetic information. Nat Rev Mol Cell Biol. 2012;13(5):328–35.PubMedPubMedCentralCrossRefGoogle Scholar
  152. 152.
    Pitt JM, Kroemer G, Zitvogel L. Extracellular vesicles: masters of intercellular communication and potential clinical interventions. J Clin Invest. 2016;126(4):1139–43.PubMedPubMedCentralCrossRefGoogle Scholar
  153. 153.
    Jayaprakash AD, Benson EK, Gone S, Liang R, Shim J, Lambertini L, et al. Stable heteroplasmy at the single-cell level is facilitated by intercellular exchange of mtDNA. Nucleic Acids Res. 2015;43(4):2177–87.PubMedPubMedCentralCrossRefGoogle Scholar
  154. 154.
    Spees JL, Olson SD, Ylostalo J, Lynch PJ, Smith J, Perry A, et al. Differentiation, cell fusion, and nuclear fusion during ex vivo repair of epithelium by human adult stem cells from bone marrow stroma. Proc Natl Acad Sci. 2003;100(5):2397–402.PubMedPubMedCentralCrossRefGoogle Scholar
  155. 155.
    Alvarez-Dolado M, Pardal R, Garcia-Verdugo JM, Fike JR, Lee HO, Pfeffer K, et al. Fusion of bone-marrow-derived cells with Purkinje neurons, cardiomyocytes and hepatocytes. Nature. 2003;425(6961):968–73.PubMedCrossRefGoogle Scholar
  156. 156.
    Oh H, Bradfute SB, Gallardo TD, Nakamura T, Gaussin V, Mishina Y, et al. Cardiac progenitor cells from adult myocardium: homing, differentiation, and fusion after infarction. Proc Natl Acad Sci. 2003;100(21):12313–8.PubMedPubMedCentralCrossRefGoogle Scholar
  157. 157.
    Vassilopoulos G, Wang P-R, Russell DW. Transplanted bone marrow regenerates liver by cell fusion. Nature. 2003;422(6934):901–4.PubMedCrossRefGoogle Scholar
  158. 158.
    Wang X, Willenbring H, Akkari Y, Torimaru Y, Foster M, Al-Dhalimy M, et al. Cell fusion is the principal source of bone-marrow-derived hepatocytes. Nature. 2003;422(6934):897–901.PubMedCrossRefGoogle Scholar
  159. 159.
    Nakajima A, Kurihara H, Yagita H, Okumura K, Nakano H. Mitochondrial extrusion through the cytoplasmic vacuoles during cell death. J Biol Chem. 2008;283(35):24128–35.PubMedPubMedCentralCrossRefGoogle Scholar
  160. 160.
    Lyamzaev KG, Nepryakhina OK, Saprunova VB, Bakeeva LE, Pletjushkina OY, Chernyak BV, et al. Novel mechanism of elimination of malfunctioning mitochondria (mitoptosis): formation of mitoptotic bodies and extrusion of mitochondrial material from the cell. Biochim Biophys Acta (BBA)-Bioenergetics. 2008;1777(7):817–25.CrossRefGoogle Scholar
  161. 161.
    Yousefi S, Gold JA, Andina N, Lee JJ, Kelly AM, Kozlowski E, et al. Catapult-like release of mitochondrial DNA by eosinophils contributes to antibacterial defense. Nat Med. 2008;14(9):949–53.PubMedCrossRefGoogle Scholar
  162. 162.
    Boudreau LH, Duchez A-C, Cloutier N, Soulet D, Martin N, Bollinger J, et al. Platelets release mitochondria serving as substrate for bactericidal group IIA-secreted phospholipase a 2 to promote inflammation. Blood. 2014;124(14):2173–83.PubMedPubMedCentralCrossRefGoogle Scholar
  163. 163.
    Caielli S, Athale S, Domic B, Murat E, Chandra M, Banchereau R, et al. Oxidized mitochondrial nucleoids released by neutrophils drive type I interferon production in human lupus. J Exp Med. 2016;213:697–713.  https://doi.org/10.1084/jem.20151876.PubMedPubMedCentralCrossRefGoogle Scholar
  164. 164.
    Babenko VA, Silachev DN, Popkov VA, Zorova LD, Pevzner IB, Plotnikov EY, et al. Miro1 enhances mitochondria transfer from multipotent mesenchymal stem cells (MMSC) to neural cells and improves the efficacy of cell recovery. Molecules. 2018;23(3):687.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Deepaneeta Sarmah
    • 1
  • Harpreet Kaur
    • 1
  • Jackson Saraf
    • 1
  • Kanchan Vats
    • 1
  • Kanta Pravalika
    • 1
  • Madhuri Wanve
    • 1
  • Kiran Kalia
    • 1
  • Anupom Borah
    • 2
  • Akhilesh Kumar
    • 3
  • Xin Wang
    • 4
  • Dileep R. Yavagal
    • 5
  • Kunjan R. Dave
    • 5
  • Pallab Bhattacharya
    • 1
  1. 1.Department or Pharmacology and ToxicologyNational Institute of Pharmaceutical Education and Research, Ahmedabad (NIPER-A)GandhinagarIndia
  2. 2.Cellular and Molecular Neurobiology Laboratory, Department of Life Science and BioinformaticsAssam UniversitySilcharIndia
  3. 3.Department of BotanyBanaras Hindu UniversityVaranasiIndia
  4. 4.Department of Neurosurgery, Harvard Medical SchoolBrigham and Women’s HospitalBostonUSA
  5. 5.Department of NeurologyUniversity of Miami Miller School of MedicineFloridaUSA

Personalised recommendations