Table of Contents
ISRN Neurology
Volume 2014, Article ID 515716, 17 pages
http://dx.doi.org/10.1155/2014/515716
Review Article

Neuroprotection in Stroke: Past, Present, and Future

1Department of Neuroscience, Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, 385A Glossop Road, Sheffield S10 2HQ, UK
2Department of Neurology and Manchester Academic Health Sciences Centre, Salford Royal Hospital, Stott Lane, Salford M6 8HD, UK

Received 7 July 2013; Accepted 16 September 2013; Published 21 January 2014

Academic Editors: M. Leone and C. Sommer

Copyright © 2014 Arshad Majid. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. S. D. Reed, S. C. Cramer, D. K. Blough, K. Meyer, and J. G. Jarvik, “Treatment with tissue plasminogen activator and inpatient mortality rates for patients with ischemic stroke treated in community hospitals,” Stroke, vol. 32, no. 8, pp. 1832–1839, 2001. View at Google Scholar · View at Scopus
  2. M. A. Moskowitz, E. H. Lo, and C. Iadecola, “The science of stroke: mechanisms in search of treatments,” Neuron, vol. 67, no. 2, pp. 181–198, 2010. View at Publisher · View at Google Scholar · View at Scopus
  3. J. Aronowski and X. Zhao, “Molecular pathophysiology of cerebral hemorrhage: secondary brain injury,” Stroke, vol. 42, no. 6, pp. 1781–1786, 2011. View at Publisher · View at Google Scholar · View at Scopus
  4. D. Zemke, M. U. Farooq, A. M. Yahia, and A. Majid, “Delayed ischemia after subarachnoid hemorrhage: result of vasospasm alone or a broader vasculopathy?” Vascular Medicine, vol. 12, no. 3, pp. 243–249, 2007. View at Publisher · View at Google Scholar · View at Scopus
  5. J. N. Stankowski and R. Gupta, “Therapeutic targets for neuroprotection in acute ischemic stroke: lost in translation?” Antioxidants & Redox Signaling, vol. 14, no. 10, pp. 1841–1851, 2011. View at Publisher · View at Google Scholar · View at Scopus
  6. A. R. Noorian, R. G. Nogueira, and R. Gupta, “Neuroprotection in acute ischemic stroke,” Journal of Neurosurgical Sciences, vol. 55, no. 2, pp. 127–138, 2011. View at Google Scholar · View at Scopus
  7. D. T. Laskowitz and B. J. Kolls, “Neuroprotection in subarachnoid hemorrhage,” Stroke, vol. 41, supplement 10, pp. S79–S84, 2010. View at Publisher · View at Google Scholar · View at Scopus
  8. C. P. Kellner and E. S. Connolly, “Neuroprotective strategies for intracerebral hemorrhage: trials and translation,” Stroke, vol. 41, supplement 10, pp. S99–S102, 2010. View at Publisher · View at Google Scholar · View at Scopus
  9. R. Liu, H. Yuan, F. Yuan, and S.-H. Yang, “Neuroprotection targeting ischemic penumbra and beyond for the treatment of ischemic stroke,” Neurological Research, vol. 34, no. 4, pp. 331–337, 2012. View at Publisher · View at Google Scholar
  10. R. J. Traystman, “Animal models of focal and global cerebral ischemia,” ILAR Journal, vol. 44, no. 2, pp. 85–95, 2003. View at Publisher · View at Google Scholar
  11. A. Manaenko, H. Chen, J. H. Zhang, and J. Tang, “Comparison of different preclinical models of intracerebral hemorrhage,” Acta Neurochirurgica, no. 111, pp. 9–14, 2011. View at Publisher · View at Google Scholar · View at Scopus
  12. E. Titova, R. P. Ostrowski, J. H. Zhang, and J. Tang, “Experimental models of subarachnoid hemorrhage for studies of cerebral vasospasm,” Neurological Research, vol. 31, no. 6, pp. 568–581, 2009. View at Publisher · View at Google Scholar · View at Scopus
  13. P. R. Krafft, E. L. Bailey, T. Lekic et al., “Etiology of stroke and choice of models,” International Journal of Stroke, vol. 7, no. 5, pp. 398–406, 2012. View at Publisher · View at Google Scholar
  14. R. Jin, G. Yang, and G. Li, “Inflammatory mechanisms in ischemic stroke: role of inflammatory cells,” Journal of Leukocyte Biology, vol. 87, no. 5, pp. 779–789, 2010. View at Publisher · View at Google Scholar · View at Scopus
  15. S. E. Lakhan, A. Kirchgessner, and M. Hofer, “Inflammatory mechanisms in ischemic stroke: therapeutic approaches,” Journal of Translational Medicine, vol. 7, article 97, 2009. View at Publisher · View at Google Scholar · View at Scopus
  16. G. J. del Zoppo, K. J. Becker, and J. M. Hallenbeck, “Inflammation after stroke: is it harmful?” Archives of Neurology, vol. 58, no. 4, pp. 669–672, 2001. View at Google Scholar · View at Scopus
  17. A. Jablonska and B. Lukomska, “Stroke induced brain changes: implications for stem cell transplantation,” Acta Neurobiologiae Experimentalis, vol. 71, no. 1, pp. 74–85, 2011. View at Google Scholar · View at Scopus
  18. J. M. Pradillo, A. Denes, A. D. Greenhalgh et al., “Delayed administration of interleukin-1 receptor antagonist reduces ischemic brain damage and inflammation in comorbid rats,” Journal of Cerebral Blood Flow and Metabolism, vol. 32, no. 9, pp. 1810–1819, 2012. View at Publisher · View at Google Scholar
  19. J. S. Yoon, J.-H. Lee, and D. Tweedie, “3, 6′-dithiothalidomide improves experimental stroke outcome by suppressing neuroinflammation,” Journal of Neuroscience Research, vol. 91, no. 5, pp. 671–680, 2013. View at Publisher · View at Google Scholar
  20. S. Wang, H. Guo, L. Hu et al., “Caffeic acid ester fraction from Erigeron breviscapus inhibits microglial activation and provides neuroprotection,” Chinese Journal of Integrative Medicine, vol. 18, no. 6, pp. 437–444, 2012. View at Publisher · View at Google Scholar
  21. T. Ewen, L. Qiuting, T. Chaogang et al., “Neuroprotective effect of atorvastatin involves suppression of TNF-α and upregulation of IL-10 in a rat model of intracerebral hemorrhage,” Cell Biochemistry and Biophysics, vol. 66, no. 2, pp. 337–346, 2013. View at Publisher · View at Google Scholar
  22. R. K. Sumbria, R. J. Boado, and W. M. Pardridge, “Brain protection from stroke with intravenous TNFα decoy receptor-Trojan horse fusion protein,” Journal of Cerebral Blood Flow and Metabolism, vol. 32, no. 10, pp. 1933–1938, 2012. View at Publisher · View at Google Scholar
  23. P. Zhang, X. Liu, Y. Zhu, S. Chen, D. Zhou, and Y. Wang, “Honokiol inhibits the inflammatory reaction during cerebral ischemia reperfusion by suppressing NF-κB activation and cytokine production of glial cells,” Neuroscience Letters, vol. 534, pp. 123–127, 2013. View at Publisher · View at Google Scholar
  24. H. Luan, Z. Kan, Y. Xu, C. Lv, and W. Jiang, “Rosmarinic acid protects against experimental diabetes with cerebral ischemia: relation to inflammation response,” Journal of Neuroinflammation, vol. 10, article 28, 2013. View at Publisher · View at Google Scholar
  25. T. Jiang, L. Gao, J. Guo, J. Lu, Y. Wang, and Y. Zhang, “Suppressing inflammation by inhibiting the NF-κB pathway contributes to the neuroprotective effect of angiotensin-(1-7) in rats with permanent cerebral ischaemia,” British Journal of Pharmacology, vol. 167, no. 7, pp. 1520–1532, 2012. View at Publisher · View at Google Scholar
  26. L. Yu, C. Chen, L.-F. Wang et al., “Neuroprotective effect of kaempferol glycosides against brain injury and neuroinflammation by inhibiting the activation of NF-κB and STAT3 in transient focal stroke,” PLoS ONE, vol. 8, no. 2, Article ID e55839, 2013. View at Publisher · View at Google Scholar
  27. A. Lanzillotta, G. Pignataro, C. Branca et al., “Targeted acetylation of NF-κB/RelA and histones by epigenetic drugs reduces post-ischemic brain injury in mice with an extended therapeutic window,” Neurobiology of Disease, vol. 49, pp. 177–189, 2012. View at Publisher · View at Google Scholar
  28. D. Michalski, M. Heindl, J. Kacza et al., “Spatio-temporal course of macrophage-like cell accumulation after experimental embolic stroke depending on treatment with tissue plasminogen activator and its combination with hyperbaric oxygenation,” European Journal of Histochemistry, vol. 56, no. 2, artivle e14, 2012. View at Publisher · View at Google Scholar
  29. J.-S. Park, J. A. Shin, J.-S. Jung et al., “Anti-inflammatory mechanism of compound K in activated microglia and its neuroprotective effect on experimental stroke in mice,” Journal of Pharmacology and Experimental Therapeutics, vol. 341, no. 1, pp. 59–67, 2012. View at Publisher · View at Google Scholar · View at Scopus
  30. M. Ohnishi, A. Monda, R. Takemoto et al., “Sesamin suppresses activation of microglia and p44/42 MAPK pathway, which confers neuroprotection in rat intracerebral hemorrhage,” Neuroscience, vol. 232, pp. 45–52, 2012. View at Publisher · View at Google Scholar
  31. H. Matsushita, M. Hijioka, A. Hisatsune, Y. Isohama, K. Shudo, and H. Katsuki, “Natural and synthetic retinoids afford therapeutic effects on intracerebral hemorrhage in mice,” European Journal of Pharmacology, vol. 683, no. 1–3, pp. 125–131, 2012. View at Publisher · View at Google Scholar · View at Scopus
  32. F. J. Ortega, J. Jolkkonen, N. Mahy, and M. J. Rodríguez, “Glibenclamide enhances neurogenesis and improves long-term functional recovery after transient focal cerebral ischemia,” Journal of Cerebral Blood Flow and Metabolism, vol. 33, no. 3, pp. 356–364, 2013. View at Publisher · View at Google Scholar
  33. F. J. Ortega, J. Gimeno-Bayon, J. F. Espinosa-Parrilla et al., “ATP-dependent potassium channel blockade strengthens microglial neuroprotection after hypoxia-ischemia in rats,” Experimental Neurology, vol. 235, no. 1, pp. 282–296, 2012. View at Publisher · View at Google Scholar · View at Scopus
  34. B. Wali, T. Ishrat, F. Atif, F. Hua, D. G. Stein, and I. Sayeed, “Glibenclamide administration attenuates infarct volume, hemispheric swelling, and functional impairments following permanent focal cerebral ischemia in rats,” Stroke Research and Treatment, vol. 2012, Article ID 460909, 6 pages, 2012. View at Publisher · View at Google Scholar
  35. E. Parada, J. Egea, I. Buendia et al., “The microglial α7-acetylcholine nicotinic receptor is a key element in promoting neuroprotection by inducing heme oxygenase-1 via nuclear factor erythroid-2-related factor 2,” Antioxidants & Redox Signaling, vol. 19, no. 11, pp. 1135–1148, 2013. View at Publisher · View at Google Scholar
  36. H. Pradeep, J. B. Diya, S. Shashikumar, and G. K. Rajanikant, “Oxidative stress—assassin behind the ischemic stroke,” Folia Neuropathologica, vol. 50, no. 3, pp. 219–230, 2012. View at Google Scholar
  37. G. H. Heeba and A. A. El-Hanafy, “Nebivolol regulates eNOS and iNOS expressions and alleviates oxidative stress in cerebral ischemia/reperfusion injury in rats,” Life Sciences, vol. 90, no. 11-12, pp. 388–395, 2012. View at Publisher · View at Google Scholar · View at Scopus
  38. K. A. Radermacher, K. Wingler, F. Langhauser et al., “Neuroprotection after stroke by targeting NOX4 as a source of oxidative stress,” Antioxidants & Redox Signaling, vol. 18, no. 12, pp. 1418–1427, 2013. View at Publisher · View at Google Scholar
  39. G. Li, H.-K. Luo, L.-F. Li et al., “Dual effects of hydrogen sulphide on focal cerebral ischaemic injury via modulation of oxidative stress-induced apoptosis,” Clinical and Experimental Pharmacology & Physiology, vol. 39, no. 9, pp. 765–771, 2012. View at Publisher · View at Google Scholar
  40. J. Li, Y. Dong, H. Chen et al., “Protective effects of hydrogen-rich saline in a rat model of permanent focal cerebral ischemia via reducing oxidative stress and inflammatory cytokines,” Brain Research, vol. 1486, pp. 103–111, 2012. View at Publisher · View at Google Scholar
  41. P. Y. Lam, N. Chen, P. Y. Chiu, H. Y. Leung, and K. M. Ko, “Neuroprotection against oxidative injury by a nucleic acid-based health product (Squina DNA) through enhancing mitochondrial antioxidant status and functional capacity,” Journal of Medicinal Food, vol. 15, no. 7, pp. 629–638, 2012. View at Publisher · View at Google Scholar
  42. H.-F. Huang, F. Guo, Y.-Z. Cao, W. Shi, and Q. Xia, “Neuroprotection by manganese superoxide dismutase (MnSOD) mimics: antioxidant effect and oxidative stress regulation in acute experimental stroke,” CNS Neuroscience & Therapeutics, vol. 18, no. 10, pp. 811–818, 2012. View at Publisher · View at Google Scholar
  43. A. Ahmad, M. M. Khan, S. S. Raza et al., “Ocimum sanctum attenuates oxidative damage and neurological deficits following focal cerebral ischemia/reperfusion injury in rats,” Neurological Sciences, vol. 33, no. 6, pp. 1239–1247, 2012. View at Publisher · View at Google Scholar · View at Scopus
  44. Y. Zhan, C. Chen, H. Suzuki, Q. Hu, X. Zhi, and J. H. Zhang, “Hydrogen gas ameliorates oxidative stress in early brain injury after subarachnoid hemorrhage in rats,” Critical Care Medicine, vol. 40, no. 4, pp. 1291–1296, 2012. View at Publisher · View at Google Scholar · View at Scopus
  45. B. J. Connell and T. M. Saleh, “Co-administration of apocynin with lipoic acid enhances neuroprotection in a rat model of ischemia/reperfusion,” Neuroscience Letters, vol. 507, no. 1, pp. 43–46, 2012. View at Publisher · View at Google Scholar · View at Scopus
  46. J. Yang, H.-N. Ahn, M. Chang, P. Narasimhan, P. H. Chan, and Y. S. Song, “Complement component 3 inhibition by an antioxidant is neuroprotective after cerebral ischemia and reperfusion in mice,” Journal of Neurochemistry, vol. 124, no. 4, pp. 523–535, 2013. View at Publisher · View at Google Scholar
  47. X. Zeng, K. Asmaro, C. Ren et al., “Acute ethanol treatment reduces blood-brain barrier dysfunction following ischemia/reperfusion injury,” Brain Research, vol. 1437, pp. 127–133, 2012. View at Publisher · View at Google Scholar · View at Scopus
  48. J. Xiang, R. Lan, Y.-P. Tang, Y.-P. Chen, and D.-F. Cai, “Apocynum venetum leaf extract attenuates disruption of the blood-brain barrier and upregulation of matrix metalloproteinase-9/-2 in a rat model of cerebral ischemia-reperfusion injury,” Neurochemical Research, vol. 37, no. 8, pp. 1820–1828, 2012. View at Publisher · View at Google Scholar
  49. D. Michalski, C. Hobohm, C. Weise et al., “Interrelations between blood-brain barrier permeability and matrix metalloproteinases are differently affected by tissue plasminogen activator and hyperoxia in a rat model of embolic stroke,” Medical Gas Research, vol. 2, no. 1, article 2, 2012. View at Publisher · View at Google Scholar
  50. Z. Wang, Y. Xue, H. Jiao, Y. Liu, and P. Wang, “Doxycycline-mediated protective effect against focal cerebral ischemia-reperfusion injury through the modulation of tight junctions and PKCδ signaling in rats,” Journal of Molecular Neuroscience, vol. 47, no. 1, pp. 89–100, 2012. View at Publisher · View at Google Scholar · View at Scopus
  51. H. Shi, B. Sheng, F. Zhang et al., “Kruppel-like factor 2 protects against ischemic stroke by regulating endothelial blood brain barrier function,” American Journal of Physiology: Heart and Circulatory Physiology, vol. 304, no. 6, pp. H796–H805, 2013. View at Publisher · View at Google Scholar
  52. D. Chen, X. Wei, J. Guan et al., “Inhibition of c-Jun N-terminal kinase prevents blood-brain barrier disruption and normalizes the expression of tight junction proteins clautin-5 and ZO-1 in a rat model of subarachnoid hemorrhage,” Acta Neurochirurgica, vol. 154, no. 8, pp. 1469–1476, 2012. View at Publisher · View at Google Scholar
  53. B. Huang, P. R. Krafft, Q. Ma et al., “Fibroblast growth factors preserve blood-brain barrier integrity through RhoA inhibition after intracerebral hemorrhage in mice,” Neurobiology of Disease, vol. 46, no. 1, pp. 204–214, 2012. View at Publisher · View at Google Scholar · View at Scopus
  54. B. Lapergue, B. Q. Dang, J.-P. Desilles et al., “High-density lipoprotein-based therapy reduces the hemorrhagic complications associated with tissue plasminogen activator treatment in experimental stroke,” Stroke, vol. 44, no. 3, pp. 699–707, 2013. View at Publisher · View at Google Scholar
  55. D. R. Pillai, N. C. Shanbhag, M. S. Dittmar, U. Bogdahn, and F. Schlachetzki, “Neurovascular protection by targeting early blood-brain barrier disruption with neurotrophic factors after ischemia-reperfusion in rats*,” Journal of Cerebral Blood Flow and Metabolism, vol. 33, no. 4, pp. 557–566, 2013. View at Publisher · View at Google Scholar
  56. A. Mdzinarishvili, R. Sumbria, D. Langc, and J. Klein, “Ginkgo extract EGb761 confers neuroprotection by reduction of glutamate release in ischemic brain,” Journal of Pharmacy & Pharmaceutical Sciences, vol. 15, no. 1, pp. 94–102, 2012. View at Google Scholar · View at Scopus
  57. S. E. Nada and Z. A. Shah, “Preconditioning with Ginkgo biloba (EGb 761) provides neuroprotection through HO1 and CRMP2,” Neurobiology of Disease, vol. 46, no. 1, pp. 180–189, 2012. View at Publisher · View at Google Scholar · View at Scopus
  58. M. M. Harraz, S. M. Eacker, X. Wang, T. M. Dawson, and V. L. Dawson, “MicroRNA-223 is neuroprotective by targeting glutamate receptors,” Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 46, pp. 2–5, 2012. View at Publisher · View at Google Scholar
  59. L. Li, W. Qu, L. Zhou et al., “Activation of transient receptor potential vanilloid 4 increases NMDA-activated current in hippocampal pyramidal neurons,” Frontiers in Cellular Neuroscience, vol. 7, article 17, 2013. View at Publisher · View at Google Scholar
  60. D. Afshari, N. Moradian, and M. Rezaei, “Evaluation of the intravenous magnesium sulfate effect in clinical improvement of patients with acute ischemic stroke,” Clinical Neurology and Neurosurgery, vol. 115, no. 4, pp. 400–404, 2013. View at Publisher · View at Google Scholar
  61. K. R. Lees, K. W. Muir, I. Ford et al., “Magnesium for acute stroke (Intravenous Magnesium Efficacy in Stroke Trial): randomised controlled trial,” The Lancet, vol. 363, no. 9407, pp. 439–445, 2004. View at Publisher · View at Google Scholar · View at Scopus
  62. J. L. Saver, C. Kidwell, M. Eckstein, and S. Starkman, “Prehospital neuroprotective therapy for acute stroke: results of the Field Administration of Stroke Therapy-Magnesium (FAST-MAG) pilot trial,” Stroke, vol. 35, no. 5, pp. e106–e108, 2004. View at Google Scholar · View at Scopus
  63. H. Li, J. Huang, W. Du, C. Jia, H. Yao, and Y. Wang, “TRPC6 inhibited NMDA receptor activities and protected neurons from ischemic excitotoxicity,” Journal of Neurochemistry, vol. 123, no. 6, pp. 1010–1018, 2012. View at Publisher · View at Google Scholar
  64. Y. Lin, J.-C. Zhang, J. Fu et al., “Hyperforin attenuates brain damage induced by transient middle cerebral artery occlusion (MCAO) in rats via inhibition of TRPC6 channels degradation,” Journal of Cerebral Blood Flow and Metabolism, vol. 33, no. 2, pp. 253–262, 2013. View at Publisher · View at Google Scholar
  65. Y. Zhang, L. Zhou, X. Zhang, J. Bai, M. Shi, and G. Zhao, “Ginsenoside-Rd attenuates TRPM7 and ASIC1a but promotes ASIC2a expression in rats after focal cerebral ischemia,” Neurological Sciences, vol. 33, no. 5, pp. 1125–1131, 2012. View at Publisher · View at Google Scholar · View at Scopus
  66. A. Majid, D. Zemke, and M. Kassab, “Pathophysiology of ischemic stroke,” in UpToDate, D. Basow, Ed., UpToDate, Waltham, Mass, USA, 2013. View at Google Scholar
  67. T. Zgavc, D. de Geyter, A.-G. Ceulemans et al., “Mild hypothermia reduces activated caspase-3 up to 1 week after a focal cerebral ischemia induced by endothelin-1 in rats,” Brain Research, vol. 1501, pp. 81–88, 2013. View at Publisher · View at Google Scholar
  68. T. Kinouchi, K. T. Kitazato, K. Shimada et al., “Activation of signal transducer and activator of transcription-3 by a peroxisome proliferator-activated receptor gamma agonist contributes to neuroprotection in the peri-infarct region after ischemia in oophorectomized rats,” Stroke, vol. 43, no. 2, pp. 478–483, 2012. View at Publisher · View at Google Scholar · View at Scopus
  69. W.-Y. Lin, Y.-C. Chang, C.-J. Ho, and C.-C. Huang, “Ischemic preconditioning reduces neurovascular damage after hypoxia-ischemia via the cellular inhibitor of apoptosis 1 in neonatal brain,” Stroke, vol. 44, no. 1, pp. 162–169, 2013. View at Publisher · View at Google Scholar
  70. P. Fu, C. Peng, J. Y. Ding et al., “Acute administration of ethanol reduces apoptosis following ischemic stroke in rats,” Neuroscience Research, vol. 76, no. 1-2, pp. 93–97, 2013. View at Publisher · View at Google Scholar
  71. Q. Zhao, C. Zhang, X. Wang, L. Chen, H. Ji, and Y. Zhang, “(S)-ZJM-289, a nitric oxide-releasing derivative of 3-n-butylphthalide, protects against ischemic neuronal injury by attenuating mitochondrial dysfunction and associated cell death,” Neurochemistry International, vol. 60, no. 2, pp. 134–144, 2012. View at Publisher · View at Google Scholar · View at Scopus
  72. Z. Xie, B. Lei, Q. Huang et al., “Neuroprotective effect of Cyclosporin A on the development of early brain injury in a subarachnoid hemorrhage model: a pilot study,” Brain Research, vol. 1472, pp. 113–123, 2012. View at Publisher · View at Google Scholar
  73. G. Hu, Z. Wu, F. Yang et al., “Ginsenoside Rdblocks AIF mitochondrio-nuclear translocation and NF-κB nuclear accumulation by inhibiting poly(ADP-ribose) polymerase-1 after focal cerebral ischemia in rats,” Neurological Sciences, vol. 34, no. 12, pp. 2101–2106, 2013. View at Publisher · View at Google Scholar
  74. G. Wei, D.-F. Chen, X.-P. Lai et al., “Muscone exerts neuroprotection in an experimental model of stroke via inhibition of the fas pathway,” Natural Product Communications, vol. 7, no. 8, pp. 1069–1074, 2012. View at Google Scholar
  75. Y. Jiang, D.-W. Liu, X.-Y. Han et al., “Neuroprotective effects of anti-tumor necrosis factor-alpha antibody on apoptosis following subarachnoid hemorrhage in a rat model,” Journal of Clinical Neuroscience, vol. 19, no. 6, pp. 866–872, 2012. View at Publisher · View at Google Scholar · View at Scopus
  76. B. Gabryel, A. Kost, and D. Kasprowska, “Neuronal autophagy in cerebral ischemia—a potential target for neuroprotective strategies?” Pharmacological Reports, vol. 64, no. 1, pp. 1–15, 2012. View at Google Scholar
  77. D. Zemke, S. Azhar, and A. Majid, “The mTOR pathway as a potential target for the development of therapies against neurological disease,” Drug News and Perspectives, vol. 20, no. 8, pp. 495–499, 2007. View at Publisher · View at Google Scholar · View at Scopus
  78. C.-H. Jing, L. Wang, P.-P. Liu, C. Wu, D. Ruan, and G. Chen, “Autophagy activation is associated with neuroprotection against apoptosis via a mitochondrial pathway in a rat model of subarachnoid hemorrhage,” Neuroscience, vol. 213, pp. 144–153, 2012. View at Publisher · View at Google Scholar
  79. M. Papadakis, G. Hadley, M. Xilouri et al., “Tsc1 (hamartin) confers neuroprotection against ischemia by inducing autophagy,” Nature Medicine, vol. 19, no. 3, pp. 351–357, 2013. View at Publisher · View at Google Scholar
  80. L. Gao, T. Jiang, J. Guo et al., “Inhibition of autophagy contributes to ischemic postconditioning-induced neuroprotection against focal cerebral ischemia in rats,” PLoS ONE, vol. 7, no. 9, 2012. View at Publisher · View at Google Scholar
  81. D. Zemke, J. L. Smith, M. J. Reeves, and A. Majid, “Ischemia and ischemic tolerance in the brain: an overview,” NeuroToxicology, vol. 25, no. 6, pp. 895–904, 2004. View at Publisher · View at Google Scholar · View at Scopus
  82. J. Lehotský, J. Burda, V. Danielisová, M. Gottlieb, P. Kaplán, and B. Saniová, “Ischemic tolerance: the mechanisms of neuroprotective strategy,” Anatomical Record, vol. 292, no. 12, pp. 2002–2012, 2009. View at Publisher · View at Google Scholar
  83. U. Dirnagl, R. P. Simon, and J. M. Hallenbeck, “Ischemic tolerance and endogenous neuroprotection,” Trends in Neurosciences, vol. 26, no. 5, pp. 248–254, 2003. View at Publisher · View at Google Scholar · View at Scopus
  84. T. Kirino, “Ischemic tolerance,” Journal of Cerebral Blood Flow and Metabolism, vol. 22, no. 11, pp. 1283–1296, 2002. View at Google Scholar · View at Scopus
  85. T. P. Obrenovitch, “Molecular physiology of preconditioning-induced brain tolerance to ischemia,” Physiological Reviews, vol. 88, no. 1, pp. 211–247, 2008. View at Publisher · View at Google Scholar · View at Scopus
  86. J. M. Gidday, “Cerebral preconditioning and ischaemic tolerance,” Nature Reviews Neuroscience, vol. 7, no. 6, pp. 437–448, 2006. View at Publisher · View at Google Scholar · View at Scopus
  87. C. Sommer, “Ischemic preconditioning: postischemic structural changes in the brain,” Journal of Neuropathology and Experimental Neurology, vol. 67, no. 2, pp. 85–92, 2008. View at Publisher · View at Google Scholar · View at Scopus
  88. V. R. Venna, J. Li, S. E. Benashski, S. Tarabishy, and L. D. McCullough, “Preconditioning induces sustained neuroprotection by downregulation of adenosine 5′-monophosphate-activated protein kinase,” Neuroscience, vol. 201, pp. 280–287, 2012. View at Publisher · View at Google Scholar · View at Scopus
  89. N. Bedirli, E. U. Bagriacik, H. Emmez, G. Yilmaz, Y. Unal, and Z. Ozkose, “Sevoflurane and isoflurane preconditioning provides neuroprotection by inhibition of apoptosis-related mRNA expression in a rat model of focal cerebral ischemia,” Journal of Neurosurgical Anesthesiology, vol. 24, no. 4, pp. 336–344, 2012. View at Publisher · View at Google Scholar
  90. O.-N. Bae, K. Rajanikant, J. Min et al., “Lymphocyte cell kinase activation mediates neuroprotection during ischemic preconditioning,” The Journal of Neuroscience, vol. 32, no. 21, pp. 7278–7286, 2012. View at Publisher · View at Google Scholar
  91. G. Pignataro, O. Cuomo, A. Vinciguerra et al., “NCX as a key player in the neuroprotection exerted by ischemic preconditioning and postconditioning,” in Sodium Calcium Exchange: A Growing Spectrum of Pathophysiological Implications, L. Annunziato, Ed., vol. 961 of Advances in Experimental Medicine and Biology, pp. 223–240, 2013. View at Publisher · View at Google Scholar
  92. G. Pignataro, F. Boscia, E. Esposito et al., “NCX1 and NCX3: two new effectors of delayed preconditioning in brain ischemia,” Neurobiology of Disease, vol. 45, no. 1, pp. 616–623, 2012. View at Publisher · View at Google Scholar · View at Scopus
  93. X.-R. Liu, M. Luo, F. Yan et al., “Ischemic postconditioning diminishes matrix metalloproteinase 9 expression and attenuates loss of the extracellular matrix proteins in rats following middle cerebral artery occlusion and reperfusion,” CNS Neuroscience & Therapeutics, vol. 18, no. 10, pp. 855–863, 2012. View at Publisher · View at Google Scholar
  94. M. N. Hoda, S. Siddiqui, S. Herberg et al., “Remote ischemic perconditioning is effective alone and in combination with intravenous tissue-type plasminogen activator in murine model of embolic stroke,” Stroke, vol. 43, no. 10, pp. 2794–2799, 2012. View at Publisher · View at Google Scholar
  95. B. Peng, Q.-L. Guo, Z.-J. He et al., “Remote ischemic postconditioning protects the brain from global cerebral ischemia/reperfusion injury by up-regulating endothelial nitric oxide synthase through the PI3K/Akt pathway,” Brain Research, vol. 1445, pp. 92–102, 2012. View at Publisher · View at Google Scholar · View at Scopus
  96. N. R. Gonzalez, R. Hamilton, A. Bilgin-Freiert et al., “Cerebral hemodynamic and metabolic effects of remote ischemic preconditioning in patients with subarachnoid hemorrhage,” Acta Neurochirurgica, vol. 115, pp. 193–198, 2013. View at Publisher · View at Google Scholar
  97. K. J. Kwon, J. N. Kim, M. K. Kim et al., “Neuroprotective effects of valproic acid against hemin toxicity: possible involvement of the down-regulation of heme oxygenase-1 by regulating ubiquitin-proteasomal pathway,” Neurochemistry International, vol. 62, no. 3, pp. 240–250, 2013. View at Publisher · View at Google Scholar
  98. H.-J. Chun, D. W. Kim, H.-J. Yi et al., “Effects of statin and deferoxamine administration on neurological outcomes in a rat model of intracerebral hemorrhage,” Neurological Sciences, vol. 33, no. 2, pp. 289–296, 2012. View at Publisher · View at Google Scholar
  99. Y. Hong, S. Guo, S. Chen, C. Sun, J. Zhang, and X. Sun, “Beneficial effect of hydrogen-rich saline on cerebral vasospasm after experimental subarachnoid hemorrhage in rats,” Journal of Neuroscience Research, vol. 90, no. 8, pp. 1670–1680, 2012. View at Publisher · View at Google Scholar
  100. S. Gatti, C. Lonati, F. Acerbi et al., “Protective action of NDP-MSH in experimental subarachnoid hemorrhage,” Experimental Neurology, vol. 234, no. 1, pp. 230–238, 2012. View at Publisher · View at Google Scholar · View at Scopus
  101. F. Atif, S. Yousuf, I. Sayeed, T. Ishrat, F. Hua, and D. G. Stein, “Combination treatment with progesterone and vitamin D hormone is more effective than monotherapy in ischemic stroke: the role of BDNF/TrkB/Erk1/2 signaling in neuroprotection,” Neuropharmacology, vol. 67, pp. 78–87, 2013. View at Publisher · View at Google Scholar
  102. Y. Du, X. Zhang, H. Ji, H. Liu, S. Li, and L. Li, “Probucol and atorvastatin in combination protect rat brains in MCAO model: upregulating Peroxiredoxin2, Foxo3a and Nrf2 expression,” Neuroscience Letters, vol. 509, no. 2, pp. 110–115, 2012. View at Publisher · View at Google Scholar · View at Scopus
  103. X. Guo, X. Bu, J. Jiang, P. Cheng, and Z. Yan, “Enhanced neuroprotective effects of co-administration of G-CSF with simvastatin on intracerebral hemorrhage in rats,” Turkish Neurosurgery, vol. 22, no. 6, pp. 732–739, 2012. View at Publisher · View at Google Scholar
  104. B. Kallmünzer, S. Schwab, and R. Kollmar, “Mild hypothermia of 34°C reduces side effects of rt-PA treatment after thromboembolic stroke in rats,” Experimental & Translational Stroke Medicine, vol. 4, no. 1, article 3, 2012. View at Publisher · View at Google Scholar · View at Scopus
  105. Y. Wang, Z. Zhang, N. Chow et al., “An activated protein C analog with reduced anticoagulant activity extends the therapeutic window of tissue plasminogen activator for ischemic stroke in rodents,” Stroke, vol. 43, no. 9, pp. 2444–2449, 2012. View at Publisher · View at Google Scholar
  106. F. Campos, T. Qin, J. Castillo et al., “Fingolimod reduces hemorrhagic transformation associated with delayed tissue plasminogen activator treatment in a mouse thromboembolic model,” Stroke, vol. 44, no. 2, pp. 505–511, 2013. View at Publisher · View at Google Scholar
  107. D. Zemke and A. Majid, “The potential of minocycline for neuroprotection in human neurologic disease,” Clinical Neuropharmacology, vol. 27, no. 6, pp. 293–298, 2004. View at Publisher · View at Google Scholar · View at Scopus
  108. M. V. P. Srivastava, A. Bhasin, R. Bhatia et al., “Efficacy of minocycline in acute ischemic stroke: a single-blinded, placebo-controlled trial,” Neurology India, vol. 60, no. 1, pp. 23–28, 2012. View at Publisher · View at Google Scholar · View at Scopus
  109. X. Fan, E. H. Lo, and X. Wang, “Effects of minocycline plus tissue plasminogen activator combination therapy after focal embolic stroke in type 1 diabetic rats,” Stroke, vol. 44, no. 3, pp. 745–752, 2013. View at Publisher · View at Google Scholar
  110. X. Jin, J. Liu, K. J. Liu, G. A. Rosenberg, Y. Yang, and W. Liu, “Normobaric hyperoxia combined with minocycline provides greater neuroprotection than either alone in transient focal cerebral ischemia,” Experimental Neurology, vol. 240, pp. 9–16, 2013. View at Publisher · View at Google Scholar
  111. E. C. S. Franco, M. M. Cardoso, A. Gouvêia, A. Pereira, and W. Gomes-Leal, “Modulation of microglial activation enhances neuroprotection and functional recovery derived from bone marrow mononuclear cell transplantation after cortical ischemia,” Neuroscience Research, vol. 73, no. 2, pp. 122–132, 2012. View at Publisher · View at Google Scholar · View at Scopus
  112. M. M. Cardoso, E. C. S. Franco, C. C. de Souza, M. C. Da Silva, A. Gouveia, and W. Gomes-Leal, “Minocycline treatment and bone marrow mononuclear cell transplantation after endothelin-1 induced striatal ischemia,” Inflammation, vol. 36, no. 1, pp. 197–205, 2013. View at Publisher · View at Google Scholar
  113. H. Sakata, K. Niizuma, H. Yoshioka et al., “Minocycline-preconditioned neural stem cells enhance neuroprotection after ischemic stroke in rats,” Journal of Neuroscience, vol. 32, no. 10, pp. 3462–3473, 2012. View at Publisher · View at Google Scholar · View at Scopus
  114. F. Bellia, G. Vecchio, S. Cuzzocrea, V. Calabrese, and E. Rizzarelli, “Neuroprotective features of carnosine in oxidative driven diseases,” Molecular Aspects of Medicine, vol. 32, no. 4–6, pp. 258–266, 2011. View at Publisher · View at Google Scholar · View at Scopus
  115. A. A. Boldyrev, S. L. Stvolinsky, T. N. Fedorova, and Z. A. Suslina, “Carnosine as a natural antioxidant and geroprotector: from molecular mechanisms to clinical trials,” Rejuvenation Research, vol. 13, no. 2-3, pp. 156–158, 2010. View at Publisher · View at Google Scholar · View at Scopus
  116. O.-N. Bae, K. Serfozo, S.-H. Baek et al., “Safety and efficacy evaluation of carnosine, an endogenous neuroprotective agent for ischemic stroke,” Stroke, vol. 44, no. 1, pp. 205–212, 2013. View at Publisher · View at Google Scholar
  117. Y. Shen, P. He, Y.-Y. Fan et al., “Carnosine protects against permanent cerebral ischemia in histidine decarboxylase knockout mice by reducing glutamate excitotoxicity,” Free Radical Biology & Medicine, vol. 48, no. 5, pp. 727–735, 2010. View at Publisher · View at Google Scholar · View at Scopus
  118. G. K. Rajanikant, D. Zemke, M.-C. Senut et al., “Carnosine is neuroprotective against permanent focal cerebral ischemia in mice,” Stroke, vol. 38, no. 11, pp. 3023–3031, 2007. View at Publisher · View at Google Scholar · View at Scopus
  119. J. Min, M.-C. Senut, K. Rajanikant et al., “Differential neuroprotective effects of carnosine, anserine, and N-acetyl carnosine against permanent focal ischemia,” Journal of Neuroscience Research, vol. 86, no. 13, pp. 2984–2991, 2008. View at Publisher · View at Google Scholar · View at Scopus
  120. R. G. Krishnamurthy, M.-C. Senut, D. Zemke et al., “Asiatic acid, a pentacyclic triterpene from Centella asiatica, is neuroprotective in a mouse model of focal cerebral ischemia,” Journal of Neuroscience Research, vol. 87, no. 11, pp. 2541–2550, 2009. View at Publisher · View at Google Scholar · View at Scopus
  121. K. Y. Lee, O.-N. Bae, K. Serfozo et al., “Asiatic acid attenuates infarct volume, mitochondrial dysfunction, and matrix metalloproteinase-9 induction after focal cerebral ischemia,” Stroke, vol. 43, pp. 1632–1638, 2012. View at Publisher · View at Google Scholar · View at Scopus
  122. M. Xu, Y. Xiong, J. Liu, J. Qian, L. Zhu, and J. Gao, “Asiatic acid, a pentacyclic triterpene in Centella asiatica, attenuates glutamate-induced cognitive deficits in mice and apoptosis in SH-SY5Y cells,” Acta Pharmacologica Sinica, vol. 33, no. 5, pp. 578–587, 2012. View at Publisher · View at Google Scholar
  123. R. Tabassum, K. Vaibhav, P. Shrivastava et al., “Centella asiatica attenuates the neurobehavioral, neurochemical and histological changes in transient focal middle cerebral artery occlusion rats,” Neurological Sciences, vol. 34, no. 6, pp. 925–933, 2013. View at Publisher · View at Google Scholar
  124. R. Kollmar and S. Schwab, “Hypothermia and ischemic stroke,” Current Treatment Options in Neurology, vol. 14, no. 2, pp. 188–196, 2012. View at Publisher · View at Google Scholar · View at Scopus
  125. S. S. Song and P. D. Lyden, “Overview of therapeutic hypothermia,” Current Treatment Options in Neurology, vol. 14, no. 6, pp. 541–548, 2012. View at Publisher · View at Google Scholar
  126. H. A. Choi, N. Badjatia, and S. A. Mayer, “Hypothermia for acute brain injury—mechanisms and practical aspects,” Nature Reviews Neurology, vol. 8, no. 4, pp. 214–222, 2012. View at Publisher · View at Google Scholar · View at Scopus
  127. S. Nagel, M. Papadakis, K. Pfleger, C. Grond-Ginsbach, A. M. Buchan, and S. Wagner, “Microarray analysis of the global gene expression profile following hypothermia and transient focal cerebral ischemia,” Neuroscience, vol. 208, pp. 109–122, 2012. View at Publisher · View at Google Scholar · View at Scopus
  128. K.-E. Choi, C. L. Hall, J.-M. Sun et al., “A novel stroke therapy of pharmacologically induced hypothermia after focal cerebral ischemia in mice,” FASEB Journal, vol. 26, no. 7, pp. 2799–2810, 2012. View at Publisher · View at Google Scholar
  129. S. E. Lakhan and F. Pamplona, “Application of mild therapeutic hypothermia on stroke: a systematic review and meta-analysis,” Stroke Research and Treatment, vol. 2012, Article ID 295906, 12 pages, 2012. View at Publisher · View at Google Scholar · View at Scopus
  130. R. Kollmar, B. Gebhardt, and S. Schwab, “EuroHYP-1 trial: EU-funded therapy study on the effectiveness of mild therapeutic hypothermia for acute ischemic stroke,” Der Nervenarzt, vol. 83, no. 10, pp. 1252–1259, 2012. View at Publisher · View at Google Scholar
  131. S. Lorrio, V. Gómez-Rangel, P. Negredo et al., “Novel multitarget ligand ITH33/IQM9.21 provides neuroprotection in in vitro and in vivo models related to brain ischemia,” Neuropharmacology, vol. 67, pp. 403–411, 2013. View at Publisher · View at Google Scholar
  132. F. Guo, W.-L. Jin, L.-Y. Li et al., “M9, a novel region of Amino-Nogo-A, attenuates cerebral ischemic injury by inhibiting NADPH oxidase-derived superoxide production in mice,” CNS Neuroscience & Therapeutics, vol. 19, no. 5, pp. 319–328, 2013. View at Publisher · View at Google Scholar
  133. S.-W. Kim, Y. Jin, J.-H. Shin et al., “Glycyrrhizic acid affords robust neuroprotection in the postischemic brain via anti-inflammatory effect by inhibiting HMGB1 phosphorylation and secretion,” Neurobiology of Disease, vol. 46, no. 1, pp. 147–156, 2012. View at Publisher · View at Google Scholar · View at Scopus
  134. J. Y. Kim, H. Y. Jeong, H. K. Lee et al., “Neuroprotection of the leaf and stem of Vitis amurensis and their active compounds against ischemic brain damage in rats and excitotoxicity in cultured neurons,” Phytomedicine, vol. 19, no. 2, pp. 150–159, 2012. View at Publisher · View at Google Scholar · View at Scopus
  135. C. Ju, S. Hwang, G.-S. Cho et al., “Differential anti-ischemic efficacy and therapeutic time window of trans- and cis-hinokiresinols: stereo-specific antioxidant and anti-inflammatory activities,” Neuropharmacology, vol. 67, pp. 465–475, 2013. View at Publisher · View at Google Scholar
  136. X. Zhang, X. Zhang, C. Wang et al., “Neuroprotection of early and short-time applying berberine in the acute phase of cerebral ischemia: up-regulated pAkt, pGSK and pCREB, down-regulated NF-κB expression, ameliorated BBB permeability,” Brain Research, vol. 1459, pp. 61–70, 2012. View at Publisher · View at Google Scholar · View at Scopus
  137. M. Khan, T. S. Dhammu, H. Sakakima et al., “The inhibitory effect of S-nitrosoglutathione on blood-brain barrier disruption and peroxynitrite formation in a rat model of experimental stroke,” Journal of Neurochemistry, vol. 123, supplement s2, pp. 86–97, 2012. View at Publisher · View at Google Scholar
  138. P. M. Gharibani, J. Modi, C. Pan et al., “The mechanism of taurine protection against endoplasmic reticulum stress in an animal stroke model of cerebral artery occlusion and stroke-related conditions in primary neuronal cell culture,” Advances in Experimental Medicine and Biology, vol. 776, pp. 241–258, 2013. View at Publisher · View at Google Scholar
  139. C. Cheyuo, A. Jacob, R. Wu et al., “Recombinant human MFG-E8 attenuates cerebral ischemic injury: its role in anti-inflammation and anti-apoptosis,” Neuropharmacology, vol. 62, no. 2, pp. 890–900, 2012. View at Publisher · View at Google Scholar · View at Scopus
  140. Y. Sun, P. Yu, G. Zhang et al., “Therapeutic effects of tetramethylpyrazine nitrone in rat ischemic stroke models,” Journal of Neuroscience Research, vol. 90, no. 8, pp. 1662–1669, 2012. View at Publisher · View at Google Scholar · View at Scopus
  141. A. Nehlig, “The neuroprotective effects of cocoa flavanol and its influence on cognitive performance,” British Journal of Clinical Pharmacology, vol. 75, no. 3, pp. 716–727, 2013. View at Publisher · View at Google Scholar
  142. T.-L. Yen, C.-K. Hsu, W.-J. Lu et al., “Neuroprotective effects of xanthohumol, a prenylated flavonoid from hops (humulus lupulus), in ischemic stroke of rats,” Journal of Agricultural and Food Chemistry, vol. 60, no. 8, pp. 1937–1944, 2012. View at Publisher · View at Google Scholar · View at Scopus
  143. S. S. Raza, M. M. Khan, A. Ahmad et al., “Neuroprotective effect of naringenin is mediated through suppression of NF-κB signaling pathway in experimental stroke,” Neuroscience, vol. 230, pp. 157–171, 2013. View at Publisher · View at Google Scholar
  144. S. Li, C. Wu, L. Zhu et al., “By improving regional cortical blood flow, attenuating mitochondrial dysfunction and sequential apoptosis galangin acts as a potential neuroprotective agent after acute ischemic stroke,” Molecules, vol. 17, no. 11, pp. 13403–13423, 2012. View at Publisher · View at Google Scholar
  145. M. Gelderblom, F. Leypoldt, J. Lewerenz et al., “The flavonoid fisetin attenuates postischemic immune cell infiltration, activation and infarct size after transient cerebral middle artery occlusion in mice,” Journal of Cerebral Blood Flow and Metabolism, vol. 32, no. 5, pp. 835–843, 2012. View at Publisher · View at Google Scholar · View at Scopus
  146. Q.-B. Zhou, Q. Jia, Y. Zhang, L.-Y. Li, Z.-F. Chi, and P. Liu, “Effects of baicalin on protease-activated receptor-1 expression and brain injury in a rat model of intracerebral hemorrhage,” The Chinese Journal of Physiology, vol. 55, no. 3, pp. 202–209, 2012. View at Publisher · View at Google Scholar
  147. L. S. A. Capettini, S. Q. Savergnini, R. F. Da Silva et al., “Update on the role of cannabinoid receptors after ischemic stroke,” Mediators of Inflammation, vol. 2012, Article ID 824093, 8 pages, 2012. View at Publisher · View at Google Scholar
  148. P. Pacher and K. Mackie, “Interplay of cannabinoid 2 (CB2) receptors with nitric oxide synthases, oxidative and nitrative stress, and cell death during remote neurodegeneration,” Journal of Molecular Medicine, vol. 90, no. 4, pp. 347–351, 2012. View at Publisher · View at Google Scholar · View at Scopus
  149. J. G. Zarruk, D. Fernández-López, I. García-Yébenes et al., “Cannabinoid type 2 receptor activation downregulates stroke-induced classic and alternative brain macrophage/microglial activation concomitant to neuroprotection,” Stroke, vol. 43, no. 1, pp. 211–219, 2012. View at Publisher · View at Google Scholar · View at Scopus
  150. J. Sun, Y. Fang, H. Ren et al., “WIN55, 212-2 protects oligodendrocyte precursor cells in stroke penumbra following permanent focal cerebral ischemia in rats,” Acta Pharmacologica Sinica, vol. 34, no. 1, pp. 119–128, 2013. View at Publisher · View at Google Scholar
  151. D. Fernández-López, J. Faustino, N. Derugin et al., “Reduced infarct size and accumulation of microglia in rats treated with WIN 55,212-2 after neonatal stroke,” Neuroscience, vol. 207, pp. 307–315, 2012. View at Publisher · View at Google Scholar · View at Scopus
  152. N. Suzuki, M. Suzuki, K. Hamajo, K. Murakami, T. Tsukamoto, and M. Shimojo, “Contribution of hypothermia and CB1 receptor activation to protective effects of TAK-937, a cannabinoid receptor agonist, in rat transient MCAO model,” PLoS ONE, vol. 7, no. 7, Article ID e40889, 2012. View at Publisher · View at Google Scholar
  153. N. Suzuki, M. Suzuki, K. Murakami, K. Hamajo, T. Tsukamoto, and M. Shimojo, “Cerebroprotective effects of TAK-937, a cannabinoid receptor agonist, on ischemic brain damage in middle cerebral artery occluded rats and non-human primates,” Brain Research, vol. 1430, pp. 93–100, 2012. View at Publisher · View at Google Scholar · View at Scopus
  154. S.-Y. Xu and S.-Y. Pan, “The failure of animal models of neuroprotection in acute ischemic stroke to translate to clinical efficacy,” Medical Science Monitor Basic Research, vol. 19, pp. 37–45, 2013. View at Publisher · View at Google Scholar
  155. B. A. Sutherland, J. Minnerup, J. S. Balami, F. Arba, A. M. Buchan, and C. Kleinschnitz, “Neuroprotection for ischaemic stroke translation from the bench to the bedside,” International Journal of Stroke, vol. 7, no. 5, pp. 407–418, 2012. View at Publisher · View at Google Scholar
  156. A. Dávalos, J. Alvarez-Sabín, J. Castillo et al., “Citicoline in the treatment of acute ischaemic stroke: an international, randomised, multicentre, placebo-controlled study (ICTUS trial),” The Lancet, vol. 380, no. 9839, pp. 349–357, 2012. View at Publisher · View at Google Scholar
  157. W.-D. Heiss, M. Brainin, N. M. Bornstein, J. Tuomilehto, and Z. Hong, “Cerebrolysin in patients with acute ischemic stroke in Asia: results of a double-blind, placebo-controlled randomized trial,” Stroke, vol. 43, no. 3, pp. 630–636, 2012. View at Publisher · View at Google Scholar · View at Scopus
  158. X. Liu, L. Wang, A. Wen et al., “Ginsenoside-Rd improves outcome of acute ischaemic stroke—a randomized, double-blind, placebo-controlled, multicenter trial,” European Journal of Neurology, vol. 19, no. 6, pp. 855–863, 2012. View at Publisher · View at Google Scholar · View at Scopus
  159. T. J. England, M. Abaei, D. P. Auer et al., “Granulocyte-colony stimulating factor for mobilizing bone marrow stem cells in subacute stroke: the stem cell trial of recovery enhancement after stroke 2 randomized controlled trial,” Stroke, vol. 43, no. 2, pp. 405–411, 2012. View at Publisher · View at Google Scholar · View at Scopus
  160. M. D. Hill, R. H. Martin, D. Mikulis et al., “Safety and efficacy of NA-1 in patients with iatrogenic stroke after endovascular aneurysm repair (ENACT): a phase 2, randomised, double-blind, placebo-controlled trial,” The Lancet Neurology, vol. 11, no. 11, pp. 942–950, 2012. View at Publisher · View at Google Scholar
  161. S. M. D. Mees, A. Algra, W. P. Vandertop et al., “Magnesium for aneurysmal subarachnoid haemorrhage (MASH-2): a randomised placebo-controlled trial,” The Lancet, vol. 380, no. 9836, pp. 44–49, 2012. View at Publisher · View at Google Scholar
  162. J. I. Suarez, R. H. Martin, E. Calvillo et al., “The albumin in subarachnoid hemorrhage (ALISAH) multicenter pilot clinical trial: safety and neurologic outcomes,” Stroke, vol. 43, no. 3, pp. 683–690, 2012. View at Publisher · View at Google Scholar · View at Scopus
  163. M. Fisher, “Recommendations for standards regarding preclinical neuroprotective and restorative drug development,” Stroke, vol. 30, no. 12, pp. 2752–2758, 1999. View at Google Scholar · View at Scopus
  164. G. W. Albers, J. Bogousslavsky, M. A. Bozik et al., “Recommendations for clinical trial evaluation of acute stroke therapies,” Stroke, vol. 32, no. 7, pp. 1598–1606, 2001. View at Google Scholar · View at Scopus
  165. U. Dirnagl and M. Fisher, “International, multicenter randomized preclinical trials in translational stroke research: it's time to act,” Journal of Cerebral Blood Flow and Metabolism, vol. 32, no. 6, pp. 933–935, 2012. View at Publisher · View at Google Scholar · View at Scopus
  166. U. Dirnagl, A. Hakim, M. Macleod et al., “A concerted appeal for international cooperation in preclinical stroke research,” Stroke, vol. 44, no. 6, pp. 1754–1760, 2013. View at Publisher · View at Google Scholar