Neurochemical Research

, Volume 34, Issue 4, pp 707–710 | Cite as

Therapeutic Strategy for Ischemic Stroke

  • Toru Yamashita
  • Kentaro Deguchi
  • Yoshihide Sehara
  • Violeta Lukic-Panin
  • Hanzhe Zhang
  • Tatsushi Kamiya
  • Koji Abe
Original Paper


Possible strategies for treating ischemic stroke include: (1) Neuroprotection: preventing damaged neurons from undergoing apoptosis in the acute phase of cerebral ischemia; (2) Stem cell therapy: the repair of broken neuronal networks with newly born neurons in the chronic phase of cerebral ischemia. Firstly, we studied the neuroprotective effect of a calcium channel blocker, azelnidipine, or a by-product of heme degradation, biliverdin, in the ischemic brain. These results revealed both azelnidipine and biliverdin had a neuroprotective effect in the ischemic brain through their anti-oxidative property. Secondly, we investigated the role of granulocyte colony-stimulating factor (G-CSF) by administering G-CSF to rats after cerebral ischemia and found G-CSF plays a critical role in neuroprotection. Lastly, we developed a restorative stroke therapy with a bio-affinitive scaffold, which is able to provide an appropriate environment for newly born neurons. In the future, we will combine these strategies to develop more effective therapies for treatment of strokes.


Cerebral ischemia Free radical G-CSF Neural stem cells Scaffold 


  1. 1.
    Abe K (2000) Therapeutic potential of neurotrophic factors and neural stem cells against ischemic brain injury. J Cereb Blood Flow Metab 20:1393–1408. doi: 10.1097/00004647-200010000-00001 PubMedCrossRefGoogle Scholar
  2. 2.
    Chan PH (2001) Reactive oxygen radicals in signaling and damage in the ischemic brain. J Cereb Blood Flow Metab 21:2–14. doi: 10.1097/00004647-200101000-00002 PubMedCrossRefGoogle Scholar
  3. 3.
    Sharma SS, Kaundal RK (2007) Neuroprotective effects of 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (Trolox), an antioxidant in middle cerebral artery occlusion induced focal cerebral ischemia in rats. Neurol Res 29:304–309. doi: 10.1179/016164107X158983 PubMedCrossRefGoogle Scholar
  4. 4.
    Hsiao G, Lee JJ, Chen YC et al (2007) Neuroprotective effects of PMC, a potent alpha-tocopherol derivative, in brain ischemia-reperfusion: reduced neutrophil activation and anti-oxidant actions. Biochem Pharmacol 73:682–693. doi: 10.1016/j.bcp.2006.11.009 PubMedCrossRefGoogle Scholar
  5. 5.
    Kuroda S, Tsuchidate R, Smith ML et al (1999) Neuroprotective effects of a novel nitrone, NXY-059, after transient focal cerebral ischemia in the rat. J Cereb Blood Flow Metab 19:778–787. doi: 10.1097/00004647-199907000-00008 PubMedCrossRefGoogle Scholar
  6. 6.
    Abe K, Yuki S, Kogure K (1988) Strong attenuation of ischemic and postischemic brain edema in rats by a novel free radical scavenger. Stroke 19:480–485PubMedGoogle Scholar
  7. 7.
    Lees KR, Zivin JA, Ashwood T et al (2006) NXY-059 for acute ischemic stroke. N Engl J Med 354:588–600. doi: 10.1056/NEJMoa052980 PubMedCrossRefGoogle Scholar
  8. 8.
    Shuaib A, Lees KR, Lyden P et al (2007) NXY-059 for the treatment of acute ischemic stroke. N Engl J Med 357:562–571. doi: 10.1056/NEJMoa070240 PubMedCrossRefGoogle Scholar
  9. 9.
    The Edaravone Acute Brain Infarction Study Group (2003) Effect of a novel free radical scavenger, edaravone (MCI-186), on acute brain infarction. Randomized, placebo-controlled, double-blind study at multicenters. Cerebrovasc Dis 15:222–229. doi: 10.1159/000069318 CrossRefGoogle Scholar
  10. 10.
    Yao K, Ina Y, Nagashima K et al (2000) Antioxidant effects of calcium antagonists in rat brain homogenates. Biol Pharm Bull 23:766–769PubMedGoogle Scholar
  11. 11.
    Lukic-Panin V, Kamiya T, Zhang H et al (2007) Prevention of neuronal damage by calcium channel blockers with antioxidative effects after transient focal ischemia in rats. Brain Res 1176:143–150. doi: 10.1016/j.brainres.2007.07.038 PubMedCrossRefGoogle Scholar
  12. 12.
    Stocker R (2004) Antioxidant activities of bile pigments. Antioxid Redox Signal 6:841–849PubMedGoogle Scholar
  13. 13.
    Deguchi K, Hayashi T, Nagotani S et al (2008) Reduction of cerebral infarction in rats by biliverdin associated with amelioration of oxidative stress. Brain Res 1188:1–8. doi: 10.1016/j.brainres.2007.07.104 PubMedCrossRefGoogle Scholar
  14. 14.
    Iadecola C, Alexander M (2001) Cerebral ischemia and inflammation. Curr Opin Neurol 14:89–94. doi: 10.1097/00019052-200102000-00014 PubMedCrossRefGoogle Scholar
  15. 15.
    Loddick SA, Rothwell NJ (1996) Neuroprotective effects of human recombinant interleukin-1 receptor antagonist in focal cerebral ischaemia in the rat. J Cereb Blood Flow Metab 16:932–940. doi: 10.1097/00004647-199609000-00017 PubMedCrossRefGoogle Scholar
  16. 16.
    Yang GY, Schielke GP, Gong C et al (1999) Expression of tumor necrosis factor-alpha and intercellular adhesion molecule-1 after focal cerebral ischemia in interleukin-1beta converting enzyme deficient mice. J Cereb Blood Flow Metab 19:1109–1117. doi: 10.1097/00004647-199910000-00007 PubMedCrossRefGoogle Scholar
  17. 17.
    Yamashita T, Sawamoto K, Suzuki S et al (2005) Blockade of interleukin-6 signaling aggravates ischemic cerebral damage in mice: possible involvement of Stat3 activation in the protection of neurons. J Neurochem 94:459–468. doi: 10.1111/j.1471-4159.2005.03227.x PubMedCrossRefGoogle Scholar
  18. 18.
    Sehara Y, Hayashi T, Deguchi K et al (2007) Decreased focal inflammatory response by G-CSF may improve stroke outcome after transient middle cerebral artery occlusion in rats. J Neurosci Res 85:2167–2174. doi: 10.1002/jnr.21341 PubMedCrossRefGoogle Scholar
  19. 19.
    Schneider A, Kuhn HG, Schabitz WR (2005) A role for G-CSF (granulocyte-colony stimulating factor) in the central nervous system. Cell Cycle 4:1753–1757PubMedGoogle Scholar
  20. 20.
    Nakatomi H, Kuriu T, Okabe S et al (2002) Regeneration of hippocampal pyramidal neurons after ischemic brain injury by recruitment of endogenous neural progenitors. Cell 110:429–441. doi: 10.1016/S0092-8674(02)00862-0 PubMedCrossRefGoogle Scholar
  21. 21.
    Teramoto T, Qiu J, Plumier JC et al (2003) EGF amplifies the replacement of parvalbumin-expressing striatal interneurons after ischemia. J Clin Invest 111:1125–1132PubMedGoogle Scholar
  22. 22.
    Yamashita T, Ninomiya M, Hernandez Acosta P et al (2006) Subventricular zone-derived neuroblasts migrate and differentiate into mature neurons in the post-stroke adult striatum. J Neurosci 26:6627–6636. doi: 10.1523/JNEUROSCI.0149-06.2006 PubMedCrossRefGoogle Scholar
  23. 23.
    Hayashi J, Takagi Y, Fukuda H et al (2006) Primate embryonic stem cell-derived neuronal progenitors transplanted into ischemic brain. J Cereb Blood Flow Metab 26(7):906–914PubMedCrossRefGoogle Scholar
  24. 24.
    Hou S, Xu Q, Tian W et al (2005) The repair of brain lesion by implantation of hyaluronic acid hydrogels modified with laminin. J Neurosci Methods 148:60–70. doi: 10.1016/j.jneumeth.2005.04.016 PubMedCrossRefGoogle Scholar
  25. 25.
    Kataoka K, Suzuki Y, Kitada M et al (2001) Alginate, a bioresorbable material derived from brown seaweed, enhances elongation of amputated axons of spinal cord in infant rats. J Biomed Mater Res 54:373–384. doi :10.1002/1097-4636(20010305)54:3<373::AID-JBM90>3.0.CO;2-QGoogle Scholar
  26. 26.
    Tian WM, Hou SP, Ma J et al (2005) Hyaluronic acid-poly-d-lysine-based three-dimensional hydrogel for traumatic brain injury. Tissue Eng 11:513–525. doi: 10.1089/ten.2005.11.513 PubMedCrossRefGoogle Scholar
  27. 27.
    Ren L, Tsuru K, Hayakawa S et al (2002) Novel approach to fabricate porous gelatin-siloxane hybrids for bone tissue engineering. Biomaterials 23:4765–4773. doi: 10.1016/S0142-9612(02)00226-0 PubMedCrossRefGoogle Scholar
  28. 28.
    Deguchi K, Tsuru K, Hayashi T et al (2006) Implantation of a new porous gelatin-siloxane hybrid into a brain lesion as a potential scaffold for tissue regeneration. J Cereb Blood Flow Metab 26(10):1263–1273PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Toru Yamashita
    • 1
  • Kentaro Deguchi
    • 1
  • Yoshihide Sehara
    • 1
  • Violeta Lukic-Panin
    • 1
  • Hanzhe Zhang
    • 1
  • Tatsushi Kamiya
    • 1
  • Koji Abe
    • 1
  1. 1.Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical SciencesOkayama UniversityOkayamaJapan

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